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a3c0b71a33c28036f6d512412e530d5608220e20	pubmed	Testing for HCV Infection: An Update of Guidance for Clinicians and Laboratorians	Testing for HCV Infection: An Update of Guidance for Clinicians and Laboratorians ## Testing for hcv infection: an update of guidance for clinicians and laboratorians In the United States, an estimated 4.1 million persons have been infected with hepatitis C virus (HCV), of whom an estimated 3.2 (95% confidence interval [CI] = 2.7-3.9) million are living with the infection. New infections continue to be reported particularly among persons who inject drugs and persons exposed to HCV-contaminated blood in health-care settings with inadequate infection control. Since 1998, CDC has recommended HCV testing for persons with risks for HCV infection. In 2003, CDC published guidelines for the laboratory testing and result reporting of antibody to HCV. In 2012, CDC amended testing recommendations to include one-time HCV testing for all persons born during 1945-1965 regardless of other risk factors. CDC is issuing this update in guidance because of 1) changes in the availability of certain commercial HCV antibody tests, 2) evidence that many persons who are identified as reactive by an HCV antibody test might not subsequently be evaluated to determine if they have current HCV infection, and 3) significant advances in the development of antiviral agents with improved efficacy against HCV. Although previous guidance has focused on strategies to detect and confirm HCV antibody, reactive results from HCV antibody testing cannot distinguish between persons whose past HCV infection has resolved and those who are currently HCV infected. Persons with current infection who are not identified as currently infected will not receive appropriate preventive services, clinical evaluation, and medical treatment. Testing strategies must ensure the identification of those persons with current HCV infection. This guidance was written by a workgroup convened by CDC and the Association of Public Health Laboratories (APHL), comprising experts from CDC, APHL, state and local public health departments, and academic and independent diagnostic testing laboratories, in consultation with experts from the Veterans Health Administration and the Food and Drug Administration (FDA). The workgroup reviewed laboratory capacities and practices relating to HCV testing, data presented at the CDC 2011 symposium on identification, screening and surveillance of HCV infection, and data from published scientific literature on HCV testing. Unpublished data from the American Red Cross on validation of HCV antibody testing also were reviewed. ## Changes in hcv testing technologies Since the 2003 guidance was published (4), there have been two developments with important implications for HCV testing: 1. Availability of a rapid test for HCV antibody. The OraQuick HCV Rapid Antibody Test (OraSure Technologies) is a rapid assay for the presumptive detection of HCV antibody in fingerstick capillary blood and venipuncture whole blood. Its sensitivity and specificity are similar to those of FDA-approved, laboratory-conducted HCV antibody assays. In 2011, a Clinical Laboratory Improvements Amendments waiver was granted to the test by FDA. The waiver provides wider testing access to persons at risk for HCV infection, permitting use of the assay in nontraditional settings such as physician offices, hospital emergency departments, health department clinics, and other freestanding counseling and testing sites. 2. Discontinuation of RIBA HCV. The Chiron RIBA HCV 3.0 Strip Immunoblot Assay (Novartis Vaccines and Diagnostics) that was recommended (4) for supplemental testing of blood samples after initial HCV antibody testing is no longer available. As a result, the only other FDA-approved supplemental tests for HCV infection are those that detect HCV viremia. ## Identifying current hcv infections In 2011, FDA approved boceprevir (Victrelis, Merck & Co.) and telaprevir (Incivek, Vertex Pharmaceuticals) for treatment of chronic hepatitis C genotype 1 infection, in combination with pegylated interferon and ribavirin, in adult patients with compensated liver disease. Boceprevir and telaprevir interfere directly with HCV replication. Persons who complete treatment using either of these drugs combined with pegylated interferon and ribavirin are more likely to clear virus (i.e., have virologic cure), compared to those given standard therapy based on pegylated interferon and ribavirin. Viral clearance, when sustained, stops further spread of HCV and is associated with reduced risk for hepatocellular carcinoma (10) and all-cause mortality. Other compounds under study in clinical trials hold promise for even more effective therapies. Because antiviral treatment is intended for persons with current HCV infection, these persons need to be distinguished from persons whose infection has resolved. HCV RNA in blood, by nucleic acid testing (NAT), is a marker for HCV viremia and is detected only in persons who are currently infected. Persons with reactive results after HCV antibody testing should be evaluated for the presence of HCV RNA in their blood. On , this report was posted as an MMWR Early Release on the MMWR website (http://www.cdc.gov/mmwr). ## Benefits of testing for current hcv infection Accurate testing to identify current infection is important to 1) help clinicians and other providers correctly identify persons infected with HCV, so that preventive services, care and treatment can be offered; 2) notify tested persons of their infection status, enabling them to make informed decisions about medical care and options for HCV treatment, take measures to limit HCV-associated disease progression (e.g., avoidance or reduction of alcohol intake, and vaccination against hepatitis A and B), and minimize risk for transmitting HCV to others; and 3) inform persons who are not currently infected of their status and the fact that they are not infectious. ## Recommended testing sequence The testing sequence in this guidance is intended for use by primary care and public health providers seeking to implement CDC recommendations for HCV testing. In most cases, persons identified with HCV viremia have chronic HCV infection. This testing sequence is not intended for diagnosis of acute hepatitis C or clinical evaluation of persons receiving specialist medical care, for which specific guidance is available. Testing for HCV infection begins with either a rapid or a laboratory-conducted assay for HCV antibody in blood . A nonreactive HCV antibody result indicates no HCV antibody detected. A reactive result indicates one of the following: 1) current HCV infection, 2) past HCV infection that has resolved, or 3) false positivity. A reactive result should be followed by NAT for HCV RNA. If HCV RNA is detected, that indicates current HCV infection. If HCV RNA is not detected, that indicates either past, resolved HCV infection, or false HCV antibody positivity. Initial Testing for HCV Antibody. An FDA-approved test for HCV antibody should be used. If the OraQuick HCV Rapid Antibody Test is used, the outcome is reported as reactive or nonreactive. If a laboratorybased assay is used, the outcome is reported as reactive or nonreactive without necessarily specifying signal-to-cutoff ratios. Testing for HCV RNA. An FDA-approved NAT assay intended for detection of HCV RNA in serum or plasma from blood of at-risk patients who test reactive for HCV antibody should be used. There are several possible operational steps toward NAT after initial testing for HCV antibody: 1. Blood from a subsequent venipuncture is submitted for HCV NAT if the blood sample collected is reactive for HCV antibody during initial testing. 2. From a single venipuncture, two specimens are collected in separate tubes: one tube for initial HCV antibody testing; and a second tube for HCV NAT if the HCV antibody test is reactive. ## Figure. recommended testing sequence for identifying current hepatitis c virus (hcv) infection * For persons who might have been exposed to HCV within the past 6 months, testing for HCV RNA or follow-up testing for HCV antibody is recommended. For persons who are immunocompromised, testing for HCV RNA can be considered. † To differentiate past, resolved HCV infection from biologic false positivity for HCV antibody, testing with another HCV antibody assay can be considered. Repeat HCV RNA testing if the person tested is suspected to have had HCV exposure within the past 6 months or has clinical evidence of HCV disease, or if there is concern regarding the handling or storage of the test specimen. 3. The same sample of venipuncture blood used for initial HCV antibody testing, if reactive, is reflexed to HCV NAT without another blood draw for NAT (13). ## A separate venipuncture blood sample is submitted for hcv NAT if the OraQuick HCV Rapid Antibody Test for initial testing of HCV antibody has used fingerstick blood. ## Supplemental testing for hcv antibody If testing is desired to distinguish between true positivity and biologic false positivity for HCV antibody, then, testing may be done with a second HCV antibody assay approved by FDA for diagnosis of HCV infection that is different from the assay used for initial antibody testing. HCV antibody assays vary according to their antigens, test platforms, and performance characteristics, so biologic false positivity is unlikely to be exhibited by more than one test when multiple tests are used on a single specimen. ## Test interpretation and further action SeeLaboratory Reporting "Acute hepatitis C" and "hepatitis C (past or present)" are nationally notifiable conditions, and are subject to mandated reporting to health departments by clinicians and laboratorians, as determined by local, state or territorial law and regulation. Surveillance case definitions are developed by the Council of State and Territorial Epidemiologists in collaboration with CDC. In all but a few jurisdictions, positive results from HCV antibody and HCV RNA testing that are indicative of acute, or past or present HCV infection, are reportable. Specific policies for laboratory reporting are found at health department websites. ## Future studies Research, development, validation, and cost-effectiveness studies are ongoing to inform the best practices for detecting HCV viremia and for distinguishing between resolved HCV infection and biologic false positivity for HCV antibody in persons in whom HCV RNA is not detected. Outcomes of these studies will provide comprehensive guidance on testing, reporting, and clinical management, and will improve case definitions for disease notification and surveillance. If distinction between true positivity and biologic false positivity for HCV antibody is desired, and if sample is repeatedly reactive in the initial test, test with another HCV antibody assay. In certain situations § follow up with HCV RNA testing and appropriate counseling. * If HCV RNA testing is not feasible and person tested is not immunocompromised, do follow-up testing for HCV antibody to demonstrate seroconversion. If the person tested is immunocompromised, consider testing for HCV RNA. † It is recommended before initiating antiviral therapy to retest for HCV RNA in a subsequent blood sample to confirm HCV RNA positivity. § If the person tested is suspected of having HCV exposure within the past 6 months, or has clinical evidence of HCV disease, or if there is concern regarding the handling or storage of the test specimen.	None	None	In the United States, an estimated 4.1 million persons have been infected with hepatitis C virus (HCV), of whom an estimated 3.2 (95% confidence interval [CI] = 2.7-3.9) million are living with the infection. New infections continue to be reported particularly among persons who inject drugs and persons exposed to HCV-contaminated blood in health-care settings with inadequate infection control.
fa6d86e3ffab26604e8ce45d9ec7564c318dc0a1	pubmed	The clinical application of genome-wide sequencing for monogenic diseases in Canada: Position Statement of the Canadian College of Medical Geneticists	The clinical application of genome-wide sequencing for monogenic diseases in Canada: Position Statement of the Canadian College of Medical Geneticists # Introduction There are approximately 7000 individually rare monogenic diseases that, as a group, affect 1 in 50 individualsand collectively contribute to significant morbidity, mortality and healthcare costs. Despite extensive investigations to identify the specific cause of a rare disease, the underlying aetiology remains unidentified for many patients. The diagnostic process employed by most medical geneticists in Canada involves clinical assessment followed by sequential laboratory testing. Recent advances, such as chromosomal microarray analyses and multigene panel DNA tests, have increased diagnostic yield, but the diagnosis remains elusive for the majority of patients in whom there is a presumed monogenic aetiology. [bib_ref] The utility of the traditional medical genetics diagnostic evaluation in the context..., Shashi [/bib_ref] In recent years, the cost of DNA sequencing has declined rapidly. [bib_ref] The Race for the $1000 Genome, Service [/bib_ref] Next-generation sequencing (NGS) technologies have made it possible to interrogate a patient's genome in a cost-effective and efficient manner. [bib_ref] Diagnostic clinical genome and exome sequencing, Biesecker [/bib_ref] While genome-wide sequencing in Canada has been performed on a research basis for several years, clinical diagnostic services based on these technologies are just now becoming available and are increasingly being requested. Ensuring that patients with genetic disease have appropriate access to these diagnostic tests has, therefore, Open Access Scan to access more free content become important. This document addresses the clinical use of genome-wide sequencing of germline DNA in the diagnosis of monogenic disease in Canada, but does not address the use of genome-wide sequencing in other medical contexts, such as molecular investigation of cancer or for population screening of healthy individuals. While the document was developed to direct practice in Canada, the applicability of the statement is not confined to Canadian borders and will be of interest to clinicians and health jurisdictions internationally. The Canadian College of Medical Geneticists (CCMG) is a Canadian professional organisation comprised of clinically trained medical and laboratory geneticists that establishes professional standards of clinical genetics practice across the country. This Position Statement provides recommendations on clinical genome-wide sequencing for those providing clinical genetic services in Canada. The statement was developed by two multidisciplinary working groups, one focusing on clinical indications and one on incidental findings. It was posted on the CCMG website on 14 January 2015 for comment by the membership and approved by the CCMG Board of Directors on 22 March 2015. ## Definitions ▸ Primary indication: The constellation of clinical features that lead to diagnostic evaluation by genome-wide sequencing. ▸ Medically actionable: A finding that may impact patient management to improve outcome. ▸ Genetic heterogeneity: The occurrence of similar or identical phenotypes as a result of disruption of different genes. ▸ Monogenic (Mendelian) condition: A genetic condition resulting from altered function of a single gene/locus. ▸ Multifactorial inheritance: Non-monogenic inheritance of specific traits that are determined by the combined action of multiple genetic and environmental factors. ▸ NGS: Massively parallel sequencing technologies that produce many hundreds of thousands or millions of reads simultaneously. ▸ Multigene panel sequencing: For the purpose of this document, multigene panel sequencing will refer to the targeted sequencing, primarily by NGS, of a selection of genes associated with a specific clinical presentation. Genes included in panels typically have a depth of coverage sufficient to minimise false negatives. ▸ Whole-genome sequencing (WGS): A process used to determine the sequence of most of the DNA content encompassing the entire genome of an individual. ▸ Whole-exome sequencing (WES): A process used to determine the DNA sequence of most of the protein-encoding exons found in the genome of an individual. ▸ Clinical genome-wide sequencing: A generic term for the process used to determine the sequence of most, if not all, clinically significant genes and its associated interpretation, including bioinformatic analysis and clinical genotypephenotype correlation. This approach would be undertaken by an appropriately certified laboratory to address a clinical question. ▸ Primary finding: Genetic variant(s) identified by genomewide sequencing that explain the primary indication for testing. ▸ Incidental finding: Genetic variant(s) identified by genomewide sequencing unrelated to the primary indication for testing. ## Considerations the shift to ngs technologies Traditional genetic sequencing uses Sanger technology, which is limited by cost and throughput to the investigation of only one or a very small number of genes at any one time. The increased throughput of NGS permits DNA sequencing to be used in numerous ways within the clinic, to analyse, for example, one particular gene in multiple individuals (generally for population screening) or multiple genes at once in a panel format (eg, for a specific disease indication). NGS can also be employed to analyse several thousand genes with known clinical impact (eg, all genes listed in OMIM associated with human disease), the protein-coding portion of the entire genome (WES) or an individual's genome in its entirety (WGS). These last three approaches, referred to in this statement as clinical genome-wide sequencing, include the sequencing of genes that are not relevant to a patient's primary indication. The obvious advantage of genome-wide sequencing approaches is the potential to identify the genetic cause of a disease more efficiently. Data are now accumulating that highlight the diagnostic utility of genome-wide sequencing in the clinic. For example, a large clinical laboratory in the USA has reported a diagnostic rate of approximately 25% with WES in a cohort of >2000 patients with a range of phenotypes suggestive of monogenic disease. Other large cohorts have shown that this rate may increase to >30% with sequencing of both the proband and parents at the same time (trio analysis), [bib_ref] Clinical exome sequencing for genetic identification of rare Mendelian disorders, Lee [/bib_ref] and even further (to >40%) with careful selection of patients based on their clinical presentation. [bib_ref] Effectiveness of exome and genome sequencing guided by acuity of illness for..., Soden [/bib_ref] In many of these cases, a substantial amount of unrevealing genetic testing had been completed prior to WES. One could speculate that the success rate might be significantly higher if WES is initiated as a first-line investigation. Given the demonstrated diagnostic utility in this context, clinical genome-wide sequencing is being used increasingly in the diagnostic evaluation of patients with suspected genetic disease. ## Limitations of genome-wide sequencing approaches Depending on the particular approach, clinical genome-wide sequencing has certain technical limitations, the details of which will not be addressed here but can be found elsewhere. [bib_ref] Sequencing technologies-the next generation, Metzker [/bib_ref] [bib_ref] Next-generation sequencing: from basic research to diagnostics, Voelkerding [/bib_ref] [bib_ref] Exome sequencing: the sweet spot before whole genomes, Teer [/bib_ref] These limitations can include incomplete coverage, which may result in false negatives, as well as the current inability to reliably assess certain disease mechanisms such as variation in repetitive elements (eg, trinucleotide repeat expansions) and structural variants, particularly with WES and other targeted clinical capture methods. With respect to reporting, there are ongoing challenges with the curation of databases of presumed pathogenic mutations. [bib_ref] Guidelines for investigating causality of sequence variants in human disease, Macarthur [/bib_ref] All of these limitations must be considered when this technology is used in the clinical setting. ## Diagnostic utility of genome-wide sequencing A review of the literature was performed to identify clinical indications for which genome-wide sequencing is beneficial. Literature on both WES and WGS, published before 1 December 2013, was examined. It is important to note that the majority of reported patients who had genome-wide sequencing (mostly WES) had their testing as part of a research study; as such, not all studies can be translated to the clinical setting. Publications in which single patients or small cohorts of patients were examined with the primary purpose of novel gene discovery were excluded. Publications were reviewed in detail by a minimum of two working group members (including medical geneticists, clinical laboratory geneticists and genetic counsellors) and discussed by the larger Clinical Indications Working Group (CA, FB, KB, KC, BF, MG, TH, SH, SM, JLM, BS, CvK). Each paper was assessed for its purpose, patient cohort, methods used, diagnostic rate and conclusions. The publications were grouped into the following categories for review: genetically heterogeneous diseases (eg, neuropathy, hearing loss, mitochondrial disorders), unexplained clinical (including prenatal) presentations suspected to be monogenic (eg, multiple congenital anomalies), common neurodevelopmental phenotypes (eg, autism, epilepsy, intellectual disability) and multifactorial diseases (eg, hypertension). Overall, the Clinical Indications Working Group defined broad factors that increase the likelihood of identifying a molecular cause for a patient's disease using genome-wide sequencing (table 1). It was recognised that a number of biases exist within the literature, such as inclusion of patients with highly specific phenotypes who had previously undergone uninformative genetic testing. In general, the factors listed in table 1 increase the chance that the cause of a disease phenotype is in fact monogenic and might be identified using genome-wide sequencing. These factors need to be considered when deciding which patients are most appropriate to undergo this type of clinical testing. In addition, several factors listed in table 1 facilitate the interpretation of genome-wide data in a clinical setting. The disease presentations with the highest diagnostic yield through genome-wide sequencing were monogenic conditions associated with moderate to high genetic heterogeneity (ie, tens to hundreds of alternative genes). For example, cerebellar ataxia is a clinically and genetically heterogeneous condition that is a feature of >100 rare diseases with onset in childhood. A retrospective study of 28 families of children with cerebellar ataxia demonstrated a diagnostic success rate of 46% using WES, [bib_ref] Exome sequencing as a diagnostic tool for pediatric-onset ataxia, Sawyer [/bib_ref] suggesting that WES or appropriately targeted clinical capture methods are an effective tool in the diagnostic evaluation of this particular set of patients. Similarly, there is literature to support the role of genome-wide sequencing in various unexplained clinical presentations. In the case of intellectual disability, there is evidence for the diagnostic utility of genome-wide sequencing in isolated cases when the patient is moderatelyseverely affected or has a syndromic presentation. [bib_ref] Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an..., Rauch [/bib_ref] [bib_ref] A de novo paradigm for mental retardation, Vissers [/bib_ref] [bib_ref] Diagnostic exome sequencing in persons with severe intellectual disability, De Ligt [/bib_ref] In contrast, at this time there is little evidence for the diagnostic utility of genome-wide sequencing in patients with more complex neurodevelopmental phenotypes, such as non-syndromic autism. Nevertheless, clinical genome-wide sequencing should be considered in individuals with an autism spectrum disorder who have a comorbid intellectual disability and/or other syndromic features. [bib_ref] Sporadic autism exomes reveal a highly interconnected protein network of de novo..., O'roak [/bib_ref] There is currently no evidence to support the use of genome-wide sequencing to facilitate clinical care in patients with multifactorial diseases such as myocardial infarction. At the time of this review, there was a paucity of literature supporting the use of genome-wide sequencing in the prenatal setting. When determining the underlying cause of a suspected monogenic disease, there are a number of approaches that can be undertaken, depending on the phenotypic presentation and degree of genetic heterogeneity (figure 1). For example, in genetic conditions with a characteristic clinical presentation that is caused by disruption of one gene, or is associated with a small degree of genetic heterogeneity (eg, CHARGE syndrome or tuberous sclerosis), analysis of the individual gene(s) may be the first-line approach. For moderately specific phenotypes with moderate genetic heterogeneity, the choice of whether to use a multigene panel or clinical genome-wide sequencing may depend on the clinical scenario and resources available. For example, in patients being investigated because of a family history of inherited arrhythmias, identification of a genetic mutation has important implications for patient management, and in this scenario, a cardiac-focused multigene panel or a WES/WGS approach with comprehensive coverage may be the optimal choice of testing. A clinical genome-wide sequencing strategy accompanied by focused analysis of relevant genes may also be useful for conditions associated with a specific phenotype and high genetic heterogeneity (eg, retinitis pigmentosa) as it will allow the same approach to be used for patients with a variety of clinical presentations, thereby facilitating diagnostic access for a broad community of patients. For non-specific phenotypes (eg, moderate-severe intellectual disability) that are presumed to be monogenic and may have no clear optimal set of genetic investigations beyond chromosomal microarray, clinical genome-wide sequencing may also be indicated. For clinical presentations with low pre-test likelihood of a monogenic aetiology such as familial late adult-onset ischaemic heart disease, clinical genome-wide sequencing is not recommended. ## Approaches to incidental findings The issue of incidental findings as a challenge for diagnostic testing has been the subject of a long running debate in the clinical genetics community. Clinical genome-wide sequencing will generate data that are not related to the primary diagnostic question but may be useful in some clinical settings. The Incidental Findings Working Group (SA, KB, JF, TH, BK, A-ML, JL, JM, RM-L, TNN, JR, DLS, TS, ST, MZ) recognises that the clinical utility of the majority of incidental findings has yet to be established [bib_ref] Recommendations for returning genomic incidental findings? We need to talk, Burke [/bib_ref] and the magnitude of potential risks has not been empirically determined. In 2013, both the European Society of Human Genetics (ESHG) and the American College of Medical Genetics and Genomics (ACMG) published recommendations on how incidental findings should be approached. The ESHG recommended that bioinformatic pipelines exclude genetic variants in genes unrelated to the primary indication in order to minimise discovery of incidental findings. [bib_ref] Whole-genome sequencing in health care: recommendations of the, Van El [/bib_ref] They recommend that if an unsolicited genetic variant is detected despite the initial filtering of the data and is indicative of a serious health problem, either in the person tested or a close relative, health professionals should report such variants. In contrast, the ACMG took a more prescriptive approach. Their original recommendations called for the mandatory targeted analysis of a 'minimum list' of 56 genes for 24 inherited disorders deemed to be clinically actionable for any individual undergoing clinical genome-wide sequencing, regardless of age or primary indication. [bib_ref] American College of Medical Genetics and Genomics. ACMG recommendations for reporting of..., Green [/bib_ref] The ACMG subsequently modified their recommendations to permit patients to opt out of receiving incidental findings from clinical genomewide sequencing.This modification moved the opt-out discussion to the point of patient consent and sample submission, rather than when results are received by the ordering clinician. The ACMG recommendations permit laboratories to report or not report other kinds of incidental findings, that is, those not included in the medically actionable list, at their own discretion. The publication of such statements and recommendations by these international organisations prompted reflection on the ethical issues around the reporting of incidental findings and resulted in the development of a proposed set of considerations for the Canadian context, [bib_ref] Reporting results from whole-genome and whole-exome sequencing in clinical practice: a proposal..., Zawati [/bib_ref] which have been largely adopted here. ## The canadian context Canada's publicly funded healthcare system, through the Canada Health Act, provides universal coverage for medically necessary healthcare services on the basis of need, rather than the ability to pay. The majority of services are provided by physicians and other professionals who are paid on a fee-for-service basis. This system is perhaps best described as an interlocking set of 10 provincial and 3 territorial health insurance plans, with the federal government providing partial funding to the provinces and territories. Decisions regarding resource allocation, including availability of particular services within each province and access to out-of-province genetic testing, are made by the individual provinces and territories and differ across the country. Thus, each province and territory needs to consider how new testing technologies should be implemented. In addition, physicians practising within each province need to balance their obligations to the individual patient with the use of finite resources within the province when considering diagnostic options. These recommendations provide an opportunity for consistency in the approach to the use of clinical genome-wide sequencing across the country despite provincial jurisdiction. in the investigation of an affected individual when his/ her phenotype or family history suggests a monogenic aetiology in whom the causal mutation(s) are unknown, and one or more of the following additional conditions apply: ▸ the phenotype is associated with a high degree of genetic heterogeneity; ▸ specific genetic tests have failed to arrive at a diagnosis and testing of other clinically relevant genes is appropriate; ▸ genome-wide sequencing is a more cost-effective approach than available individual gene or gene panel testing. 1.4 Testing should always be done on the affected individual and discussion held with the clinical laboratory to determine whether additional affected relatives or unaffected parents should be analysed concurrently, if available. ## Recommendations ## Careful consideration of the issues and complexities around clinical genome-wide sequencing should be undertaken before its use prenatally, as limited evidence currently exists supporting its use. The Clinical Indications Working Group has developed a decision aid for the incorporation of genome-wide sequencing into the diagnostic evaluation of patients with rare diseases (figure 2). The most critical component of this process is clinical phenotyping. This suggested framework is based on our current understanding and will be re-evaluated over time as new data become available. Ultimately, the ordering physician's clinical judgement should prevail. 2. Pre-test recommendations 2.1 Standard clinical assessment, including detailed phenotyping, should be undertaken prior to testing to facilitate interpretation of the genome-wide variants. 2.2 Prior to testing, genetic counselling for the patient/ family should be undertaken and documented in the A schematic indicating the utility of different sequencing approaches based on phenotype specificity and genetic heterogeneity. Each of these technologies has strengths and weakness; genome-wide sequencing provides broader coverage in general but may have less coverage of specific regions, and thus has a risk of missing deleterious variants. Genome-wide sequencing may be considered for highly genetically heterogeneous conditions or in instances of undefined clinical syndromes suggestive of a genetic aetiology. The clinician must weigh the pros and cons of different approaches that are available. medical record by a qualified individual with a thorough understanding of clinical genome-wide sequencing. The counselling should include: ▸ formal written informed consent obtained prior to testing; ▸ information regarding the limitations of the test methodology used, occurrence of variants of unknown or uncertain significance, and the possibility of incidental findings; ▸ discussion of expected outcomes and what will, and will not, be reported from the test, including variant classes of both primary findings and various kinds of incidental findings, and the choices pertaining thereto; ▸ potential issues related to insurance and discrimination; ▸ possible (or definite) need for parental samples and additional testing, and information about what will, and will not, be reported with respect to samples obtained from the parents, or other unaffected family members; ▸ an explanation of what will happen with data, including how long they will be stored, and if and when additional analysis or re-analysis will be performed in the future. 2.3 All patients/families should be given the option of having coded or anonymised genome-wide and phenotypic data deposited and stored in an international database to assist in interpretation of genome-wide studies of themselves and other patients. 2.4 All patients/families should be given the opportunity to enrol in current or future research studies to understand the relationship of genome-wide variants found in them and clinical abnormalities. ## Recommendations for incidental findings The CCMG recognises that the reporting of incidental findings is a controversial issue, due to the nature of the potential risks and benefits, coupled with a lack of empiric knowledge. Consequently, until the benefits of reporting incidental findings are established, the CCMG recommends a cautious approach; we do not endorse the intentional clinical analysis of disease genes unrelated to the primary indication, even if the results might be medically actionable. Thus, to minimise the discovery of incidental findings, bioinformatic analysis of genome-wide sequencing may be performed using selective filtering (in silico gene panels) that are highly specific to the primary indication (ie, comparable to a multigene panel often requested now for a specific clinical presentation). This will minimise unanticipated and potentially high-cost (dollar or emotional) impacts on the healthcare system, patients, and their families, and will result in faster analysis for variants that are relevant to the patient's primary indication. However, we recognise that some clinical laboratories may wish to offer a broader genetic analysis that includes the assessment of genes that may be associated with diseases unrelated to the primary indication for testing. In this instance, the possibility of identifying incidental findings exists, and should such a finding be detected, then, in principle, 3.1 Competent adults should be given the option prior to testing to receive (or not receive) incidental findings unrelated to the primary test indication. Adult patients should be fully informed about what type of incidental findings could occur with the specific test being considered, which incidental findings will not be returned to them (eg, incidental variants of uncertain significance or low-penetrance genetic predispositions) and which incidental findings the patient may have returned if s/he so chooses. 3.2 In children, incidental results that reveal risk for a highly penetrant condition that is medically actionable during childhood should be reported to the parents. A child's risk for adult-onset genetic conditions should not be communicated unless (1) the parents request such disclosure, AND (2) disclosure of the information could prevent serious harm to the health of a parent or family member, as determined on a case-by-case basis. There is no obligation to re-contact paediatric patients as adults to let them know of potentially later-onset monogenic diseases. 3.3 For incompetent adults, results revealing a highly penetrant medically actionable condition should be reported to the legal representative, unless the incompetent adult concerned expressed wishes to the contrary while still competent. 4. Clinical testing and results reporting recommendations 4.1 Clinical genome-wide sequencing should be performed in an appropriately accredited clinical laboratory. 4.2 Laboratory reports should include specific information describing the clinical genome-wide sequencing methodology used and approach to analysis. Supplemental information should include lists of genes examined if the analysis is limited to a subset of genes. 4.3 The laboratory report for clinical genome-wide sequencing should include an interpretation by a clinically trained and certified PhD or MD molecular geneticist; in Canada, this would typically be one with CCMG certification. 4.4 Interpretation of results should include assessment of current peer-reviewed literature and databases of known variation, and take into account the known limitations of these resources. 4.5 In instances where parental samples are analysed to help interpret a child's data, laboratories should establish, and make available, policy on whether parental reports will be issued and what kind of information they will include. 5. Post-test recommendations 5.1 The ordering clinician should review the report and place the findings into context with other relevant medical considerations when discussing the results with the patient/family. 5.2 The patient (and family when appropriate) should receive standard-of-care genetic counselling and management regarding any new diagnosis. 5.3 In the case in which the laboratory identifies multiple candidate variants, additional literature review, database searching and phenotyping should be considered by the ordering clinician. 5.4 If no pathogenic variant is identified, patients should be counselled that: ▸ Further analysis might lead to a diagnosis at a later date when more knowledge is available. Requests for re-analysis of the sequencing data should be initiated by a referring physician based on an established policy. This may involve re-testing rather than re-analysis, at the discretion of the laboratory. ▸ Further analysis of the sequencing data through research may be an option. A clear distinction should be made between clinical and research analysis, and explicit informed consent obtained for the latter (see points 2.3 and 2.4). # Conclusion Genome-wide sequencing is a useful diagnostic test in a number of clinical scenarios for patients with known or suspected genetic disease. These recommendations were developed on the basis of evidence to facilitate clinical translation of this technology and contribute to best practices in Canada. The indications and approaches we outline here will evolve over time as more data are generated. All Canadian jurisdictions need to discuss and plan for the implementation of clinical genome-wide sequencing in the near term. These recommendations may also prove useful to other countries in the process of translating these technologies to the care of patients with monogenic diseases. [fig] Figure 2: Decision aid to facilitate the diagnostic evaluation of patients with rare disease of suspected monogenic aetiology. This decision aid highlights where genome-wide sequencing may prove useful in the evaluation process. The conditions listed in each box are representative examples only. For specific clinical presentations associated with genetic heterogeneity, the decision regarding the use of a targeted panel versus genome-wide sequencing is dependent on a number of factors, including the availability of the testing options and the yield of such panels. Patients with negative targeted gene panels may benefit from subsequent clinical genome-wide sequencing. Conversely, consideration of a targeted panel subsequent to uninformative clinical genome-wide sequencing would be dependent on the depth of coverage achieved in the latter instance. [/fig] [table] Table 1: Factors that increase the likelihood of monogenic disease and/or facilitate the interpretation of genome-wide data [/table]	None	https://jmg.bmj.com/content/jmedgenet/52/7/431.full.pdf	Purpose and scope The aim of this Position Statement is to provide recommendations for Canadian medical geneticists, clinical laboratory geneticists, genetic counsellors and other physicians regarding the use of genome-wide sequencing of germline DNA in the context of clinical genetic diagnosis. This statement has been developed to facilitate the clinical translation and development of best practices for clinical genome-wide sequencing for genetic diagnosis of monogenic diseases in Canada; it does not address the clinical application of this technology in other fields such as molecular investigation of cancer or for population screening of healthy individuals. Methods of statement development Two multidisciplinary groups consisting of medical geneticists, clinical laboratory geneticists, genetic counsellors, ethicists, lawyers and genetic researchers were assembled to review existing literature and guidelines on genome-wide sequencing for clinical genetic diagnosis in the context of monogenic diseases, and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada. Results and conclusions Recommendations include (1) clinical genome-wide sequencing is an appropriate approach in the diagnostic assessment of a patient for whom there is suspicion of a significant monogenic disease that is associated with a high degree of genetic heterogeneity, or where specific genetic tests have failed to provide a diagnosis; (2) until the benefits of reporting incidental findings are established, we do not endorse the intentional clinical analysis of disease-associated genes other than those linked to the primary indication; and (3) clinicians should provide genetic counselling and obtain informed consent prior to undertaking clinical genome-wide sequencing. Counselling should include discussion of the limitations of testing, likelihood and implications of diagnosis and incidental findings, and the potential need for further analysis to facilitate clinical interpretation, including studies performed in a research setting. These recommendations will be routinely re-evaluated as knowledge of diagnostic and clinical utility of clinical genome-wide sequencing improves. While the document was developed to direct practice in Canada, the applicability of the statement is broader and will be of interest to clinicians and health jurisdictions internationally.
4c7732ec5f973f14a01580c8b137ebded9da0470	pubmed	Redesigning the Practice Model for General Internal Medicine. A Proposal for Coordinated Care	Redesigning the Practice Model for General Internal Medicine. A Proposal for Coordinated Care [fig_ref] Figure 1: Medicare spending for beneficiaries with chronic conditions [/fig_ref] [bib_ref] The growing burden of chronic disease in America, Anderson [/bib_ref] [fig_ref] Figure 3: Percent change in the average income of physicians compared with other professional/technical... [/fig_ref] [bib_ref] The quality of health care delivered to adults in the United States, Mcglynn [/bib_ref] ## Effect of the dysfunctional payment system on cognitive specialties The care of complex patients with multiple chronic illnesses requires careful management by thoughtful physicians who have the scope of expertise and are able to devote the time to understanding all of the active problems and how they interact and affect the patient. As opposed to physicians who spend most of their time performing procedures, these physicians are often referred to as cognitive specialists because they devote most of their time and effort to interviewing, examining, treating and counseling patients. The environment for these cognitive specialists, who include primary care physicians (General Internal Medicine, Pediatrics, and Family Medicine), non-procedural medical subspecialists (e.g., Endocrinology, Rheumatology, Genetics, and Infectious Diseases), and other medical fields (e.g., Psychiatry), is becoming increasingly hostile. The demands of this type of clinical practice have increased dramatically, while remuneration has steadily declined in relative terms. During the period 1995-2005, physicians spent an increase amount of time on direct patient care, which is defined as face-to-face contact with patients, patient record keeping and office work, travel time connected with seeing patients, and communication with other physicians, hospitals, pharmacies, and others on a patient's behalf. As a result, the number of physicians entering these fields has dropped precipitously, and serious shortages of such physicians are predicted [fig_ref] Figure 2: Change in number of residency positions 2000-2006 [/fig_ref]. Conversely, physicians in specialties that entail performance of technical procedures have experienced dramatic improvements in their practice environments and have been able to effectively limit their working hours while incomes have risen more briskly. Correspondingly, procedural specialties are now viewed as more appealing than cognitive specialties and are attracting record numbers of trainees. Even within Internal Medicine, the number of physicians entering the higher paid procedural specialties such as Interventional Cardiology, Gastroenterology, and Nephrology has steadily risen over the past decade, whereas that entering cognitive specialties such as Endocrinology, Infectious Diseases, and Rheumatology that provide long-term care to patients with serious chronic diseases such as diabetes, HIV/AIDS, and rheumatoid arthritis, has been slowly decreasing, as has the number of medical school graduates electing to enter General Internal Medicine. The major reason for this shift has been a system of reimbursement that rewards the diagnosis and treatment of disease with procedures and devices rather than primarily with careful examination and management. Between 1999 and 2003, payment for imaging services grew by 45%, and in 2004, the cost of imaging to all payers was approximately $100 billion, equivalent to $350 per person in the United States. [bib_ref] The new era of medical imaging-progress and pitfalls, Iglehart [/bib_ref] For reading an ultrasound image, the radiologist, who may never actually see the patient, is paid as much or more than a cognitive specialist who thoughtfully interviews and examines the patient, determines the need for and orders the ultrasound examination, and ultimately, crafts a treatment plan. Although the rationale for this disparity may be that procedures and devices are easily counted and controlled, the net result is increasingly to drive the medical care system toward an impersonal, technological, and expensive approach to care. General Internal Medicine is a prototypical cognitive specialty with few procedures and has suffered declining fortunes along with the others. Disparities in financial rewards coupled with high levels of indebtedness plus a higher perceived job satisfaction and better lifestyle in other medical specialties are the major factors driving trainees away from primary care. High-tech proceduralists are paid vastly more than physicians whose work is mainly cognitive, and trainees have taken notice. The national average compensation of a Dermatologist is twice that of a General Internist or a Family Physician, while that of an Orthopedic Surgeon is nearly 2 1/2 times higher. In some community settings, the disparity can be much greater, with proceduralists earning up to 6 times as much as a cognitive specialist. This is not necessarily to argue for parity, but to highlight explicitly the power of the incentives that are presently operating in the medical marketplace. Moreover, although in real terms the income of physicians has declined in recent years, that decline has been much more severe for physicians engaged in primary care practice [fig_ref] Figure 3: Percent change in the average income of physicians compared with other professional/technical... [/fig_ref]. It should be noted that in some countries, England, for example, the incentives are tilted in precisely the opposite direction. Generalist Physicians there are now paid on average more than specialists to attract the best and brightest into general practice and reward efficient, high quality care. Many cognitive physicians in the United States, such as General Internists, practice in settings in which it is difficult to deliver optimal health care to patients over time. Heavy demands for productivity, micromanagement by insurers, and limited practice support have eroded continuity and opportunities for truly personalized care. Performance of Generalist Physicians is measured in terms of numbers of visits, patients, or relative value units (RVUs), rather than results or quality. Current attempts to address these problems, such as typical disease management programs, that are external to the physician's practice rather than integrated with it, may produce targeted improvements but also lead to more fragmentation and disease-centric care. These circumstances can easily lead to higher use of medical services (including procedures), lower quality, and higher costs. It is for this reason that every other developed country in the world has a health care system that links each patient to a generalist provider. Accumulating evidence supports the model of care where the patient has a strong relationship with a primary care physician as improving quality of care and lowering costs. Continuity of care is a prime determinant of patient satisfac-tion. [bib_ref] Continuity of care and other determinants of patient satisfaction with primary care, Fan [/bib_ref] Ironically, wealthier patients have recognized these problems and now often seek out "boutique" physicians who have divorced themselves from the systems that pay for disease care and offer a more comprehensive model focused on maintaining health. This reflects the fact that practically no patient wants production line, generic care, and that when substantial economic incentives exist, personalized, continuous care is available. The United States has reached a crossroad. Unless the decline in cognitive specialists is reversed and new approaches to care for chronic illness are made readily available to all who need them, our health care system will continue to disintegrate and grow unaffordable to the majority of Americans. Patients will undergo an endlessly growing number of expensive procedures for a diminishing benefit. The elderly, who use most of the health services in this country, will continue to find themselves increasingly adrift in a complex system, required to shuttle on their own between single system specialists, each armed with a procedure. Rather than simply accept this inevitability, the alternative is to create a rational system in which all components of care are sensibly integrated within a highly functional environment that is strongly anchored by a skillful Generalist Physician who is able to match the medical needs and personal preferences of individual patients to the complex array of available tests and therapies. This physician is truly a specialist in managing complex, chronic illness. Although only a limited number of highly integrated systems such as the Veterans Health Administration and group-model health maintenance organizations have begun to move toward this goal, it is possible to envision other settings in which this type of care could readily be provided. Achieving this goal will require vision and commitment by the medical profession and by policy makers as well as a serious restructuring of the current methods of paying for health care. In the remainder, we highlight principles of effective care for patients with chronic illness and suggest a potential strategy forward. We also address the special role of academic General Internists in addressing this impending crisis. ## Creating a practice model for chronic illness that works-coordinated care For the past three decades, the predominant approach to delivery of routine health for most Americans has been a primary care model. Several groups, including the Institute of Medicine, have carefully delineated the essential attributes of effective primary care. Although these remain thoroughly relevant to the provision of high quality health care, they are general attributes and do not provide detail about how they might be effectively translated into the delivery of care in real world settings such as that described above. More recently, professional organizations such as the American College of Physicians (ACP) and the American Academy of Family Practice (AAFP) have issued very thoughtful and forward thinking position papers that address the current plight of Generalist Physicians. These statements also set forth potential solutions that might help to resurrect the important role of generalists. The ACP has proposed the concept of the Advanced Medical Home consisting of a competent team, including a physician specialist in complex, chronic care management, and coordination and active involvement by informed patients.AAFP has also issued policy statements supporting the notion of a medical home.We applaud and endorse these efforts and hope that the efforts of Society of General Internal Medicine (SGIM) will support and bolster those of our colleagues in those other organizations. We now propose a set of adjunctive principles that are intended to supplement the work of other organizations by establishing an approach that will sustain quality and enhance the attractiveness and viability of care delivered by highly trained General Internists who specialize in the provision of coordinated, longitudinal care of adult patients with acute and chronic illness. These principles address critical components of health care delivery such as clinical support, organization, information management, and access. We discuss the implications for training and for future research. ## Primary care versus coordinated care In the early 1970s, it was recognized that the rapidly increasing specialization of physicians was leading to care that was fragmented and focused on specific organ systems rather than whole patients. Furthermore, the care was expensive and lacked sufficient emphasis on prevention. The primary care movement was established in response to these circumstances. Over the ensuing three decades, however, the term primary care has come to subsume several types of health care that include: Although all of these types of care share certain elements such as a focus on prevention and provision of first contact care, they also differ in important ways. GIM, in particular, focuses on providing care to patients with multiple chronic conditions. For the purposes of this report, we concentrate on the demands of providing effective, high-quality care to adults with multiple chronic conditions. Management of these patients represents a special type of primary care that is very different from the episodic care for acute illness and prevention that otherwise healthy individuals require. Because of these differences, we refer to this type of health care as Coordinated Care as distinct from the more general term, Primary Care. Coordinated Care is also very different from the disease-based approach to care that is encouraged by our present system of payment. Coordinated Care embodies a true system of care in which continuity, coordination, comprehensiveness, and patient-focus, as a whole, are the goals. ## Principles of coordinated care that is effective, efficient and rewarding 1. Coordinated care should be viewed as a process rather than a series of episodes. The organization and financing of the current health care system is oriented around the notion that certain events, such as scheduled or unscheduled visits, constitute the central activity of health care delivery. This view of health care as episodic for persons with chronic illness should be abandoned. The delivery and payment systems must be reoriented toward supporting longitudinal and continuous care that provides and maintains meaningful improvements in health. ## Patients value and benefit from a longitudinal relationship with a highly trained physician who understands the context of all their conditions and personal circumstances. Patients' satisfaction is directly related to continuity of care, yet little noticed over the past decade has been the disintegration of the fundamental value of a long-standing relationship between a capable physician and a patient. Propelled by frequently changing insurance coverage, constant changes in benefits and eligibility for covered services, complex physician coverage systems, confusing procedures for access, and a piecework mentality toward measuring productivity, any semblance of continuity of care has evaporated for many patients. Not only has this produced frustration and dissatisfaction on the part of both the providers and recipients of health care, but has also caused fragmentation and unnecessary health services. Patients with sufficient financial means have sought to recover continuity with their physician in expensive "boutique" practices seeking the undivided attention of their personal physician. ## A well-organized team of capable health care providers, coordinated by a knowledgeable and well-trained general Internist is optimally suited to providing Coordinated Care. Described in greater detail below, the composition of the team comprised of medical and nonmedical personnel working closely together to assure accessibility, continuity, and high quality care that includes effective communication with, education of, and outreach to patients. The current primary care practice model is inefficient for patients with chronic illness and is economically unsustainable. Ultimately, providing care efficiently and satisfying both patients and providers will depend upon delegating and matching the manifold tasks of patient care to members of an integrated team, according to their individual competencies. Long-held traditions, limitations of information systems, and restrictions imposed by the reimbursement system are presently barriers to developing more efficient and effective approaches to longitudinal care. In a few other sectors of the economy is the highest level professional responsible for the majority of production, customer service, and clerical work. The ever-growing burden of administrative tasks is perceived by established physicians and trainees as a major disincentive to remaining in or entering GIM. Given the expense of training and the impending shortage of qualified physicians, it is not only sensible but essential that the unique competencies of physicians be utilized to their fullest. These include the synthesis of large volumes of complex medical information, estimations of risks and benefits customized to the individual patient, and the recognition of biological, psychosocial, and economic factors in the management of health and disease. Without sacrificing the ability of a physician to establish a long-standing, personal relationship with his or her patients, models of care that provide effective, efficient, and personalized longitudinal care must be created. In some settings, General Internists may have to abandon the ideal of providing all care to their patients (e.g., ordinary acute care and routine follow-up for stable chronic illness). The trade-off for this sacrifice is improved access and greater availability of the physician for complex problems. 4. Capable use of a comprehensive, functional electronic health record (EHR) is critical to high quality practiceespecially for care of chronically ill patients. Central to the concept of providing effective Comprehensive Care is the availability of a full-featured EHR that makes all essential data readily available to the health care team, facilitates communication between team members, and simplifies tasks such as order entry. When properly implemented, EHRs have been shown to reduce errors. In routine practice, most errors are a result not of poor judgment but of deficient management of information such as difficulties with the gathering and display of information, breakdowns in communication among multiple care providers, incomplete data, or failure to act on critical information. Although there are many barriers to full and widespread implementation of the EHR in the outpatient setting, the burgeoning amount and complexity of clinical information facing providers make it essential. Health care systems such as the Veterans Health Administration have demonstrated that a fully deployed and functional EHR can support the delivery of quality less expensively than in most other parts of the health care sector. For these systems to be embraced by practitioners, however, they must be time-neutral or time-saving. Moreover, they should not be used to add additional clerical duties to already overtaxed physicians. Medical information that is consolidated, concise, standardized in format, contextualized, presented "just-in-time", and processed only once by the physician facilitates the complex cognitive tasks involved in coordinated care. Information presented in this manner minimizes errors, increases efficiency, and makes the process of care more rewarding for the patient and the providers. 5. Payment mechanisms must be modified to support coordinated care. Current payment mechanisms for care of chronic illness are woefully inadequate. As noted above, these mechanisms largely pay only for face-to-face visit with a single provider. This type of encounter represents only one aspect of high-quality coordinated care; payment mechanisms focused exclusively on the face-to-face visit do not lend themselves to care by a coordinated team. In some integrated health care systems, up to 25% of patient encounters now occur via secure e-mail systems. Some health care systems are also deploying internet-based applications for managing patients. As advocated by the ACP in its recent position statement, payment should be available for physician services that provide essential oversight and coordination of other practitioners who participate in delivering care. In addition, current payment mechanisms do not account for the fact that much of the important work of patient care occurs outside of face-toface visits. This includes communication between health care providers and patients and among health care providers. Effective use of staff, educational and community resources, and electronic forms of communication can create an environment in which health problems and concerns are addressed promptly, effectively, and efficiently. These activities have the potential to prevent more serious problems and avert costs related to avoidable visits and hospital admissions. At present, however, there is essentially no mechanism to pay for these activities, which in the long-run, adds to the cost of medical care and detracts from quality. 6. The infrastructure necessary for coordinated care must also support acute symptom evaluation and prevention. Patients with chronic problems and generally healthy patients who have not yet developed a chronic illness still require prompt evaluation and effective management for acute intercurrent symptoms and comprehensive prevention and health maintenance. Clinical support systems, EHRs, coding schemes, and payment mechanisms should be constructed to accommodate these functions as well. The clinical environment should provide easy and convenient access as patients have made it abundantly clear that they do not want to pay for care that is inconvenient or not perceived to meet their needs. 7. The health care system and physicians must be accountable to patients and payers. General Internists have led the health professions in defining methods to measure the quality of processes and outcomes of care. In the care of an individual patient with multiple medical problems, however, a new generation of performance measures is necessary to define the outcomes of longitudinal coordinated care. Current measures largely reflect actions taken as part of episodic care and are not geared to long-term coordinated care. General Internists need to provide leadership in establishing a new generation of "tightly linked measures" as described by Kerr and her colleagues. [bib_ref] Building a better quality measure: are some patients with 'poor quality' actually..., Kerr [/bib_ref] These measures should be hierarchical in nature and recognize the competing demands that derive from multiple conditions and need to set priorities. [bib_ref] The new era of medical imaging-progress and pitfalls, Iglehart [/bib_ref]. Trainees in Internal Medicine must learn in settings in which high quality coordinated care is practiced. The basic structure of training in Internal Medicine has been relatively static for several decades and no longer provides much of the knowledge, skills, and attitudes necessary to be a successful General Internist. This has, in part, been responsible for the decreasing attractiveness of Internal Medicine, in general, and GIM specifically. Unless the current generation of physicians is well schooled in not only traditional areas of disease etiology, diagnosis, and treatment, but also use of information systems, care coordination, and quality improvement, they will be doomed to fail in the practice of 21st century medicine. In fact, these reforms must be extended back into medical school before the point when medical students start to make long-term career decisions. To successfully address these deficiencies in training, new mechanisms to fund Graduate Medicine Education will be necessary. So long as essentially the sole source of federal support for training of physicians derives from payment to hospitals, genuine and necessary reforms in medical education will not be possible. [bib_ref] Continuity of care and other determinants of patient satisfaction with primary care, Fan [/bib_ref]. Researchers in GIM must aggressively design and test innovative methods for delivering coordinated care. Academic generalists in many settings have fallen behind forward-thinking community providers in designing new approaches to care. Partnerships between these physicians and other health professionals practicing in academic and community setting need to collaborate to design and test improved system designs. The Centers for Medicare and Medicaid Services (CMS) and other entities have begun to fund pilot projects. But without rigorous evaluation, it may not be possible to generalize the successes and failures of these projects to other settings. This presents an ideal opportunity for collaboration between physicians in private practice and academic setting. Unfortunately, few if any of these demonstration projects are being conducted in academic General Internal Medicine Clinics where residents are being trained. The opportunities to engage trainees in innovative efforts to improve health care for chronic conditions will provide them with a broad set of skills and experiences that will be valuable throughout their careers. ## A proposed model for providing coordinated care The key to providing high-caliber, coordinated care by a General Internist will be to create a practice environment that incorporates improvements in workflow and information management, but still retains the essential characteristics of primary care models such as maintaining a trusting, long-term relationship with the patient. In the new model, the pre-appointment, intra-appointment, and post-appointment work are designed to maximize the quality and efficiency of the patient care encounter and to optimize the satisfaction of patients, staff, and physicians. The specific components of the new model are described in terms of clinical support, medical information management, and scheduling. Such seemingly mundane issues are vitally important to provision of excellent health care. It has become increasingly apparent that how systems of care are structured and operated is as or more important than the expertise or decisions of individual physicians. To take good care of patients, General Internists need a viable practice model. ## Clinical support There are numerous ways in which the office or clinic of a General Internist might be restructured to facilitate coordinated care. The physician might work side-by-side with one or more clinical assistants who are not independent clinicians but have substantial training and experience in clinical settings. For each patient, a clinical assistant completes an initial intake, reviews medical records, assesses the patient's status, solicits agenda items, obtains vital signs, and performs any necessary point of care testing. The clinical assistant confers with the physician to review this information and joins the physician with the patient. The physician confirms and supplements key aspects of the history in an efficient and directed manner. During this process, the patient, clinical assistant, and physician formulate a plan and the clinical assistant simultaneously completes documentation. The physician then moves on to the next patient while the clinical assistant works with the patient to implement the plan and provides further education/explanation. If the patient calls later in the week with a question, she/he can be confident that this clinical assistant works closely with the physician and is personally familiar with the patient's situation. The clinical assistant is continually learning in this environment, and like the physician, is rewarded by close interactions with patients. Alternatively, routine interval visits could be scheduled with a nurse practitioner or physician assistant. The physician could visit briefly with the patient at the end of the encounter. The patient would understand that his or her physician remains firmly engaged and can look forward to a one-on-one appointment with the physician in the future. In larger practices, the services of pharmacists, health educators, nutritionists, and others may be warranted by the size of the patient population. In some clinics, pharmacists now initiate insulin therapy and titrate dosage or adjust antihypertensive medications. ## Medical information management The typical Generalist Physician still depends heavily upon paper records and forms that are inefficient to complete, store, access, and transmit. Moreover, it is difficult and expensive to use paper records for effective quality improvement or measurement. EHRs overcome many of these limitations, but despite their increasing adoption, their potential for improving the health of patients remains relatively untapped. Even in settings in which extensive EHRs have been deployed, the system is typically used in the same fashion as a paper record, i.e., simply for documentation, and most of the data are not systematically used for quality improvement. This is not only because of limitations of EHRs themselves, but also to the fact that physicians are too busy and poorly trained for such efforts. In the setting of high quality coordinated care, the General Internist becomes the expert in the use of the EHR, not only in caring for an individual patient but also in managing a large number of patients within a practice. Moreover, the EHR is specifically designed to support this model of practice. When collecting and compiling clinical data, a clinical assistant is easily able to assemble prespecified reports that display all relevant information about patients, irrespective of the source (e.g., history, laboratory results, procedures, etc.) in a readily understandable, standardized format. This facilitates informa-tion exchange and eliminates time that would otherwise be spent searching through multiple sections of a record. Data in the record automatically link to context-sensitive resources such as clinical practice guidelines or alerts about newly recognized drug toxicities. The EHR also automatically links to other useful resources, such as patient education material and community resources. Patients can access and enter relevant information that is then available to the health care team. The EHR in this setting also supports systematic methods for ensuring that patients receive a consistently high quality of care. The staff routinely devotes time each day to reviewing regular reports that identify patients who are due to receive indicated services such as cancer screening tests. Patients with certain parameters that are out-of-range, such as blood pressure, low-density lipoprotein (LDL)-cholesterol, or creatinine are identified, and plans to address these problems are devised. Patients can be confident that important results and findings do not slip through the cracks. Because most medical errors reflect problems in information gathering and display, the EHR has the potential to play a critical role in improving efficiency and quality. The EHR should assist the physician in managing and using information. It must support physicians' "thought-flow" as well as work-flow. To achieve this goal, however, the EHR must meet critical performance standards including: a. Rapid accessibility and response time In the outpatient setting, physicians presently spend hours daily using computer systems. A few seconds delay with each transaction accumulates into hours of wasted time. These delays directly reduce efficiency and are a barrier to physicians' embrace of the EHR. b. Intelligent and flexible data presentation The visual interface and format or presentation of information is critical. Key information should be readily accessible with a minimum of "clicks", and unnecessary clutter should be eliminated from the display field. Because of varied preferences, the interface should be customizable by the user, but should not require the user to reconstruct the desired format with each use. This flexibility should permit a high level of information density that relieves the user of the necessity to page through multiple screens to obtain a particular bit of information. c. Consistency Information should be presented in a consistent and familiar format. Inconsistency in display promotes inefficiency and likely contributes to errors. This is particularly useful in settings in which novices such as trainees might be using the system and must learn to do so rapidly. d. Contextual sensitivity By and large, EHRs are presently used mainly for storage and retrieval of data. Rarely do these systems have the capacity for awareness of important issues related to the individual patient or the needs of the provider. Although it will require substantially more sophistication than is currently available, an EHR should ultimately maintain awareness of key aspects and issues relevant to an individual patient (e.g., active problems or symptoms). The system should also then actively assist the provider with ready access to resources and decision aids. Providing information in context should promote more effective and efficient medical decisions and reduce errors. ## E. prioritization The timing and prominence of information presented should be based upon its importance and urgency. The EHR should help protect the physician against information overload and assist in attending to the most important information. Redundancy should be eliminated. f. Promotion of Quality Improvement The EHR should be a platform for quality improvement. The possible avenues are limitless but include rule-driven alerts for extreme values and potential clinical problems (e.g., rising creatinine values) and evidence-based clinical reminders. Such alerts need to be judiciously applied to avoid causing information overload or unnecessary distraction, which, in turn, can reduce attention to truly important messages. The EHR should also provide the capability to summarize and analyze data in a relational fashion. ## G. electronic communication The EHR is an effective and reliable means of communication among health care providers and patients. Secure messaging provides a fast and inexpensive means for Generalist Physicians to communicate with consultants and support staff as well as patients. Computerized order entry that capably manages consultation requests ensures that these requests are not lost and can be readily tracked. h. Patient Involvement Modern EHRs also provide the opportunity for patients to access and supplement their health records. They can verify and amend, when warranted, personal health information. They can also supply records about health habits such as exercise, diet, weight loss or self-monitored disease parameters such as glucose and symptoms. This information can be linked to relevant resources and assist with chronic disease management. The potential of the EHR to improve the efficiency of longitudinal care and the health of patients has barely been tapped. Realizing this potential, through the design of interfaces, implementation and application of the advanced EHR should become the province of physicians who specialize in coordinated care and assume responsibility for the oversight of patients' overall health care. ## Access and scheduling The modern General Internist must simultaneously manage three basic sets of issues: evaluation of acute symptoms, management of chronic illness, and disease prevention. The typical practice relies mainly on routinely scheduled visits plus a variable number of acute or drop-in visits, although some practices are beginning to commit a substantial proportion of visits to open access. Advance planning for either type of visit is often minimal, but in a setting in which coordinated care is practiced, the staff carefully manage schedules to optimize efficiency. In the Coordinated Care model, staff assembles necessary data from other providers or the laboratory before the visit to facilitate management of chronic illnesses and to provide opportunities to enhance preventive health. Many offices would continue to provide same-day access for acute problems, but simultaneously dovetail provision of preventive services to potentially obviate routine scheduled visits in the future. In general, routine tests are ordered according to predetermined protocols and accepted clinical practice guidelines. This process is aided by the EHR, which tracks and recommends indicated tests and procedures and functions to reduce unnecessary or duplicative procedures. In this way patients can be automatically contacted at prescribed intervals for tests and visits. When preferred by the patient and the physician, preventive care can be provided at a dedicated visit that provides sufficient time for the physician and staff to properly assess and counsel the patient. The intelligent EHR relieves the physician and staff of many routine tracking and scheduling tasks and permits them to focus on gathering critical information directly from the patient. The patient has confidence in the system because she/he has come to expect that necessary tests, and treatments are accomplished in a timely and predictable fashion. ## Payment for coordinated care Implicit in all of the foregoing discussion is that few, if any, of these changes can occur without a change in the method of paying for care. The present evaluation and management system reinforces an inefficient and expensive care delivery system that rewards piecework yet ignores the finished product. Unless and until the payment system is revamped, providers will be motivated to provide high volumes of visits without investing the time, energy, or resources into improved approaches to delivering health care to all people, but especially those who are chronically ill. In particular, there must be a mechanism to fairly reimburse physicians who provide leadership to teams that deliver high quality coordinated care. Payers must recognize that teams can provide better care than individuals and provide a mechanism to reasonably support this type of care. By furnishing a mechanism to provide coordinated, longitudinal care, payers will ultimately reap benefits by avoiding preventable complications and unnecessary care. As advocated by ACP, CMS should fund pilot programs to develop better practice models. Some of these should be conducted in academic settings so that the next generation of physicians can furnish leadership in moving toward coordinated care. ## The special role of sgim As the premier organization for academic General Internists, SGIM has a critical role to play in discussions regarding the future of GIM and the role of General Internists in caring for patients in the 21st century. In particular, SGIM must lead the way by: & working in close partnership with other organizations such as ACP to advocate for the importance of concepts such as coordinated care and the "advanced medical home" and by seeking new mechanisms of payment and funding for pilot projects. [fig] Figure 1: Medicare spending for beneficiaries with chronic conditions. [/fig] [fig] Figure 2: Change in number of residency positions 2000-2006. [/fig] [fig] Figure 3: Percent change in the average income of physicians compared with other professional/technical workers, adjusted for inflation, 1996-2000. [/fig] [fig] &: Fundamental changes in workforce and training policies to assure an adequate supply of physicians who are trained to deliver care in this model. Research and pilot testing on the advanced medical home model and a revised reimbursement system. [/fig]	None	https://link.springer.com/content/pdf/10.1007/s11606-006-0082-3.pdf	None
bcd304ecac8c3b44fabad8db8b6afd9e2aba7632	pubmed	Standardized cardiovascular magnetic resonance (CMR) protocols 2013 update	Standardized cardiovascular magnetic resonance (CMR) protocols 2013 update This document is an update to the 2008 publication of # Introduction This document is an update to the 2008 publication of the Society for Cardiovascular Magnetic Resonance (SCMR) Board of Trustees Task Force on Standardized Protocols . Since the time of the original publication, 3 additional task forces have published documents that should be referred to in conjunction with the present document. The first is the document on Reporting published by that SCMR Task Force in 2010 [bib_ref] Society for cardiovascular magnetic resonance guidelines for reporting cardiovascular magnetic resonance examinations, Hundley [/bib_ref]. All references to reporting of the findings from the protocols listed have been removed from the present document as they are covered in the aforementioned document. In addition, all references to analysis methodologies have been removed from the current protocols document as they are covered in their entirety in the recent publication of the SCMR Task Force on Post-Processing . All protocols relative to congenital heart disease have been removed, as a separate document has been recently published in regards to this topic [bib_ref] Guidelines and protocols for cardiovascular magnetic resonance in children and adults with..., Fratz [/bib_ref]. The section on general principles and techniques has been expanded as more of the techniques common to CMR have been standardized. There is still a great deal of development in the area of tissue characterization/ mapping, so these protocols have been in general left as optional. The authors hope that this document continues to standardize and simplify the patient-based approach to clinical CMR. It will be updated at regular intervals as the field of CMR advances. ## General techniques Field Strength Considerations 1. CMR can be performed at different field strength. 1.5T systems are currently used for the majority of examinations. 2. CMR at 3T requires careful shimming and adjustment of the radiofrequency pulses to avoid artifacts. 3. As a result of improved signal-to-noise ratio (SNR), 3T is advantageous for first pass contrast-enhanced perfusion imaging. Furthermore tagging sequences and 4D flow techniques may benefit from 3T. 4. Steady-state free precession sequences, often the choice for cine imaging at 1.5T, have several challenges at 3T including increased dark banding artifacts, flow artifacts, and suboptimal flip angle choices because of specific absorption rate (SAR) restrictions. 5. Devices that have been tested at 1.5 T may not be safe at 3T: check specific information relating to MRI safety of devices at higher magnetic field strength. 2nd or 3rd degree atrioventricular (AV) block or sinus node dysfunction Systolic blood pressure less than 90 mm Hg Sinus bradycardia (heart rate<40 bpm) Active bronchoconstrictive or bronchospastic disease with regular use of inhalors Known hypersensitivity to adenosine or regadenoson (Side effects are described as less significant with regadenoson than with adenosine, however, the half life of regadenoson is longer) ## Patient preparation 1. Obtain informed consent for the stress test 2. To fully exert its effects patients should optimally refrain from the following medications for 12-24 hours prior to the examination due to potential of counteraction against stress agent. Dobutamine: ß-blockers and nitrates. Adenosine/regadenoson: caffeine (coffee, tea, caffeinated beverages or foods e.g. chocolate, caffeinated medications), theophylline, dipyridamole Note: There is increasing data that the effects of caffeine and nicotine can be overcome by higher doses of adenosine as well as regadenoson. 1. Fasting is not mandatory, but is often advised because recognized adverse effects of stress drugs include nausea and vomiting, which may be problematic when lying supine in the restricted space of the magnet 2. Two intravenous lines should be available, one for gadolinium and one for adenosine, one in each arm. Preferential site of contrast infusion is antecubital. Blood pressure cuff should be used with care taken not to interfere with gadolinium or adenosine infusion. For regadenoson only one line is required. 1. Volumes and injection rates depend on scan duration: the given values are recommendations for typical scan times. 2. Injection rates are different for 1 molar contrast agents. As a general rule, divide the given injection rates by a factor of 2. 3. Contrast agents with higher relaxivity (e.g., gadobenate dimeglumine) require smaller doses. 4. Throughout the protocols, the term "gadolinium" refers to gadolinium chelates ## Potential adverse effects Safety considerations: 1. The use of gadolinium contrast should be avoided in patients with stage 4 or 5 chronic kidney disease (estimated glomerular filtration rate <30 mL/min/ 1.73 m 2 ), particularly for those on dialysis, as well as patients with acute renal failure and chronic liver disease, due to concerns regarding nephrogenic systemic fibrosis (NSF). 2. The dose of gadolinium contrast used should be as low as possible to achieve adequate image quality. 3. The risk of NSF depends in part upon the gadolinium chelate used. Use institutional, regional, or national guidelines to guide choice of agent in patients with renal dysfunction. 4. If no alternative is available in dialysis patients such that gadolinium must be used, dialysis should be performed as per institutional, regional or national guidelines. Left ventricular structure and function module 1. Scout imagingtransaxial, coronal, sagittal 2. Transaxial (8-10 mm) set of steady state free precession (SSFP) or fast spin echo images through the chest. 3. Scout to line up short axis imagescine acquisitions are preferable to single shot as long axis motion and inflow should be visualized a. Vertical long axis prescribed orthogonal to transaxial scouts aligned through the apex and center of the mitral valve b. Horizontal long axis aligned orthogonal to the vertical long axis, passing through the apex and center of the mitral valve 4. SSFP is the method of choice for cine imaging because it provides high SNR and excellent contrast between myocardium and blood pool a. At 3T, SSFP cine images may be compromised by artifact and spoiled gradient-echo sequences can be considered as an alternative b. Strategies to reduce or move banding artifact include shimming, reducing the TR, and adjusting the RF frequency (frequency 'scout' sequence can be helpful for this) 5. Steady state free precession short axis cine images, from the mitral valve plane through the apex. The basal most short axis slice should be located immediately on the myocardial side of the atrioventricular junction at end-diastole prescribed from the previously acquired long axis cines. a. Slice thickness 6-8 mm, with 2-4 mm interslice gaps to equal 10 mm. b. Temporal resolution ≤45 ms between phases c. Parallel imaging used as available 6. Steady state free precession long axis cine images a. The 4 chamber long axis is prescribed from the vertical long axis through the apex and center of the mitral and tricuspid valves. This can be cross-checked on basal short axis cines, using the costophrenic angle (margin) of the RV free wall. b. Vertical long axis, prescribed from the scout already acquired c. LV outflow tract (LVOT) long axis, passing through the apex, the center of the mitral valve b. Single-shot imaging (SSFP readout) performed as backup for patients with irregular heart rhythm, and/or difficulty breath holding. 2. Need at least 10 minute wait after gadolinium injection (for gadolinium-chelate dosing see [fig_ref] Table 1: Contrast and chasing bolus doses and injection ratesand aligned with the center... [/fig_ref]. Note -The delay may be shorter than 10 minutes if lower doses are used as blood pool signal falls below that of late enhanced myocardium. Images are to be acquired during diastolic stand-still. 3. Same views as for cine imaging (short-and longaxis views) 4. Slice thickness, same as for cine imaging 5. In-plane resolution,~1.4-1.8 mm 6. Acquisition duration per R-R interval below 200 ms, but should be less in the setting of tachycardia to avoid image blurring. 7. Inversion time set to null normal myocardium. Alternatively, a PSIR sequence can be used, requiring less frequent adjustment of the TI. 8. Read-out is usually every other heart beat, but should be modified to every heart beat in the setting of bradycardia, and every third heart beat in the setting of tachycardia or arrhythmia. Adenosine/Regadenoson stress perfusion CMR 1. LV structure and function module (alternatively this can be performed between stress and rest perfusion, although performance immediately after gadolinium infusion may reduce the contrast of the blood-endocardium interface) 2. Adenosine stress perfusion imaging (at least 3 minute infusion of 140 ug/kg body weight/min, optional up to 210 ug/kg body weight/min). Optioninitial adenosine infusion may be performed with the patient outside the bore of the magnet. a. First pass perfusion module b. During last minute of adenosine, gadolinium is injected c. After imaging for 40-50 heart beats by which time gadolinium has passed through the LV myocardium, adenosine is stopped. d. Continuous ECG monitoring and BP measured at baseline, during infusion, and for at least 2 minutes post-infusion of adenosine. 3. Alternatively: Regadenoson stress perfusion imaging (bolus injection of 0.4 mg). a. First pass perfusion module b. Approximately 2 minutes after regadenoson injection, inject gadolinium c. Image for 40-50 heart beats by which time gadolinium has passed through the LV myocardium d. Continuous ECG monitoring and BP measured at baseline and every other minute for at least 6 minutes post injection of regadenoson. 4. Rest Perfusion a. Need at least 10 minute wait for gadolinium to wash out from stress perfusion imaging. During this period stress images can be reviewed, cine imaging can be completed (e.g. long-axis views), valvular evaluation can be performed, etc. b. Perfusion imaging repeated without adenosine/ regadenoson using same dose of gadolinium (Note: flow may not have returned to baseline at 10 minutes after regadenoson) c. If stress images are normal and free of artifacts, rest perfusion can be eliminated. Additional gadolinium may be given as needed for late gadolinium enhancement (for a total of 0.1 -0.2 mmol/kg) 5. Late Gadolinium Enhancement module a. Need to wait at least 5 minutes after rest perfusion if performed 6. Optional -Full quantification a. Consider using a dual bolus approach to eliminate effect of nonlinearity between contrast agent concentration and signal intensity. This requires injection of a diluted pre-bolus in a standardized fashion. b. Consider using a dual contrast sequence. Similarly to the dual bolus approach this corrects for non-linearity of signal intensity and contrast agent concentration without additional contrast dilution and injection but requires specific scanner software that may not be available on all scanners c. Consider adding proton density images before the contrast injection. This can be used as baseline correction for full quantification but requires specific scanner software that may not be available on all scanners. Sequence: one-direction ("through-plane") motionencoded cine gradient echo sequences are typically applied 3. For optimal results, the imaging plane should be a) centered in the vessel of interest b) aligned orthogonally to the expected main blood flow direction in two spatial directions c) centered in the iso-center of the magnet 4. Imaging parameters: slice thickness 5-8 mm; in-plane resolution at least 1/10th of the vessel diameter. Velocity encoding sensitivity (V enc ) has to be adapted to the expected velocitiesafter each scan, phase difference images have to be checked for aliasing. If aliasing is present, V enc settings need to be adapted accordingly. If available, a velocity scout may allow optimal setting of the V enc . 5. Acquired time frames on the order of 20-30 suffice for clinical routine. For read-out, k-space segmentation over multiple heart beats can be used within limits of breath holding capabilities. Navigator-based non-breathhold techniques can be applied to improve the temporal or spatial resolution if necessary. 6. Echo time (TE) should be set to minimal, particularly when stenoses are imaged ## Advanced tissue characterization module The area of tissue characterization is a rapidly developing field and the pulse sequences available on different vendor platforms vary significantly. Thus, the modules listed below are general guidelines only as there is no standardization yet in this arena. Normal values should be developed at individual or partner institutions using similar platforms and pulse sequences. 1. Performed to assess cardiac iron deposition in disease entities such as thalassemia major. Images typically acquired in concert with LV function imaging. If T2* images are acquired as part of a contrast-enhanced evaluation for cardiomyopathy, the T2* images should be obtained prior to contrast administration. 2. The pulse sequence is a single breathhold, gradientecho, multi-echo scan with a series of 6-9 echo times beginning at~2 ms and extending to~18 ms, with each echo iteratively spaced by~2 ms. A delay time of 0 ms after the R wave typically is used. Optional -In patients with severe iron deposition a pulse sequence with shorter echo spacing could be helpful to accurately determine T2* values: a series of 6-9 echo times beginning at~1 ms and extending to~12 ms, with each echo iteratively spaced by~1 ms. 3. A single mid-ventricular short-axis image is acquired. 4. Slice thickness of 8-10 mm; In-plane resolution, 1.6-3.0 mm 5. (Optional) An imaging sequence similar to the above, though non-ECG-gated, is acquired in the axial orientation through the mid portion of the liver to evaluate hepatic iron deposition. The absence of ECG-gating will allow for closer spacing of iteratively advanced echo times, and therefore a greater number of echoes will be acquired. Disease specific protocols -Ischemic heart disease Acute MI or acute coronary syndromes Valve morphology assessment with SSFP cine in the plane of the valve in question. Care must be taken to optimize the level and angle of imaging b. Noteif planimetry of a stenotic valve is to be attempted, a contiguous or slightly overlapping stack of high resolution cines transecting the line of the jet and moving from orifice level to immediately downstream is recommended. Planimetry is most likely to be valid where the cross section of the orifice, or rather of the jet, is clearly delineated. This may not always be the case due to fragmented or oblique jet flow. c. Gradient echo or hybrid gradient echo/echo planar imaging may visualize regurgitant jets with a higher sensitivity (for qualitative purposes only). d. In mitral or tricuspid regurgitation, a contiguous stack of 5 mm cines is recommended aligned with the direction of inflow and transecting the principal line of coaptation, moving from the more superior commissure to the inferior. The orientation can be that of the LVOT plane for the mitral and transaxial for the tricuspid. Such a stack enables assessment of tethering, prolapse, or regurgitation through the scallops of both mitral leafletes. e. Adapt velocity encoding to actual velocity (using lowest velocity without aliasing). f. Use lowest TE possible for high velocity jet flows. ## Pericardial disease 1. LV structure and function module 2. T1 or T2-weighted fast spin echo images a. 2-3 representative long axis images and 3-4 representative short axis images to measure pericardial thickness (normal ≤3 mm) b. If pericardial cyst is suspected, refer to masses protocol 3. Optional -If regions of thickened pericardium noted -T1-weighted gradient echo myocardial tagged cine sequences to demonstrate presence or absence of epicardial/pericardial slippage (2-3 long axis images and 1-2 short axis images) 4. Real-time imaging during dynamic breathing maneuvers is valuable for evaluation of ventricular interdependence a. Mid-ventricular short-axis plane is preferred b. Cine imaging temporal resolution is preferably below 60 ms c. Patients are instructed to breathe deeply in and out and the total imaging period should be at least 2 complete respiratory cycles d. Abnormal septal motion (early diastolic septal flattening or inversion) during onset of inspiration is consistent with a constrictive physiology 5. Late Gadolinium Enhancement module a. Acquisition with and without fat saturation is helpful to distinguish pericardial inflammation from epicardial or pericardial fat Cardiac and paracardiac masses, including thrombi [table] Table 1: Contrast and chasing bolus doses and injection ratesand aligned with the center of LVOT to aortic valve, as seen on a basal short axis cine. d. Optionala set of more than 3 rotational long axis views can be obtained.Right ventricular structure and function 1. Right ventricular (RV) short axis views can be obtained in a similar fashion to the LV structure and function module. If the short axis is used for quantification, it is important to place the basal short axis slice immediately on the myocardial side of the right ventricle and to take extra care to exclude appropriate amounts of atrial volume from at least one basal slice at end systole. 2. Transaxial stack of cines covering the RV should be considered for RV volumetry. 3. Long axis images should include an RV vertical long axis view aligned with tricuspid inflow and a RV outflow tract view (sagittal or oblique sagittal plane through the pulmonary valve). [/table]	None	https://jcmr-online.biomedcentral.com/counter/pdf/10.1186/1532-429X-15-91	None
bf272432d58c8d29c88b231ef215630716b81653	pubmed	Speech and swallow rehabilitation in head and neck cancer: United Kingdom National Multidisciplinary Guidelines	Speech and swallow rehabilitation 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. The disease itself and the treatment can have far reaching effects on speech and swallow function, which are consistently prioritised by survivors as an area of concern. This paper provides recommendations on the assessments and interventions for speech and swallow rehabilitation in this patient group.Recommendations- All multidisciplinary teams should have rehabilitation patient pathways covering all stages of the patient's journey including multidisciplinary and pre-treatment clinics. (G) - Clinicians treating head and neck cancer patients should consult the National Cancer Rehabilitation Pathway for head and neck cancers. (G) - All head and neck cancer patients should have a pre-treatment assessment of speech and swallowing. (G) - A programme of prophylactic exercises and the teaching of swallowing manoeuvres can reduce impairments, maintain function and enable a speedier recovery. (R) - Continued speech and language therapist input is important in maintaining voice and safe and effective swallow function following head and neck cancer treatment. (R) - Disease recurrence must be ruled out in the management of stricture and/or stenosis. (R) - Continuous radial expansion balloons offer a safe, effective dilation method with advantages over gum elastic bougies. (R) - Site, length and completeness of strictures as well as whether they are in the presence of the larynx or not, need to be assessed when establishing the likelihood of surgically improved outcome. (G) - Primary surgical voice restoration should be offered to all patients undergoing laryngectomy. (R) - Attention to surgical detail and long-term speech and language therapist input is required to optimise speech and swallowing after laryngectomy. (G) - Patients should commence wearing heat and moisture exchange devices as soon as possible after laryngectomy. (R) # Introduction Most head and neck cancers and their treatments affect speech and swallowing and this section therefore concentrates on the rehabilitation of these functions. [bib_ref] Speech and swallowing rehabilitation for head and neck cancer patients, Logemann [/bib_ref] [bib_ref] Role of flexible laryngoscopy for evaluating aspiration, Langmore [/bib_ref] [bib_ref] Comprehensive approach to restoration of function in patients with radiation induced pharyngo-oesophageal..., Urken [/bib_ref] Allied health professional (AHP) head and neck cancer rehabilitation pathways are required as part of the implementation of the Improving Outlines Guidance rehabilitation measures and are required for peer review. These pathways should cover all stages of the patient's journey from diagnosis, through treatment, to survivorship and end of life care and should include relevant intervention from dietetics, physiotherapy, occupational therapy and speech and language therapy. Pathways for oral rehabilitation with input from hygienists, restorative dentists, dental implantologists, prosthetic technicians should also be considered. The stages of the pathways and the allied health professional interventions appropriate to each stage are detailed along with an extensive evidence review in the National Cancer Rehabilitation Pathway for Head and Neck Cancers.Responsibility for the rehabilitation of voice, speech and swallowing rests with the whole multidisciplinary team (MDT), but is the specific role of the speech and language therapist within this team. Speech and language therapists should discuss their role and outline the need for the patient's active participation in therapy to maximise outcomes. The patient's family and carers are also involved in this rehabilitation. Within the MDT, the decision on an appropriate course of treatment should take into account the effects on functions such as voice, speech and swallowing as well as survival so as to suit each individual's preferences and lifestyle. ## Recommendations ## Rehabilitation of voice, speech and swallow Goals of rehabilitation - Achieve the best possible functional outcome and quality of life (QoL) - Identify and carry out interventions which are most effective for both the specific treatment and the individual patient at the optimal time - Provide support and rehabilitation to patients and their carers. ## Assessment All head and neck cancer patients should have a pretreatment assessment of speech and swallowing. [bib_ref] Speech and swallowing rehabilitation for head and neck cancer patients, Logemann [/bib_ref] [bib_ref] Role of flexible laryngoscopy for evaluating aspiration, Langmore [/bib_ref] [bib_ref] Comprehensive approach to restoration of function in patients with radiation induced pharyngo-oesophageal..., Urken [/bib_ref] Baseline assessments should be undertaken by the speech and language therapist and appropriate interventions to maintain functions before treatment should be undertaken. Assessments of voice, speech and swallowing should be carried out at all stages of the pathway. Clinical assessments include: oral-motor examination (lip closure, range of motion), articulation, tongue control and strength; evaluation of the oropharyngeal swallow (timing, efficiency, aspiration, tongue and laryngeal motion) and perceptual evaluation of voice quality. Instrumental assessments of swallowing include flexible endoscopic examination of swallowing, videofluoroscopy and/or modified barium swallow. [bib_ref] Role of flexible laryngoscopy for evaluating aspiration, Langmore [/bib_ref] Instrumental assessments of voice include: endoscopy, stroboscopy and speech studio/laryngograph. These assessments can provide useful biofeedback to patients and demonstrate the effectiveness of interventions. ## Therapy/interventions Pre-treatment. Pre-treatment counselling by AHP teams should be provided to advise on the anticipated effects of the cancer as well as subsequent treatments (chemoradiation, radiotherapy (RT), surgery and palliation). [bib_ref] Pretreatment swallowing exercises improve swallow function after chemoradiation, Carroll [/bib_ref] A strict programme of prophylactic exercises and the teaching of swallowing manoeuvres can reduce specific impairments, maintain functions and enable a speedier recovery ensuring post-treatment rehabilitation is more successful. [bib_ref] Prophylactic swallowing exercise for patients receiving radiotherapy for head and neck cancer, Roe [/bib_ref] For those undergoing surgery the teaching of swallow strategies beforehand can reduce risk and maximise function. This may also reduce the need for tube feeding during treatment and the length of post-treatment tube feeding. ## Post-treatment Voice. Specific therapy techniques can be targeted at projection, pitch, reduction of fatigue, increased adduction, coordination of respiration, vocal hygiene and amplification. These are particularly relevant to those having laser surgery or RT to the larynx. Speech. For those undergoing oral resections a programme of compensations, articulation and intelligibility can be started once suture lines have healed. Swallowing. Following instrumental assessment, interventions should be targeted at specific physiological deficits and volitional control to compensate for the changes to the anatomy and physiology. This can reduce the risk of aspiration, malnutrition and improve QoL. These interventions include: 9 - Postures to reduce aspiration, e.g. head turn, chin tuck - Manoeuvres, e.g. supraglottic swallow, Mendelsohn. - Therapeutic exercises, e.g. thermal tactile stimulation, range of motion, shaker - Diet modifications regarding textures and recommendations on oral or non-oral intake. Oral rehabilitation. Intra-oral prostheses providing palatal lift, obturation and augmentation can improve speech and swallow function after oral resections and the speech and language therapist and restorative dental surgeon and/or prosthetic technician need to work closely together. Radiationinduced fibrosis can present with trismus. This can cause pain, difficulty with oral intake, poor oral hygiene and lack of dental care. Exercises with tongue depressors or a specific device can increase mouth opening. - All head and neck cancer patients should have a pre-treatment assessment of speech and swallowing (G) - A programme of prophylactic exercises and the teaching of swallowing manoeuvres can reduce impairments, maintain function and enable a speedier recovery (R) - Continued speech and language therapist input is important in maintaining voice and safe and effective swallow function following head and neck cancer treatment (R) ## Management of stenosis and stricture Prevention, assessment and diagnosis Dysphonia following RT and chemoradiotherapy to the oro/hypopharynx is multifactorial and difficult to treat. Xerostomia, loss of tongue base bulk and fibrosis/ reduced function of constrictors all play a part. Speech and language therapy and AHPs' input as above remains of utmost importance, but stenosis and stricture can also develop. Stenosis of the (hypo)pharynx and neopharynx is common following treatment for laryngeal and pharyngeal cancer. [bib_ref] Presentation and management of treatment-induced pharyngo-esophageal stricture, Prisman [/bib_ref] [bib_ref] Prevalence of pharyngeal and esophageal stenosis following radiation for head and neck..., Nguyen [/bib_ref] After treatment of cervical oesophageal cancer some degree of stenosis is almost inevitable in this region especially following CRT. [bib_ref] Comprehensive approach to restoration of function in patients with radiation induced pharyngo-oesophageal..., Urken [/bib_ref] Reported rates vary from 8 per cent following primary chemoradiotherapy to 40 per cent or more following salvage surgery after (chemo)radiotherapy, particularly if preceded by a pharyngocutaneous fistula. [bib_ref] Presentation and management of treatment-induced pharyngo-esophageal stricture, Prisman [/bib_ref] Additional dysphagia occurs in extended surgery, particularly with posterior tongue resection and with extended neck surgery with sacrifice of glossopharyngeal and hypoglossal nerves (lesser), and vagus nerve (major). [bib_ref] Swallowing dysfunction is a common sequelae after chemoradiation for oropharynx carcinoma, Greven [/bib_ref] [bib_ref] Factors associated with pharyngoesophageal stricture in patients treated with concurrent chemotherapy and..., Best [/bib_ref] No standardised definition exists to help to measure stenosis rates. Anatomical stenosis might be of greatest interest to the surgeon, but functional stenosis is of no less impact and interest to the patient. Videofluoroscopy, supplemented by axial imaging, is the tool best able to identify the nature of a stenosis of the (neo)pharynx and assess the degree of impact on swallowing. Importantly, barium swallows also have the capacity to identify a proportion of occult recurrences masquerading as benign stenosis. Predictors of stenosis are helpful to surgeons. Studies have shown that following laryngectomy and partial pharyngectomy a 3 cm (unstretched) to 8 cm (stretched) posterior pharyngeal strip is sufficient to allow normal post-treatment swallow and voice rehabilitation. Circular/circumferential rather than linear scars remain more stenosis prone, but no data exist on the minimum luminal diameter with a circular scar to allow normal swallowing. Repair of the suprahyoid muscles (which include the middle constrictor) to the thyropharyngeus muscles after laryngectomy has been advocated and may improve swallow by reducing the size and effect of a pseudoepiglottis as well as allowing better function of the middle constrictor. Cricopharyngeal myotomy and horizontal closure of the pharynx with laryngectomy is generally held to improve speech and swallow outcomes especially when performed with primary tracheo-oesophageal puncture and valve reconstruction for speech rehabilitation. In addition, the relationship between luminal diameter and the use of peristaltic vs non-peristaltic flaps have yet to be quantified in maintaining a functional post-operative voice and swallow. The role of salivary bypass tubes may reduce fistula rates and hence possible stricture rates, but this needs further study. ## Treatment This depends on the type (functional vs anatomical, scar vs recurrence), site and comorbid factors such as fitness for further reconstructive surgery. Median feeding tube placement times following all forms of treatment for head and neck cancer are in the region of 20-26 weeks, and up to 50 per cent of patients reconstructed with free or pedicle flaps are tube-feed dependent at one year post-surgery. Reported rates of complication with percutaneous endoscopic gastrostomy and radiologically inserted gastrostomy tubes vary considerably with up to 3 per cent mortality rates reported in some series and 10 per cent significant complication in others. Clearly the use of different supplemental feeding techniques will depend on local experience in this respect. Dilation of isolated short segment strictures remains a valuable means of controlling symptoms for patients with poor life expectancy or multiple comorbidities. [bib_ref] Presentation and management of treatment-induced pharyngo-esophageal stricture, Prisman [/bib_ref] Continuous radial expansion balloons allow dilation up to 20 mm diameter and may be safer and more effective than traditional bougies. They can also be utilised without general anaesthesia. It is clear that many patients require multiple dilations, often without longlasting relief of dysphagia. Sternomastoid flaps can be useful in the nonirradiated patient, but are less reliable than pectoralis major, radial forearm flap (RFF), anterolateral thigh (ALT) and jejunal flaps. Choice of and reasons for a particular free flap vary depending on familiarity with the flap and perceptions of function vs cosmesis. Reported case series for RFF, jejunum or ALT describe similar complication rates (<5 per cent flap failure, up to 50 per cent pharyngocutaneous fistula) and success rates (speech intelligibility and swallow performance). [bib_ref] National laryngopharyngectomy and reconstructive surgery survey, Richmon [/bib_ref] The length and completeness of stenosis are important factors in advising patients whether significant improvement can be obtained. Complete stricture of the hypopharynx post-chemoradiotherapy can be improved with total laryngopharyngectomy, but patients need to be warned that swallowing outcomes are often poorer in this group than primary pharyngectomy patients. ## Cricopharyngeal myotomy Cricopharyngeal myotomy appears to have little value per se for improvement of dysphagia following surgical treatment of cancers of the oropharynx. [bib_ref] Failure of cricopharyngeal myotomy to improve dysphagia following head and neck cancer..., Jacobs [/bib_ref] In combination with vocal fold medialisation, where needed, and laryngeal elevation, better success rates may be obtained. ## Recommendations - Disease recurrence must be ruled out in the management of stricture and stenosis (R) - Continuous radial expansion balloons offer a safe, effective dilation method with advantages over gum elastic bougies (R) - Site, length and completeness of strictures as well as whether they are in the presence of the larynx or not, need to be assessed when establishing the likelihood of surgically improved outcome (G) ## Rehabilitation after laryngectomy Speech Laryngectomy results in significant alteration of anatomy and often complex rehabilitation. A range of voice prostheses are now available, with Blom Singer and Provox being the commonly used ones. If visual, cognitive and fine motor skills are intact, independence should be fostered by teaching patients to self change their voice prostheses. Where appropriate, 'hands-free' outer valves should be available for patients to try. Although surgical voice restoration techniques dominate, it is important to consider the use of oesophageal speech and electrolarynges. Electrolarynges use an external vibratory source and are either placed in the mouth or against the neck or cheek to produce sound. Both these methods can have their place in the rehabilitation process. [bib_ref] Swallowing and speech therapy after definitive treatment for laryngeal cancer, Samlan [/bib_ref] Speech and language therapists with appropriate training and expertise in the management of the stoma and tracheo-oesophageal puncture should be part of all MDTs. The MDT should ensure that there are procedures to manage out of hours problems such as loss or aspiration of prosthesis. Patients and local teams should be aware that if a prosthesis cannot be replaced the puncture should be kept patent with a catheter or stent for instance. Speech and language therapists should be aware of the need for and rationale behind, amongst others, videoflouroscopy for troubleshooting, botulinum toxin, antifungals, management of leakage through as well as peripheral leakage around a prosthesis. The Royal College of Speech and Language Therapists has recently published an excellent and comprehensive document covering these topics: 'Prosthetic Surgical Voice Restoration (SVR): The role of the speech and language therapist'. ## Swallow There has been a growing appreciation in recent years that swallowing also requires rehabilitation in laryngectomy patients. [bib_ref] Swallowing and speech therapy after definitive treatment for laryngeal cancer, Samlan [/bib_ref] [bib_ref] Post laryngectomy: it's hard to swallow. An Australian study of prevalence and..., Maclean [/bib_ref] [bib_ref] Swallowing outcomes following laryngectomy and pharyngolaryngectomy, Ward [/bib_ref] Although laryngectomy patients should not aspirate unless their voice prosthesis is leaking, they may have difficulty swallowing solid foods or take significantly longer than others to finish meals. It has been suggested that as many as 42 per cent of laryngectomy patients have a degree of dysphagia three years post-surgery with a 72 per cent incidence of self-reported dysphagia. Higher levels of depression and anxiety have also been documented in laryngectomees who have dysphagia. [bib_ref] Life after total laryngectomy: a measure of long-term survival, function, and quality..., Woodard [/bib_ref] Videofluoroscopy is one of a number of swallow evaluation tools used with laryngectomy patients and can contribute to surgical consideration of interventions such as botulinum toxin and dilatation to treat dysphagia. Further rehabilitation tools include the use of exercises to strengthen specific muscles such as tongue base. Appetite can also be affected by a significant loss of ability to taste and smell after laryngectomy. Olfactory rehabilitation utilising the 'polite yawn' has been proposed to help correct this. ## Respiration Respiration is altered significantly post-laryngectomy with the patient now breathing through an open neck stoma bypassing the nasal passages and throat. As a consequence of this anatomical change, the ability to filtrate irritants such as dust from the air and to humidify inhaled air is lost. This can result in increased mucus production and crusting of dried secretions. In recent years, humidification exchange devices have been developed to restore humidification and filtration. Rehabilitation of pulmonary function should be offered to all laryngectomy patients and should involve education about the use of stoma covers and bibs. The presence of an open neck stoma causes some patients anxiety and rehabilitation may include such diverse subjects as advice about maintaining appearance and showering safely. The adjustment to life as a laryngectomee can be significant. Tools such as the EORTC Core Quality of Life Questionnaire and the University of Washington Quality of Life Tool, version 4 can be useful in identifying not only those at risk of psychosocial problems but also to help plan and focus rehabilitation. [bib_ref] Life after total laryngectomy: a measure of long-term survival, function, and quality..., Woodard [/bib_ref] SPEECH AND SWALLOW REHABILITATION IN HEAD AND NECK CANCER: UK GUIDELINES S179 ## Recommendations - Primary surgical voice restoration should be offered to all patients undergoing laryngectomy (R) - Attention to surgical detail and long-term speech and language therapist input is required to optimise speech and swallowing after laryngectomy (G) - Patients should commence wearing heat and moisture exchange devices as soon as possible after laryngectomy (R) Key points - Speech and swallow rehabilitation needs should be assessed before treatment - Assessment and appropriate interventions should take place throughout the patient journey, including ongoing after treatment - Multidisciplinary assessment and management of swallowing problems is important - Videoflouroscopy is an important tool in assessing swallow problems - Dysphagia caused by pharyngeal stenosis after chemoradiotherapy can be difficult to correct and complex cases should be managed by expert teams.	None	https://www.cambridge.org/core/services/aop-cambridge-core/content/view/3C84BBD7BF79D39C81FD17B01E59D292/S0022215116000608a.pdf/div-class-title-speech-and-swallow-rehabilitation-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. The disease itself and the treatment can have far reaching effects on speech and swallow function, which are consistently prioritised by survivors as an area of concern. This paper provides recommendations on the assessments and interventions for speech and swallow rehabilitation in this patient group. Recommendations • All multidisciplinary teams should have rehabilitation patient pathways covering all stages of the patient's journey including multidisciplinary and pre-treatment clinics. (G) • Clinicians treating head and neck cancer patients should consult the National Cancer Rehabilitation Pathway for head and neck cancers. (G) • All head and neck cancer patients should have a pre-treatment assessment of speech and swallowing. (G) • A programme of prophylactic exercises and the teaching of swallowing manoeuvres can reduce impairments, maintain function and enable a speedier recovery. (R) • Continued speech and language therapist input is important in maintaining voice and safe and effective swallow function following head and neck cancer treatment. (R) • Disease recurrence must be ruled out in the management of stricture and/or stenosis. (R) • Continuous radial expansion balloons offer a safe, effective dilation method with advantages over gum elastic bougies. (R) • Site, length and completeness of strictures as well as whether they are in the presence of the larynx or not, need to be assessed when establishing the likelihood of surgically improved outcome. (G) • Primary surgical voice restoration should be offered to all patients undergoing laryngectomy. (R) • Attention to surgical detail and long-term speech and language therapist input is required to optimise speech and swallowing after laryngectomy. (G) • Patients should commence wearing heat and moisture exchange devices as soon as possible after laryngectomy. (R)
9a860efff6108eeff45a8986d39ed2c850ea0f46	pubmed	Practice guidelines for the pathological diagnosis of primary liver cancer: 2015 update	Practice guidelines for the pathological diagnosis of primary liver cancer: 2015 update # Introduction Primary liver cancers mainly refer to malignancies that originate from hepatocytes hepatocellular carcinoma (HCC), which account for the majority of PLC, and intrahepatic cholangiocytes intrahepatic cholangio carcinoma (ICC). PLC ranks as the second leading cause of cancer death worldwide, among which HCC is one of the most lethal malignancies because of its high morbidity and mortality, as well as aggressiveness. An estimated 782500 new PLC cases and 745500 deaths occurred worldwide during 2012, with China alone accounting for about 50% of the total number of cases and deaths [bib_ref] Global cancer statistics, Torre [/bib_ref]. In China, current trends in the crude incidence and mortality of PLC are 28.71/100000 and 26.04/100000, respectively, making it the fourth most common cancer and the second leading cause of cancer relateddeath [bib_ref] Liver cancer incidence and mortality in China, Chen [/bib_ref]. Hepatic pathology is a foundational subject in the field of hepatic surgery, the preferred firstline treatment for PLC. In an effort to ensure the accuracy of pathological diagnosis, a standardized process of pathological examination is required to provide a valuable frame of reference for the clinical assessment of the risk of postoperative recurrence, longterm prognosis, as well as individualized treatment regimens. However, most current practice guidelines for PLC focus on the clinical treatment [bib_ref] Hepatocellular carcinoma: clinical frontiers and perspectives, Bruix [/bib_ref]. To our best knowledge, no consensus guidelines for the pathological diagnosis of PLC have ever been published. The lack of such guide lines has led to many contradictions and inconsistencies in the pathological characteristics and diagnostic criteria for PLC. To address this gap, Chinese pathologists developed an expert consensus on the pathological diagnosis of PLC in 2010 [bib_ref] Expert consensus on the scheme of pathological diagnosis of primary liver cancer, Cong [/bib_ref]. Since the development of these guidelines, much progress in the clinical management and pathological assessment of PLC has yielded many new concepts, such as tumor heterogeneity, pathobiological chara cteristics, molecular classification, personalized therapy and precision medicine, etc. The inclusion of these new concepts has become the cornerstone for the clinical management of PLC, placing greater demands on more stringent criteria and standards for hepatic pathological diagnosis. Therefore, in , under the guidance of renowned academicians Prof. Wu MengChao, Prof. Tang Zhaoyou and Prof. Liu TongHua, a Guideline Committee consisting of 40 specialists (supplementary materials) from Chinese Pathology, Surgery, Hepatology and Oncology Societies was created for the formulation of updated guidelines for the standardization of the pathological diagnosis of PLC. The principal goals of the Guideline Committee include (1) incorporating the results of worldwide clinicopathological studies in PLC over the past 5 years according to the Evaluation Criteria of Grades of Evidence recommended by the American Association for the Study of Liver Diseases guideline [fig_ref] Table 1: Grades of evidence and classes of recommendations [/fig_ref] [bib_ref] AASLD clinical practice guidelines: a critical review of scientific evidence and evolving..., Koh [/bib_ref] ; (2) accepting the comments and suggestions of experts in hepatic pathology, surgery and oncology; (3) responding to the clinical concerns for improving the therapeutic efficacy for PLC; and (4) creating guidelines for the standardized pathological diagnosis of PLC. To meet these goals, the Guideline Committee organized several seminars for guideline formulation, mainly focusing on the following topics: gross specimen sampling, concepts and diagnostic criteria of small HCC (SHCC), microvascular invasion (MVI), satellite nodules, immunohistochemical and molecular diagnosis. The final version of the 2015 guidelines was approved at the last Guideline Committee meeting, which was held in February 1, 2015 in Shanghai, China. ## General pathology ## Sample collection, fixation and processing Peritumoral zones are representative of tumor heterogeneity in that they are rich in highly invasive cells, susceptible to the formation of MVI and satellite nodules and, therefore, more likely to impact liver cancer metastasis, postoperative recurrence and prognosis [bib_ref] Hepatocellular carcinoma expressing cholangiocyte phenotype is a novel subtype with highly aggressive..., Lu [/bib_ref] [bib_ref] Prognostic significance of mast cell count following curative resection for pancreatic ductal..., Cai [/bib_ref]. Therefore, sampling around the periphery of tumor tissues is critical for objectively evaluating the biological behaviors of PLC. Specifically, a 7-point baseline sample collection protocol is recommended [fig_ref] Figure 1: Specimen sampling sites [/fig_ref]. (1) At least four tissue specimens should be sampled at the junction of the tumor and adjacent liver tissues in a 1:1 ratio at the 12 (A), 3 (B), 6 (C) and 9 (D) o'clock positions; (2) for the purpose of molecular pathological examination, at least one specimen should be sampled at the intratumoral zone (E), but more specimens should be sampled for tumors harboring different textures or colors; (3) specimens should be sampled from both adjacent peritumoral liver tissues (F, ≤ 1 cm from the tumor capsule) and distant peritumoral liver tissues (G, > 1 cm from the tumor capsule) or the tumor margin in order to observe MVI, satellite nodules and dysplastic foci/nodules distributed throughout the background liver tissues; and (4) Tissue blocks should be approximately 1.5 cm 2.0 cm × 1.0 cm × 0.3 cm in size and marked according to their sampling sites. Regarding tissue fixation, the following reco mmendations were made to assure the quality of the tissues for pathological and immunopathological examination [bib_ref] A review of preanalytical factors affecting molecular, protein, and morphological analysis of..., Bass [/bib_ref]. (1) The surgeons should fill an Application Form of Pathological Examination describing the clinical diagnosis, location and type of lesions and number of tissues. The surgical margin, suspected lesions, important vessels and bile duct margin Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation, procedure, or treatment is beneficial, useful, and effective Ⅱ Conditions for which there is conflicting evidence and/or divergence of opinion about the usefulness/efficacy of a diagnostic evaluation, procedure, or treatment Ⅱa Weight of evidence/opinion is in favor of the usefulness/efficacy Ⅱb Usefulness/efficacy is less well-established by evidence/opinion Ⅲ Conditions for which there is evidence and/or general agreement that a diagnostic evaluation/procedure/treatment is not useful/effective and in some cases, may be harmful Health Organization (WHO), ICCs are classified as massforming, periductalinfiltrating, and intraductal growth. [formula] A B E C D F G ≤ 1 c m > 1 cm [/formula] Although some studies considered that patient outcomes might not be impacted as tumors reach > 5 cm in size [bib_ref] Above 5 cm, size does not matter anymore in patients with hepatocellular..., Lim [/bib_ref] , discerning the presence of SHCC is important in the early diagnosis and therapy initiation for patients with liver cancer as it is a key step in the development and progression of HCC. However, the definition of SHCC varies greatly by international criteria from 2 cm to 5 cm in diameter [bib_ref] Above 5 cm, size does not matter anymore in patients with hepatocellular..., Lim [/bib_ref]. Studies indicating that HCC growing near to or larger than 3 cm in diameter is an important turning point in the transformation of a tumor from having relatively benign features to more aggressive behaviors [bib_ref] Small hepatocellular carcinoma: current and future approaches, Cong [/bib_ref] [bib_ref] Pathobiological features of small hepatocellular carcinoma: correlation between tumor size and biological..., Lu [/bib_ref]. Furthermore, the unique genetic changes in those SHCC ≤ 3 cm in diameter during the early stage have been reported [bib_ref] Methylation of multiple genes as molecular markers for diagnosis of a small,..., Moribe [/bib_ref] [bib_ref] A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in..., Llovet [/bib_ref]. More data indicated that patients with tumors > 3 cm have an increased risk for MVI, satellite nodules, as well as poor prognosis [bib_ref] Pathobiological features of small hepatocellular carcinoma: correlation between tumor size and biological..., Lu [/bib_ref] [bib_ref] Efficacy of anatomic resection vs nonanatomic resection for small nodular hepatocellular carcinoma..., Ueno [/bib_ref]. Specifically, the overall postoperative 5year survival and recurrencefree survival of patients with SHCC ≤ 3 cm are 67.8% and 52%, respectively, which are significantly higher than that of 42.3% and 29.3% in patients with HCC > 3 cm, respectively (P < 0.001) [bib_ref] Pathobiological features of small hepatocellular carcinoma: correlation between tumor size and biological..., Lu [/bib_ref]. Moreover, up to now, most studies on patients with SHCC ≤ 2 cm are based on multicenter joint studies with longterm data collection because too few surgical cases in a single center exist. At present, there are almost no systematic studies or knowledge based on a large series of cases that describe the pathobiological characteristics of SHCC ≤ 2 cm [bib_ref] Small hepatocellular carcinoma: current and future approaches, Cong [/bib_ref] [bib_ref] A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in..., Llovet [/bib_ref] [bib_ref] Early and very early hepatocellular carcinoma: when and how much do staging..., Farinati [/bib_ref]. ## Recommendations: (1) SHCC of ≤ 3 cm is frequently welldifferentiated with expansive growth, and has a low risk for MVI and satellite nodules [bib_ref] Pathobiological features of small hepatocellular carcinoma: correlation between tumor size and biological..., Lu [/bib_ref] , which is suggestive of a relatively benign biological behavior in the progression to malignancy and is the basis of radical therapy. Thus, radical therapy should be initiated at an early stage before the tumor becomes highly invasive (B, I); and (2) in a small number of cases, SHCC may be poorly differentiated, invasive, or containing MVI and satellite nodules, which is indicative of highly malignant behavior. Given the heterogeneity of HCC, complete sampling of SHCC ≤ 3 cm should be performed to assess its biological behavior, and in surgical practice, therapeutic borders should also be preserved, even in SHCC (B, I). ## Description of microscopic characteristics Previous studies have described the analysis of microscopic tissue characteristics that include the following: (1) histological types of HCC, including common histological types (e.g., thin trabecular type, thick trabecular type, pseudoglandular type, compact type and fibrolamellar type, etc); (2) HCC cell type (e.g., clear cell type, lipidrich type, spindle cell type and undifferentiated type, etc); (3) differentiation state should be marked with a dye or suture by surgeons. Small resected tissues, such as lymph nodes, should be placed into different containers and labeled with corresponding descriptions; (2) to maximally preserve the integrity of intracellular nucleic acids and proteins for avoiding autocytolysis, tumor specimens should be transferred to the Department of Pathology as soon as possible after resection, ideally within 30 min after surgical removal for sectioning and fixation; (3) the fresh specimens should be cut consecutively into 1cm thick multiple sections at the maximal diameter; a portion should remain unfixed fresh or cryopreserved for molecular examination; and (4) at room temperature, tissues should be fixed in a neutral formalin solution (v:v, 1:4-5) for 12-24 h and embedded in paraffin. Sections of 5μm thickness should be cut from each block and stained with hematoxylin and eosin for histological examination. Recommendations: (1) Hepatic tumor samples should be collected using the 7point baseline sampling protocol; (2) the location and number of liver tissues collected should be determined as appropriate according to the size, shape and number of the liver tumors as well as the adjacent liver tissues; (3) because the detection rate of MVI and satellite nodules is related to the extent of adjacent liver tissues, it is necessary to describe the size of the adjacent liver tissues, and the suspected lesions should be sampled after reviewing several sections (C, I); and (4) when the tumor tissue is close to the surgical margin, sampling should be done at the region vertical to the margin closest to the cancer. When the tumor tissue is far away from the surgical margin, sampling should be done parallel to the surgical margin. The status of the surgical margin should be determined using the section with maximal area (C, I). ## Description of macroscopic characteristics and clinical significance of shcc In the description of general hepatic tissue chara cteristics, pathologists should emphasize the size, number, color and texture of the tumor, its relationship with blood vessels and the bile duct, tumor capsule, tumor involvement, peripheral liver lesions, type of hepatic cirrhosis, the shortest distance between the tumor and surgical margin, and the status of the surgical margin. For tumor tissues with atypical morphology, the tissues should be photographed. Gross classification of HCC may reference the criteria developed by the Chinese Pathology Working Group for Liver Cancer [bib_ref] Pathology of Hepatocellular Carcinoma, Ying [/bib_ref] , and the Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2011 Edition) proposed by the Chinese Minister of Health , in which a single tumor ≤ 1 cm in diameter is defined as microtumor, and a single tumor from > 1 cm to ≤ 3 cm in diameter is defined as SHCC. According to the classification system proposed by the World of HCC as assessed by the EdmondsonSteiner four grading system; (4) the area and severity of tumor necrosis (e.g., interventional therapy), lymphocyte infiltration and interstitial fibrosis; (5) adenocarcinoma is the most common histological type of ICC, although it may also present in other special histological and cell types and its differentiation degree can be classified as well, intermediate and poor; (6) tumor growth patterns, including peritumoral invasion, capsule invasion, MVI and satellite nodules; and (7) the presence of chronic liver disease, such as chronic hepatitis or hepatic cirrhosis. Although there are many systems for grading and staging chronic viral hepatitis , a simple histologic scoring system is recommended for routine pathological diagnosis, such as the Scheuer scoring system, etc. Further more, Masson's trichrome staining and reticular fiber staining can be routinely undertaken to assess the degrees of hepatic fibrosis and lobule reconstruction, respectively [bib_ref] Comparison of Histochemical Staining Methods and Correlation with Transient Elastography in Acute..., Cabibi [/bib_ref]. ## Description of precancerous lesions The main types of precancerous HCC lesions include the following [bib_ref] Advanced precancerous lesions in the liver, Tommaso [/bib_ref] : liver cell dysplasia, dysplastic foci, lowgrade dysplastic nodule (LGDN), and highgrade dysplastic nodule (HGDN). Liver cell dysplasia refers to either large cellular changes, including increased cellular and nuclear volumes, nuclear pleomorphism, hyperchromatic chromatin and multinucleation, and small cellular changes, including decreased cell volume, increased nucleartocytoplasm ratio with mild pleomorphism and hyperchromasia, but showing crowded nuclei. Dysplastic foci are lesions that are ≤ 1.0 mm in diameter and commonly composed of hepatocytes with small cell changes. LGDN is a nodule mainly comprising large cellular changes without obvious atypia, isolated interstitial arteries, or expansive growth patterns. In contrast, HGDN is composed of small cellular changes with increased atypia, isolated interstitial arteries, and expansive growth. "Noduleinnodule" is used to describe a focal malignant lesion occurring within a HGDN. According to the WHO classification system, hepatocellular adenoma (HCA) can be classified into four molecular pathological subtypes, including hepatocyte nuclear factor 1 αinactivated HCA, βcateninactivated HCA, inflammatory HCA and unclassified HCA, among which, βcateninactivated HCA may have a higher risk of malignant transformation [bib_ref] Advanced precancerous lesions in the liver, Tommaso [/bib_ref]. The main types of precancerous lesions in ICC include biliary intraepithelial neoplasia (BilIN) and intraductal papillary biliary neoplasm (IPBN), as well as others. BilIN is usually graded as BilIN1 (low grade lesions), BilIN2 (intermediategrade lesions), and BilIN3 (highgrade lesions or carcinoma in situ), according to the degree of nuclear atypia observed in biliary epithelial cells. IPBN refers to tubular papillary tumors with growth confined to the bile duct lumen. In addition, IPBN may have BilIN with different grades. Along with BilIN and IPBN, other types of precancerous lesions in ICC include mucinous cystic neoplasms and biliary hamartomas harboring a high degree of BilIN, which may also correlate with increased risk of ICC. Recommendations: It is important to conduct a differential diagnosis between HGDN and well differentiated SHCC, the latter of which may manifest morphologically as varying degrees of increased cellular density and nucleartocytoplasmic ratio, widened trabecular space, pseudoglandular structures, infiltrative growth, increased MVD as assessed by CD34 staining, higher Ki67 index, and positive expression of p53 and glypican3 (GPC3), etc (B, I). ## Pathological diagnosis of mvi MVI is also known as microvascular cancer embolus and refers to the cancer cell nest in vessels lined with endothelial cells. The incidence of MVI in liver cancer patients ranges from 15% to 57.1% [bib_ref] A systematic review of microvascular invasion in hepatocellular carcinoma: diagnostic and prognostic..., Rodríguez-Perálvarez [/bib_ref] , which may be partly ascribed to differences in the sample collection protocol and diagnostic criteria between studies. MVI is most frequently found in the small branches of the portal vein in the adjacent liver tissues (including vessels of the cancer capsule) because these vessels are the major ones exiting the tumor, as the portal vein shows disordered hemodynamics [bib_ref] Pathologic and radiographic studies of intrahepatic metastasis in hepatocellular carcinoma; the role..., Toyosaka [/bib_ref] [bib_ref] Intrahepatic metastases in hepatocellular carcinoma: evidence for spread via the portal vein..., Toyosaka [/bib_ref]. Branches of the hepatic vein are the secondary vessels exiting the tumor and may also develop MVI. Occasionally, the hepatic tumor may invade the hepatic artery, bile duct and lymphatic vessels, which should be reported independently [bib_ref] A systematic review of microvascular invasion in hepatocellular carcinoma: diagnostic and prognostic..., Rodríguez-Perálvarez [/bib_ref] [bib_ref] Predictor for histological microvascular invasion of hepatocellular carcinoma: a lesson from 229..., Eguchi [/bib_ref]. To differentiate the vascular nature of the tumor, immunohistochemistry may be performed to examine the expression of CD34 (vascular endothelium), smooth muscle αactin (vascular smooth muscle), elastic fibers (elastic fiber layer of tiny blood vessel wall) and D240 (lymphatic endothelium). Clinical studies indicate that MVI is related to poor prognosis in patients with HCC, including increased risk for postoperative recurrence and reduced longterm survival. In patients with HCC, a correlation between higher MVI grade and shorter disease-specific survival and recurrencefree survival has been noted [bib_ref] The significance of classifying microvascular invasion in patients with hepatocellular carcinoma, Sumie [/bib_ref]. [bib_ref] A systematic review of microvascular invasion in hepatocellular carcinoma: diagnostic and prognostic..., Rodríguez-Perálvarez [/bib_ref]. A similar correlation between MVI and poor prognosis was also observed in patients with SHCC of ≤ 3 cm [bib_ref] Microvascular invasion (MVI) is a poorer prognostic predictor for small hepatocellular carcinoma, Du [/bib_ref]. Furthermore, Pawlik et al [bib_ref] Tumor size predicts vascular invasion and histologic grade: Implications for selection of..., Pawlik [/bib_ref] found that the occurrence of MVI was positively correlated with the size of HCC, suggesting that the size and number of tumors are important predictive indices for MVI. Furthermore, Roayaie et al [bib_ref] A system of classifying microvascular invasion to predict outcome after resection in..., Roayaie [/bib_ref] found that vascular smooth muscle involvement of MVI and > 5 MVIs were closely related Cong WM et al . Pathological guidelines of primary liver cancer to postoperative recurrence, and MVI located > 1 cm away from the adjacent liver tissues was associated with postoperative survival [bib_ref] New Pathologic Stratification of Microvascular Invasion in Hepatocellular Carcinoma: Predicting Prognosis After..., Iguchi [/bib_ref]. There is also evidence showing that the presence of ≥ 50 loosely suspended cancer cells in MVI is closely related to the prognosis of patients with PLC. In contrast, the presence of < 50 loosely suspended cells in the lumen should be described in the report sheet and may be indicative of a low risk for recurrence [bib_ref] Pathologic and radiographic studies of intrahepatic metastasis in hepatocellular carcinoma; the role..., Toyosaka [/bib_ref]. ## Recommendations MVI is an independent prognostic marker for HCC patients (A, I); therefore, its presence should be evaluated in all tissue sections and graded according to the risk stratification based upon the number and distribution as follows: M0: no MVI; M1 (lowrisk): MVI of < 5 and at ≤ 1 cm away from the adjacent liver tissues; and M2 (highrisk): MVI of > 5 or at > 1 cm away from the adjacent liver tissues (B, I). ## Pathological diagnosis of satellite nodules Satellite nodules refer to the macroscopic or micro scopic tumor cell nests located around or near, but separated from the main tumor with similar histological features as observed in the primary tumor. Generally, satellite nodules are derived from MVI. While difficult to distinguish from each other histologically, a diagnosis of satellite nodules is appropriate. Studies show that the maximum micrometastasis spread distance (MMSD) in the distal area was < 3 cm in 92.3% of HCCs, and the MMSD in the proximal edge was < 1.5 cm in 91.7% of HCCs, suggesting that this area is important for pathological diagnosis and therapy. Lim et al [bib_ref] Above 5 cm, size does not matter anymore in patients with hepatocellular..., Lim [/bib_ref] found that the incidence of satellite nodules was 7% and 23% in patients with HCC of < 5 cm and > 5 cm, respectively, indicating that satellite nodules were a factor predicting poor overall survival. Moreover, the presence of satellite nodules is also an important predictor of postoperative recurrence. The presence of MVI and satellite nodules may also provide a reference for the selection of clinical therapeutic modules. For example, Meniconi et al [bib_ref] Recurrent hepatocellular carcinoma: a Western strategy that emphasizes the impact of pathologic..., Meniconi [/bib_ref] found that in the absence of MVI and satellite nodules in the first resected HCC, a second hepatectomy or radiofrequency ablation for early intrahepatic recurrence predicted a better overall survival as compared to hepatic arterial chemoembolization. ## Recommendations Pathological diagnosis of satellite nodules should include the following pathological parameters [bib_ref] Satellite lesions in patients with small hepatocellular carcinoma with reference to clinicopathologic..., Okusaka [/bib_ref] : (1) number; (2) distribution and extent; and (3) presence of cancerous nodes in the distant adjacent liver tissues, including multinodular HCC (MNHCC), which may represent either intrahepatic metastases or de novo HCC arising from a polycentric origin. Molecular cloning detection may then be helpful to elucidate the origin of the satellite nodules (B, I). ## Processing of liver tissues ## Collected by liver biopsy Regarding the diagnosis of hepatic spaceoccupying lesions, a 16gauge puncture needle is usually used to obtain a biopsy specimen containing junctional areas between the tumor and peritumoral zones or one from each zone. A relatively longer biopsy sample is required for the assessment of the degree of hepatic fibrosis or cirrhosis in the setting of chronic viral hepatitis. The appropriate tissue length should be longer than 1.5 cm and fixed with 10% neutral buffered formalin for 12 h, and ≥ 6 intermittent and consecutive sliced tissue sections should be placed on each slide for pathological evaluation [bib_ref] Liver biopsy, Rockey [/bib_ref]. ## Immunohistochemical diagnosis For HCC, commonly used immunohistochemical markers for diagnosis include hepatocyte paraffin-1 (Hep Par-1), GPC3, CD34, polyclonal carcinoembryonic antigen (pCEA), CD10, arginase1, heat shock protein70, and glutamine synthetase [bib_ref] Tumors of the liver and intrahepatic bile ducts, Cong [/bib_ref] [bib_ref] Arginase-1 is a novel immunohistochemical marker of hepatocellular differentiation, Ordóñez [/bib_ref]. Although Hep Par1, CD10, arginase1 and pCEA are hepatocyte specific antigens, they cannot be used to distinguish benign and malignant hepatocellular tumors [bib_ref] Tumors of the liver and intrahepatic bile ducts, Cong [/bib_ref]. For the immunohistochemical diagnosis of ICC, staining with antibodies specific for biliary cytokeratins, such as CK19, CK7 and mucin1, is commonly employed. The diagnosis of dual phenotype HCC (DPHCC), a new highly aggressive subtype of HCC, is generally characterized by the expression of both HCC and ICC biomarkers [bib_ref] Hepatocellular carcinoma expressing cholangiocyte phenotype is a novel subtype with highly aggressive..., Lu [/bib_ref] [bib_ref] Keratin 19: a key role player in the invasion of human hepatocellular..., Govaere [/bib_ref] , and the diagnosis of DPHCC can only be made by immunohistochemical detection. Although some reported biomarkers may aid in the evaluation and prediction of certain biological features of liver cancer, including risk for invasiveness, recurrence and longterm survival [bib_ref] Upregulated FoxM1 expression induced by hepatitis B virus X protein promotes tumor..., Xia [/bib_ref] [bib_ref] SUOX is a promising diagnostic and prognostic biomarker for hepatocellular carcinoma, Jin [/bib_ref] , but further studies are required to confirm their clinical importance in multiple patient populations. ## Recommendations (1) Currently used biomarkers for liver cancer are somewhat imperfect in their diagnostic specificity and sensitivity; thus, a biomarker panel in combination with other tissuespecific markers could represent a useful tool for diagnosis and differential diagnosis between benign and malignant hepatocellular tumors, HCC and ICC, other specific types of hepatic tumors, and primary and metastatic liver cancer (B, I); and (2) although immunohistochemical staining for CD34 does not directly label hepatic parenchymal cells, it is valuable for determining the extent of MVD and examining its unique distribution pattern in different liver tumors. For instance, a diffuse staining pattern is indicative for HCC, a scattered staining pattern for ICC, a patchy staining pattern for HCA, and a cordlike staining pattern for focal nodular hyperplasia, etc (B, I). ## Molecular pathological diagnosis Development of molecular classification techniques, including the detection of molecular targets and assessment of clonal origin, represents a promising new development in the field. Although many new systems based on molecular typing and predictive biomarkers have been reported in the literature [bib_ref] Deciphering cancer heterogeneity: the biological space, Roessler [/bib_ref] , validation of their clinical significance is still required through the use of controlled studies across multiple centers with large sample sizes. Specifically, the selection, detection and clinical significance of molecular targets for targeted drug therapy for PLC are still under investigation, but the results of preliminary clinical trials are worthy of high expectations [bib_ref] MicroRNA-26a suppresses angiogenesis in human hepatocellular carcinoma by targeting hepatocyte growth factor-cMet..., Yang [/bib_ref]. Regarding risk evaluation of precancerous lesions, molecular identification may be better suited than histopathological evaluation to detect the genomic instability for hepatocarcinogenesis and impact of clinical treatment modalities for patients with precancerous lesions, such as HGDN and HCA [bib_ref] Molecular pathogenesis of hepatic adenomas and its implications for surgical management, Liau [/bib_ref]. Molecular pathology detection is conducive to optimization and choice of clinical treatment modalities. Postoperative recurrence of HCC (RHCC) seriously restricts the longterm curative effect of HCC treat ments. Based on the clonal origin theory, a RHCC may originate from either a monocentric (monoclonal) origin or multicentric (polyclonal) origin. Theoretically, interventional therapy and targeted drug therapy are more suitable for RHCC that originate from residual cancer cells (monoclonal origin) after initial tumor resection, while repeated resections or liver transplantation are more appropriate for RHCC of multicentric origin that resembles a new primary tumor arising from a de novo tumor clone [bib_ref] Determination of clonal origin of recurrent hepatocellular carcinoma for personalized therapy and..., Wang [/bib_ref]. However, due to longterm "latency" and "dormancy" of residual cancer cells left in the liver after resection, monoclonal recurrence may occur even in the socalled "late period" (> 2 years) after surgical resection, clinically coinciding with a special period for RHCC derived from multicentric origins. Although other researchers have proposed histological criteria for the clonal evaluation of RHCC [bib_ref] Multicentric occurrence of hepatocellular carcinoma: diagnosis and clinical significance, Matsumoto [/bib_ref] , the accuracy of such morphological criteria requires further validation of the molecular detection. The clonal origin theory of RHCC is also applicable to MNHCC. Finkelstein et al [bib_ref] Microdissection-based allelotyping discriminates de novo tumor from intrahepatic spread in hepatocellular carcinoma, Finkelstein [/bib_ref] reported that posto perative survival after LT was significantly better in patients with multicentric MNHCC than in those with monocentric MNHCC, indicating that genotyping has the potential to serve as a reference for LT recipient screening and prognostic evaluation. Gehrau et al [bib_ref] Molecular classification and clonal differentiation of hepatocellular carcinoma: the step forward for..., Gehrau [/bib_ref] also recommended a diagnostic and therapeutic roadmap based on the clonal detection of MNHCC that would assist with patient selection for LT. Specifically, patients with MNHCC derived from multicentric origins could be ranked in the waiting lists to receive a LT, while those patients with monocentric MNHCC would be better suited for interventional treatment or targeted drug therapy using sorafenib [bib_ref] Molecular classification and clonal differentiation of hepatocellular carcinoma: the step forward for..., Gehrau [/bib_ref]. ## Recommendation Evaluating the clonal origins of RHCC and MNHCC is vital to developing individualized therapeutic regimens and subsequently improving longterm clinical outcomes. Therefore, assessing the clonal origins of RHCC and MNHCC using molecular cloning methods may provide objective references for the formulation of individualized therapy plans (B, I). # Conclusion A standardized pathological diagnostic process is the first precondition required for a correct pathological diagnosis, scientific clinical decisionmaking and precision treatment of PLC from the origin. Considering the high prevalence of PLC worldwide, especially in China, we report updated guidelines for pathological diagnosis of PLC, which includes standardized guidelines for specimen fixation, 7point baseline sampling protocol and examination, a grading system for MVI in a routine pathology diagnosis, and immunohistochemical diagnostic panels, as well as molecular diagnostic principles, such as the importance of clonal typing of RHCC and MNHCC for determining therapeutic strategy and evaluating clinical prognosis. [fig] Figure 1: Specimen sampling sites. [/fig] [table] Table 1: Grades of evidence and classes of recommendations [/table]	None	None	In 2010, a panel of Chinese pathologists reported the first expert consensus for the pathological diagnosis of primary liver cancers to address the many contradictions and inconsistencies in the pathological characteristics and diagnostic criteria for PLC. Since then considerable clinicopathological studies have been conducted globally, prompting us to update the practice guidelines for the pathological diagnosis of PLC. In April 18, 2014, a Guideline Committee consisting of 40 specialists from seven Chinese Societies (including Chinese Society of Liver Cancer, Chinese Anti-Cancer Association; Liver Cancer Study Group, Chinese Society of Hepatology, Chinese Medical Association; Chinese Society of Pathology, Chinese Anti-Cancer Association; Digestive Disease Group, Chinese Society of Pathology, Chinese Medical Association; Chinese Society of Surgery, Chinese Medical Association; Chinese Society of Clinical Oncology, Chinese Anti-Cancer Association; Pathological Group of Hepatobiliary Tumor and Liver Transplantation, Chinese Society of Pathology, Chinese Medical Association) was created for the formulation of the first guidelines for the standardization of the pathological diagnosis of PLC, mainly focusing on the following topics: gross specimen sampling, concepts and diagnostic criteria of small hepatocellular carcinoma (SHCC), microvascular invasion (MVI), satellite nodules, and immunohistochemical and molecular diagnosis. The present updated guidelines are reflective of current clinicopathological studies, and include a novel 7-point baseline sampling protocol, which stipulate that at least four tissue specimens should be sampled at the junction of the tumor and adjacent liver tissues in a 1:1 ratio at the 12, 3, 6 and 9 o’clock reference positions. For the purposes of molecular pathological examination, at least one specimen should be sampled at the intratumoral zone, but more specimens should be sampled for tumors harboring different textures or colors. Specimens should be sampled at both adjacent and distant peritumoral liver tissues or the tumor margin in order to observe MVI, satellite nodules and dysplastic foci/nodules distributed throughout the background liver tissues. Complete sampling of whole SHCC ≤ 3 cm should be performed to assess its biological behavior, and in clinical practice, therapeutic borders should be also preserved, even in SHCC. The diagnostic criteria of MVI and satellite nodules, immunohistochemical panels, as well as molecular diagnostic principles, such as clonal typing, for recurrent HCC and multinodule HCC were also proposed and recommended. The standardized process of pathological examination is aimed at ensuring the accuracy of pathological PLC diagnoses as well as providing a valuable frame of reference for the clinical assessment of tumor invasive potential, the risk of postoperative recurrence, long-term survival, and the development of individualized treatment regimens. The updated guidelines could ensure the accuracy of pathological diagnoses of PLC, and provide a valuable frame of reference for its clinical assessment.
22d550e8ff8d412258f17f8e7ce8172cbf181358	pubmed	Optimizing the Management and Outcomes of Failed Back Surgery Syndrome: A Consensus Statement on Definition and Outlines for Patient Assessment	Optimizing the Management and Outcomes of Failed Back Surgery Syndrome: A Consensus Statement on Definition and Outlines for Patient Assessment Failed back surgery syndrome (FBSS) is a controversial term for identifying patients affected by new, recurrent, or persistent pain in the low back and/or legs following spinal surgery. e lack of a comprehensive standardized care pathway compromises the appropriate management of FBSS patients, which is associated with a heavy financial burden. An international panel of spine surgeons, neurosurgeons, and pain specialists with a particular interest in FBSS established the chronic back and leg pain (CBLP) network with the aim of addressing the challenges and barriers in the clinical management of FBSS patients by building a common transdisciplinary vision. Based on literature reviews, additional input from clinical expertise of multiple professional disciplines, and consensus among its members, the network attempted to provide recommendations on the management of patients with FBSS utilizing a multidisciplinary team (MDT) approach. e presentation of this work has been divided in two separate parts to enhance its clarity. is first paper, in favour of selecting appropriate validated tools to improve the FBSS patient assessment, focuses on FBSS taxonomy and its clinical implications for evaluation. Concise recommendations for assessment, treatment, and outcome evaluation using a MDT approach would be an important resource for specialists and nonspecialist clinicians who manage patients with FBSS, to improve decision-making, reduce variation in practice, and optimize treatment outcomes in this difficult-to-treat population. # Introduction Failed back surgery syndrome (FBSS) is a subcategory of a broader group of pain conditions referred to as chronic back and leg pain (CBLP) [bib_ref] From "mechanical" to "neuropathic" back pain concept in FBSS patients. A systematic..., Blond [/bib_ref]. e majority of published definitions for FBSS include new, recurrent, or persistent pain in the back and/or legs following spinal surgery [bib_ref] Failed back surgery syndrome, Long [/bib_ref] [bib_ref] e failed back surgery syndrome": definition and therapeutic algorithms-an update, Buyten [/bib_ref] [bib_ref] Failed back surgery syndrome-definition, epidemiology and demographics, Omson [/bib_ref] [bib_ref] Failed back surgery syndrome: what's in a name? A proposal to replace..., Rigoard [/bib_ref] [bib_ref] Prevalence, characteristics, and burden of failed back surgery syndrome: the influence of..., Inoue [/bib_ref] [bib_ref] Failed back surgery syndrome, Chan [/bib_ref] , with an incidence estimated to be around 20% in the most recent publications on this topic [bib_ref] Incidence of low back pain after lumbar discectomy for herniated disc and..., Parker [/bib_ref] [bib_ref] e incidence and healthcare costs of persistent postoperative pain following lumbar spine..., Weir [/bib_ref]. is is a complex condition with a complicated pathophysiology comprising various aetiologies and pain characteristics that negatively impact function, behaviour, and mental and social well-being [bib_ref] From "mechanical" to "neuropathic" back pain concept in FBSS patients. A systematic..., Blond [/bib_ref] [bib_ref] Failed back surgery syndrome: what's in a name? A proposal to replace..., Rigoard [/bib_ref] [bib_ref] Pathophysiological characterisation of back pain generators in failed back surgery syndrome (part..., Rigoard [/bib_ref] [bib_ref] Failed back surgery syndrome: who has failed?, Kaisy [/bib_ref]. Use of the term FBSS has provoked decades of controversy because of a lack of consensus for a single definition and the inherently restrictive and confusing meaning of this acronym, implying unsuccessful treatment with connotations of blame aimed towards the surgery [bib_ref] Failed back surgery syndrome: who has failed?, Kaisy [/bib_ref]. A diverse nomenclature has consequently been developed over the last three decades. "Postlaminectomy syndrome" [bib_ref] Failed back surgery syndrome, Long [/bib_ref] [bib_ref] Low back pain and the post-laminectomy pain syndrome, Shipton [/bib_ref] , "rebound radicular syndrome" [bib_ref] Hyaluronidase in the management of pain due to post-laminectomy scar tissue, Borg [/bib_ref] , "postoperative persistent pain syndrome" [bib_ref] Failed back surgery syndrome: what's in a name? A proposal to replace..., Rigoard [/bib_ref] , and "chronic postsurgical pain"have been proposed as replacements for FBSS. e complexity of FBSS suggests that a multidisciplinary strategy to patient assessment, treatment, and therapy evaluation is important for optimization of outcomes [bib_ref] Interventional pain management for failed back surgery syndrome, Hussain [/bib_ref] [bib_ref] Medical management of failed back surgery syndrome in Europe: evaluation modalities and..., Durand [/bib_ref] [bib_ref] Failed back surgery syndrome: current perspectives, Baber [/bib_ref] [bib_ref] Multimodale therapiekonzepte beim postnukleotomiesyndrom, Casser [/bib_ref] , but no consensus has been clearly defined yet. An international panel of clinicians with a special interest in FBSS established the chronic back and leg pain (CBLP) network and set a list of precise objectives to bridge this gap. e purpose of this paper is to (i) delineate a clear definition of FBSS and specify the criteria for appropriate diagnosis and (ii) suggest recommended treatment evaluation tools to validate and standardize a care pathway for this patient group. # Materials and methods ## E chronic back and leg pain network constitution and Goals. To address the challenges and barriers in the management of patients diagnosed with FBSS, an international panel of clinical specialists with a specific interest in FBSS established the CBLP network in 2012. e main goals of the network were to provide consensus on (1) a definition of FBSS, (2) recommendations for validated tools to improve FBSS patient assessment and evaluation of treatment outcomes, and (3) a proposal for a standardized care pathway to support clinicians in their decision-making on how to manage patients with FBSS based on a MDT approach. Since FBSS remains a standardized subjective term assigned by indexers for both MeSH (MEDLINE/PubMed) and EMTREE (Embase) and since the proposition of a replacement term was not an objective of this paper, the CBLP network focused specifically on the definition of FBSS and patient evaluation and treatment. # Methodology. In order to achieve the set goals, the following methodology was used: (a) Participants in the CBLP panel were included based on their extensive clinical experience in managing FBSS patients with a focus on representation from the three specialties that are most involved in the treatment of this patient population: spine surgeons, neurosurgeons, and pain specialists, including anesthesiologists. Invitations were sent to potential participants and accepted prior to formal engagement. Formal face-to-face meetings were held annually between 2012 and 2016 with subsequent teleconferences for an additional feedback prior to drafting the manuscript. e meetings were chaired by a trained facilitator to help the consensus process. (b) Literature searches in PubMed, MEDLINE, LILACS, Embase, and the National Guideline Clearing House were conducted by two separate reviewers: one independent reviewer (GB) and one reviewer on the behalf of the clinical group (NN), on a regular basis up to September 2018, without any restrictions regarding language or year of publication. e search strategy was developed in order to maximise sensitivity of article identification, using controlled vocabulary and title/ abstract words combining variations of "Failed back surgery syndrome," "Back pain," "Chronic leg pain" with "Multidisciplinary" OR "Team," "Clinical pathway" OR "Practice guideline" OR "Algorithm" OR "Guideline" OR "Protocol," detailed here after. e independent reviewer (GB) performed a comprehensive electronic search of peer-reviewed full-text papers published between February 2, 2005, and February 21, 2018, in PubMed, MedLine, Embase, and the National Guideline Clearing House. Key words and terms pertaining to the condition (i.e., "failed back surgery syndrome," "low back pain," and "leg pain") were cross referenced with terms pertaining to reports presenting recommendations for MDT involvement in management (i.e., "interdisciplinary communication," "multidisciplinary" OR "multidisciplinary team" OR "multidisciplinary care" OR "patient referral") in relevant combinations. Handsearching of reference lists of identified reports and relevant review articles were also carried out. For the group reviewer (NN), the search strategy varied according to the database as follows: (i) Medline ("Failed back surgery syndrome" OR "Chronic Back pain" OR "Chronic leg pain") AND ("Definition" OR "Characterisation" OR "Characterization" OR "Evaluation") (ii) LILACS ("Failed back surgery syndrome" OR "Back pain") AND ("Definition") All references retrieved from databases were exported to Zotero where duplicates were discarded using the "find duplicates" tool. In addition, book chapters dealing with "FBSS," "postoperative low back pain," and the same controlled vocabulary used previously were initially identified from a systematic review of the electronic literature and of all pathophysiology, anatomy, and physiology textbooks available in the following medical libraries: e methodology is summarized in [fig_ref] Figure 1: Schematic diagram of steps in the literatures searches [/fig_ref]. (c) Additional input was provided by relevant clinical specialists (psychologist, psychiatrist, physiotherapist, and rehabilitation physician) involved in the multidisciplinary evaluation and treatment of patients with FBSS. (d) Consensus was defined as full agreement among the members of the CBLP network on the set goals which was achieved by face-to-face meetings with facilitated round table discussions focusing on the outcome of the literature overview, each member's personal experience, and input from additional clinical specialists. e consensus process did not include any ranking questionnaires based on the Delphi method since the number of participants was considered to be too small and the purpose of the discussions was not to measure consensus based on specific statements but to develop full consensus (resolve disagreement) on the set tasks [bib_ref] Qualitative Research: consensus methods for medical and health services research, Jones [/bib_ref]. [formula] (i) [/formula] # Results ## Definition of fbss. e CBLP network's proposed definition of FBSS is based on the prediction that no further spine surgery is indicated after an appropriate somatic, radiological, and psychosocial assessment [bib_ref] Failed back surgery syndrome: diagnostic evaluation, Guyer [/bib_ref]. e key elements for definition of FBSS can be summarized in 4 aspects: (1) Back and/or leg pain that persists for at least six months following the most recent spinal surgery (2) e patient has undergone a thorough clinical and radiological assessment (3) ere is no clear surgical target on clinical examination and imaging that is concordant with presenting symptoms (4) ere is interdisciplinary agreement that additional surgical intervention (decompression and/or fusion) is not appropriate It is important to ensure that the temporal relationship between the most recent surgery and the presentation of pain is explored adequately so that complications that are known to occur within the first six months of surgery (e.g., hardware failure, recurrent herniation, and infection, including discitis and abscess) can be identified and taken care of promptly [bib_ref] Failed back surgery syndrome: what's in a name? A proposal to replace..., Rigoard [/bib_ref]. As a consequence, our definition of FBSS is found on the generally accepted definition of chronic pain in the context of surgery as "pain that persists 6 months after an injury and beyond the usual course of an acute disease or a reasonable time for a comparable injury to heal" [bib_ref] Comprehensive review of epidemiology, scope, and impact of spinal pain, Manchikanti [/bib_ref]. ## Multidisciplinary approach in the management of fbss. Out of 12 pain-related guidelines or health technology assessments that were identified in the literature overview, nine recommended the practice of involving a MDT as the standard-of-care [bib_ref] Failed back surgery syndrome: who has failed?, Kaisy [/bib_ref] [bib_ref] Diagnosis and treatment of low back pain: a joint clinical practice guideline..., Chou [/bib_ref] [bib_ref] Practice guidelines for chronic pain management: an updated report by the American..., Benzon [/bib_ref] [bib_ref] Arbeitsgemeinschaft der Wissenschaftlichen medizinischen fachgesellschaften-association of scientific medical societies (AWMF), National disease..., Bundesärztekammer-German [/bib_ref]. Importantly, a previous metaanalysis of 41 randomized controlled trials (RCTs) (N � 6,858) yielded by a systematic literature review up to March 2014 revealed that a MDT approach was significantly more effective than usual care in reducing pain and disability in patients with chronic low back pain [bib_ref] Multidisciplinary biopsychosocial rehabilitation for chronic low back pain, Kamper [/bib_ref]. In a general statement about pain management, the International Association for the Study of Pain (IASP) recommended that, "clinicians who assess and treat patients in a pain center should include physicians, nurses, mental health professionals (e.g., clinical psychologist and psychiatrist), and physical therapists". However, many patients do not have access to a pain center, making access to a MDT challenging. To date, recommendations for the composition of a FBSS-specific MDT provided by governments and experts alike suggest the involvement of a neurologist, a rheumatologist, a pain physician, a spine surgeon, a neurospine surgeon, a functional neurosurgeon, a rehabilitation physician, a radiologist, a physiatrist, a pain nurse, and a psychologist/psychiatrist [bib_ref] Failed back surgery syndrome: who has failed?, Kaisy [/bib_ref] [bib_ref] Medical management of failed back surgery syndrome in Europe: evaluation modalities and..., Durand [/bib_ref]. Based on the literature review [fig_ref] Table 1: Output of the review of publications with recommendations for specialties to be... [/fig_ref] , additional specialist input and consensus among its members, the CBLP network recommends that a FBSS-oriented MDT should include five types of health professionals, reflecting the continuum of the FBSS patient care pathway: (i) One or several "pain physician(s)" (i.e., anaesthetist, rheumatologist, and neurologist) representing the cornerstone of professional interactions for the assessment and treatment of pain, focusing on optimizing medical and interventional management within the FBSS care pathway (ii) One or several rehabilitation physicians, physiotherapist(s), and/or physiatrist(s) to optimize physical examination and review potential rehabilitation strategies (iii) One or several psychologist(s) and/or psychiatrist(s) to focus on psychosocial aspects and supply ongoing psychological evaluation and support [bib_ref] Behavioural treatment for chronic low-back pain, Henschke [/bib_ref] [bib_ref] e effectiveness of cognitive behavioural treatment for non-specific low back pain: a..., Richmond [/bib_ref] (iv) One or several "spine surgeon(s)" (i.e., neurosurgeon and orthopaedic surgeon) supported by a radiologist to provide an ultimate spine expertise, making sure that no further surgery is required helping to characterize the pathophysiology of pain generators (v) One or several member(s) of a "neuromodulation team" (i.e., implanter/anaesthesiologist/neurosurgeon and pain/neuromodulation nurse) to evaluate the eligibility for neurostimulation/intrathecal drug delivery (IDD) therapies in the context of a refractory patient ## Initial mdt evaluation. e initial stage in the proposed care pathway by the CBLP network is based on MDT evaluation to confirm the FBSS diagnosis. With a specific reference to our definition of FBSS, the clinical work-up of a patient should include the following: (a) history to confirm the occurrence of prior spinal surgeries; (b) precise ## Physical Examination. It remains difficult to transpose a "mechanistic" concept based on pathophysiological evaluation of pain into daily practice. Nevertheless, this approach plays a critical role to better understand FBSS management. Several authors have tried to identify, from all of the findings of spine examination, those clinical signs that are predictive of a particular type of lesion (facet joint and discogenic or muscle pain, for example), taking into account pain typology (mechanical/neuropathic) [bib_ref] Failed back surgery syndrome: what's in a name? A proposal to replace..., Rigoard [/bib_ref]. is type of pathophysiological segmentation might be used to predict the quality and the magnitude of response to the various treatments proposed (classical response to opioids in nociceptive pain and efficacy of antiepileptic drugs or neurostimulation in neuropathic pain, for example). An emphasis on the spatial dimension concerning the topographic distribution of the pain should be incorporated into the concept of pathophysiological pain characterization. us, chronic leg pain persisting despite a surgical decompression might be frequently associated to a neuropathic pain component, while the pain characterization becomes much more complex when trying to interpret axial pain, where biomechanical and neuropathic components appear to be inseparable or difficult to isolate [bib_ref] From "mechanical" to "neuropathic" back pain concept in FBSS patients. A systematic..., Blond [/bib_ref]. Even though promoting strict dichotomy between the leg pain and the back pain components might be artificial, this clinical strategy can nevertheless guide the physician in the clinical evaluation. (1) e Leg Pain Component. e first step of leg pain clinical examination aims to confirm a radicular lesion mainly indicative of neuropathic pain and to eliminate pain due to another cause. e presence of sensory dysfunction (hypoesthesia, anesthesia, or allodynia) in the painful territory and/or motor deficit is suggestive of a nerve lesion and thus a neuropathic pain. Several diagnostic tools have been validated for neuropathic pain detection: DN4 (Douleur Neuropathique in 4 questions), LANSS (Leeds assessment of neuropathic symptoms and signs), or S-LANSS (simplified version) [bib_ref] Comparison of pain syndromes associated with nervous or somatic lesions and development..., Bouhassira [/bib_ref] [bib_ref] e S-LANSS score for identifying pain of predominantly neuropathic origin: validation for..., Bennett [/bib_ref]. e DN4 questionnaire, published in 2005, is easy to use in daily practice. It is composed of four questions comprising a total of seven items scored during the clinical interview and three items based on physical examination [bib_ref] Comparison of pain syndromes associated with nervous or somatic lesions and development..., Bouhassira [/bib_ref]. A score greater than or equal to 4/10 is pathognomonic of neuropathic pain with a sensitivity of 82.9% and a specificity of 89.9%. Shamji and Shcharinsky [bib_ref] Use of neuropathic pain questionnaires in predicting persistent postoperative neuropathic pain following..., Shamji [/bib_ref] recently stated that a positive DN4 questionnaire is a powerful predictor of spine (re)surgery failure. e presence of mechanical signs of disc-nerve root conflict (impulse pain, Lasègue's sign) suggests a physical conflict at the level of the disc (disc herniation recurrence and residual conflicting elements) or at the level of the foramen (foraminal stenosis and segmental spine instability) [bib_ref] Medical management of failed back surgery syndrome in Europe: evaluation modalities and..., Durand [/bib_ref] and requires a specific spine expertise. Hip, knee, and sacroiliac joints examination are important to avoid the classical diagnostic traps associated with pain of the anterior surface of the thigh or trunked S1 sciatica. A vascular examination has to be performed in case of intermittent claudication on walking. A careful palpation of the sciatic trunk eliminates a neurinoma and a piriformis syndrome at the gluteal region. (2) e Back Pain Component. In contrast to leg pain assessment, and before considering any potential neuropathic aspect of the back pain (first described by Attal et al. in 2011) [bib_ref] e neuropathic components of chronic low back pain: a prospective multicenter study..., Attal [/bib_ref] , clinical investigation of the back pain component in FBSS patients should be based on meticulous dissection of all potential mechanical triggers that could be a source of the nociceptive pain characteristics [bib_ref] Pathophysiological characterisation of back pain generators in failed back surgery syndrome (part..., Rigoard [/bib_ref]. Examination of the spine aims to assess the global posture and stability of the spine in the different planes. Meticulous palpation aims to identify a possible vertebral or paravertebral pain trigger point. e main focus of the back assessment is guided by a somatic diagnostic process using validated diagnostic rules [bib_ref] Clinical classification in low back pain: best-evidence diagnostic rules based on systematic..., Petersen [/bib_ref]. e key potential spinal pain generators, which need to (i) Muscle pain: the muscle trophicity may be compromised by chronic degeneration related to the initial spine pathology, by physical hypoactivity, and by repeated surgery, leading to potential and progressive instability of the vertebral column. A vicious circle can occur when biomechanical overloading (created by disease progression and/or hardware failure) causes displacements of the spine and induces new tensions. Results show increased impulse activity of muscle and tendon nociceptors establishing the neurophysiological basis of postoperative muscle pain. (ii) Facet joint pain and spinal instability: spine surgery induces major changes in the biomechanical loads on all surrounding structures: muscles, ligaments, discs, facet joints, fat tissues, and fascia. is mechanical loading redistribution occurs particularly in adjacent spinal segments, around the anterior or posterior instrumentation in case of stabilization [bib_ref] Pathophysiological characterisation of back pain generators in failed back surgery syndrome (part..., Rigoard [/bib_ref]. Foraminal residual stenosis can be responsible for persistent nerve entrapment, as mentioned above: anteriorly from vertebral spurs and posteriorly from facet arthritic changes. As a consequence, patient's symptoms can be linked to facet compensation syndrome [bib_ref] Low back pain of dorselumbar origin: surgical treatment of postérlor articular capsule..., Maigne [/bib_ref] , but isolating facets as the specific source of pain is difficult in FBSS patients. (iii) Discogenic pain: it is predominantly described as a deep midline low back pain with a bilateral metameric irradiation. Mechanical and positional in nature, the pain is generally worse when upright rather than supine. It is thought that this type of pain is generated by the visceral afferents that innervate the intervertebral disc, known as "the sinuvertebral nerve" [bib_ref] e nerve supply to the human lumbar intervertebral discs, Bogduk [/bib_ref]. ## Validated tools for assessment of pain and functional Parameters. In line with the adoption of a uniform MDT approach to the management of FBSS, it is important to utilize recommended validated tools to evaluate treatment outcomes in patients with pain disorders in compliance with IMMPACT recommendations [bib_ref] Core outcome measures for chronic pain clinical trials: IMMPACT recommendations, Dworkin [/bib_ref] [bib_ref] Developing patient-reported outcome measures for pain clinical trials: IMMPACT recommendations, Turk [/bib_ref]. e aims of a standardized assessment in this context are to facilitate longitudinal patient evaluation, to increase the efficiency, clarity, and quality of patient information during the referral process and to improve dialogue between centers and disciplines in order to optimize treatment decisions. e aims of a common approach to treatment evaluation are therefore relevant to patients, clinicians, payers, and policymakers [bib_ref] e economic impact of failed back surgery syndrome, Taylor [/bib_ref]. e CBLP network recognizes that treatment evaluation should involve previously issued quality standards and guidelines for documentation of outcomes including the patient's subjective assessment of pain severity, function, and health-related quality of life (HRQoL) [bib_ref] Core outcome measures for chronic pain clinical trials: IMMPACT recommendations, Dworkin [/bib_ref] [bib_ref] Evaluating the correlation and responsiveness of patient-reported pain with function and quality-of-life..., Devine [/bib_ref]. Having considered the plethora of existing tools used to evaluate these constructs from the patient's perspective, clinical experience guided the CBLP network to recommend a choice of standardized and validated instruments [fig_ref] Table 2: Validated questionnaires recommended for completion by patients to assess pain severity, function,... [/fig_ref]. For pain severity scales, there is a choice of the visual analogue scale (VAS) or the numeric pain rating scale (NPRS) [bib_ref] Responsiveness of the numeric pain rating scale in patients with low back..., Childs [/bib_ref] [bib_ref] Validation of a verbally administered numerical rating scale of acute pain for..., Bijur [/bib_ref] [bib_ref] Core outcome measurement instruments for clinical trials in nonspecific low back pain, Chiarotto [/bib_ref]. To assess pain-specific disability/function, either the Oswestry Disability Index (ODI) [bib_ref] e Oswestry disability index, Fairbank [/bib_ref] or the Roland Morris Disability Questionnaire (RMDQ) [bib_ref] A study of the natural history of back pain. Part I: development..., Roland [/bib_ref] is recommended. To measure generic HRQoL, either the EuroQol with five dimensions (EQ-5D) [bib_ref] e EuroQol instrument: an index of health related quality of life, Kind [/bib_ref] or the short form 12/36 (SF-12/SF-36) [bib_ref] A 12-item short-form health survey: construction of scales and preliminary tests of..., Ware [/bib_ref] [bib_ref] e MOS 36-item short-form health survey (SF-36): II. Psychometric and clinical tests..., Mchorney [/bib_ref] is recommended. e shorter generic HRQoL instruments, the SF-12 and the EQ-5D, minimize patient burden. It is also recommended that clinicians continuously monitor and evaluate a patient's medication intake. ## Psychosocial assessment. It is well established that psychological factors affect pain perception [bib_ref] Psychosocial factors in chronic spinal cord injury pain, Summers [/bib_ref] and clinical outcomes [bib_ref] e nerve supply to the human lumbar intervertebral discs, Bogduk [/bib_ref] [bib_ref] Epidemiology of chronic pain with psychological comorbidity: prevalence, risk, course, and prognosis, Tunks [/bib_ref] [bib_ref] Pretreatment psychosocial variables as predictors of outcomes following lumbar surgery and spinal..., Celestin [/bib_ref] [bib_ref] Psychological predictors of recovery from low back pain: a prospective study, George [/bib_ref] [bib_ref] Evaluating psychosocial contributions to chronic pain outcomes, Meints [/bib_ref] [bib_ref] Psychosocial factors associated with change in pain and disability outcomes in chronic..., Alhowimel [/bib_ref]. ere is no accepted gold standard approach for the psychological screening of FBSS patients. Optional questionnaires can be used to assist the psychological assessment. e most recognized questionnaire in this context is the Minnesota Multiphasic Personality Inventory 2 Restructured (MMPI-2-RF) [bib_ref] MMPI-2 characteristics in a chronic pain population, Slesinger [/bib_ref] [bib_ref] Psychological risk factors for poor outcome of spine surgery and spinal cord..., Block [/bib_ref] [bib_ref] Associations between pre-implant psychosocial factors and spinal cord stimulation outcome: evaluation using..., Block [/bib_ref] [bib_ref] Prospective comparison of the Minnesota multiphasic personality inventory-2 (MMPI-2) and MMPI-2-restructured form..., Tarescavage [/bib_ref]. e Hospital Anxiety and Depression Scale (HADS) allows detection of various states of depression (HADS-D) and anxiety (HADS-A) [bib_ref] e hospital anxiety and depression scale, Zigmond [/bib_ref] [bib_ref] Validity of the hospital anxiety and depression scale in patients with chronic..., Castro [/bib_ref] [bib_ref] Pain-related distress and clinical depression in chronic pain: a comparison between two..., Rusu [/bib_ref] , and the Fear Avoidance Beliefs Questionnaire Work and Activity (FABQ) measures patient's fear of pain [bib_ref] A Fear-Avoidance Beliefs Questionnaire (FABQ) and the role of fear-avoidance beliefs in..., Waddell [/bib_ref]. Coping strategies may play an important role by determining how patients cooperate with chronic symptoms and with pain management [bib_ref] e use of coping strategies in chronic low back pain patients: relationship..., Rosenstiel [/bib_ref] [bib_ref] Coping with rheumatoid arthritis pain: catastrophizing as a maladaptive strategy, Keefe [/bib_ref]. e Coping Strategies Questionnaire (CSQ) is intended to measure six cognitive and two behavioural coping strategies. Active coping strategies are linked to positive effect, better psychological adjustment, and decreased depression, while passive strategies are linked to poorer outcomes such as depression and increased level of pain [bib_ref] Evaluating psychosocial contributions to chronic pain outcomes, Meints [/bib_ref] [bib_ref] e impact of passive coping on rheumatoid arthritis pain, Covic [/bib_ref] [bib_ref] e role of psychosocial processes in the development and maintenance of chronic..., Edwards [/bib_ref]. An important subscale of CSQ is catastrophizing. Based on the CSQ, Sullivan and colleagues [bib_ref] e pain catastrophizing scale: development and validation, Sullivan [/bib_ref] developed the Pain Catastrophizing Scale (PCS). e PCS is widely used, and elevated scores have been associated with poor treatment outcomes. e optimization of chronic pain management requires consideration of the social factors that may contribute to people's physical and mental health [bib_ref] Psychosocial predictors of health-related quality of life and health service utilisation in..., Keeley [/bib_ref] [bib_ref] Inequalities in health: definitions, concepts, and theories, Arcaya [/bib_ref]. Factors such as gender, level of education, and working status play a substantial role in pain perception and affect patient compliance and their pain management [bib_ref] Evaluating psychosocial contributions to chronic pain outcomes, Meints [/bib_ref] [bib_ref] Gender role expectations of pain: relationship to experimental pain perception, Wise [/bib_ref] [bib_ref] Sex differences in pain perception, Wiesenfeld-Hallin [/bib_ref] [bib_ref] e impact of socio-economic status on pain and the perception of disability..., Dorner [/bib_ref] [bib_ref] Factors affecting therapeutic compliance: a review from the patient's perspective, Jin [/bib_ref] [bib_ref] Trajectories and predictors of the long-term course of low back pain: cohort..., Chen [/bib_ref]. Medical professionals trained to solve a physical/somatic problem, where there is a potential biopsychosocial comorbidity may fail to anticipate and manage the vicious circle of social exclusion. ese arguments support the need for including social assessment in a MDT approach, as it affects clinical outcome in chronic pain management [bib_ref] e impact of social deprivation on chronic back pain outcomes, Carr [/bib_ref]. A proposal for a minimal psychosocial assessment toolbox is presented in [fig_ref] Table 3: Instruments to assess psychological and social well-being among patients with failed back... [/fig_ref]. ## Radiological assessment. In addition to orthopaedic, neurologic, functional, and psychosocial evaluation, spine imaging is essential in order to exclude new indications for reoperation: recurrent disc herniation (MRI), spine instability (CT, MRI, and bending X-ray), spine imbalance (fullstanding lateral and anteroposterior X-ray), EOS ® images while the patient is standing (bending X-ray), or nonunion of spinal fusion (plain X-ray, CT, scintigraphy, and positron emission tomography (PET) scan), new-onset stenosis (MRI and CT), and abscess (MRI and CT) [bib_ref] Medical management of failed back surgery syndrome in Europe: evaluation modalities and..., Durand [/bib_ref] [bib_ref] Failed back surgery syndrome: to reoperate or not to re-operate? A retrospective..., Assaker [/bib_ref]. Conditions like discitis, low-grade infections, arachnoiditis, or scar tissue which usually do not require reoperation have also to be identified before being managed conservatively [bib_ref] Failed back surgery syndrome: current perspectives, Baber [/bib_ref]. Following a robust MDT clinical evaluation to define and diagnose a patient with FBSS [fig_ref] Figure 2: e initial stage of the proposed standardized multidisciplinary team failed back surgery... [/fig_ref] , a stratification and hierarchization of the various therapeutic options can be constructed through a level approach to optimize management and outcomes. A patient who either does not present with FBSS or presents with FBSS and a significant psychosocial comorbidity, determined by psychological assessment carried out by a clinical psychologist or psychiatrist (ideally with experience in the field of pain), should be excluded from the pathway and referred to the appropriate discipline(s). # Discussion Use of the term FBSS has provoked decades of controversy because of a lack of consensus of a definition and the inherently restrictive and confusing meaning of this acronym. e term hides the challenges associated with selecting appropriate treatment for this patient population due to insufficient identification of the underlying mechanism of pain [bib_ref] Failed back surgery syndrome-definition, epidemiology and demographics, Omson [/bib_ref] [bib_ref] Failed back surgery syndrome: what's in a name? A proposal to replace..., Rigoard [/bib_ref]. In addition, cognitive, affective, and behavioural features of pain are often explanations of the disability as much as or more than abnormal sensory-related pain [bib_ref] Failed back surgery syndrome-definition, epidemiology and demographics, Omson [/bib_ref]. In response to the limitations of current practice in managing FBSS patients, an international panel of spine surgeons, neurosurgeons, and pain specialists with a special interest in FBSS established the CBLP network. Based on the broad personal experience of each member of the panel, through literature reviews, additional input from clinical expertise of multiple professional disciplines and consensus among its members, the CBLP network's primary intention is to provide recommendations on how to optimize the management and outcomes of FBSS. In this paper, we focus on the key elements for defining FBSS and outline how to clinically confirm this diagnosis. e CBLP network's definition of FBSS is found on the prediction that no further spine surgery is indicated after adequate somatic, psychosocial, and radiological assessment have been executed. Management begins with a systematic evaluation of common FBSS aetiologies. Appropriate understanding and identification of the abnormalities most commonly associated with FBSS after a meticulous clinical evaluation is required for adequate caretaking of this often hard-to-treat condition [bib_ref] From "mechanical" to "neuropathic" back pain concept in FBSS patients. A systematic..., Blond [/bib_ref] [bib_ref] Failed back surgery syndrome-definition, epidemiology and demographics, Omson [/bib_ref]. A growing body of data suggests that the adoption of a multidisciplinary approach is significantly more effective than usual care of patients with chronic low back pain [bib_ref] Multidisciplinary biopsychosocial rehabilitation for chronic low back pain, Kamper [/bib_ref] [bib_ref] Interdisciplinary treatment of failed back surgery syndrome (FBSS): a comparison of FBSS..., Miller [/bib_ref] [bib_ref] Etiology, evaluation, and treatment of failed back surgery syndrome, Sebaaly [/bib_ref]. A MDT-based approach has the potential to improve decision-making, reduce variation in practice, and optimize treatment outcomes. Clinicians should refine pain topographical and topological pain characterization to ensure that clinical evaluation becomes the guiding principle for multidisciplinary assessment. A patient who either does not present with FBSS or presents with FBSS and significant psychosocial comorbidities should be excluded from further inclusion in FBSS care pathways or algorithms and be referred to the appropriate discipline(s). For many aspects of medical practice, there is a lack of high-quality evidence and a plethora of contradictory information which makes decision-making difficult when trying to optimize treatment outcomes and provide concise recommendations for assessment, treatment, and outcome evaluation. When dealing with a lack of, or conflicting, scientific evidence, consensus statements are seen as a useful tool to establish expert agreement, to define the boundaries of acceptable practice and obtain opinions from different countries and healthcare systems [bib_ref] Qualitative Research: consensus methods for medical and health services research, Jones [/bib_ref] [bib_ref] Democracybased consensus in medicine, Greco [/bib_ref]. Due to the paucity of evidence-based guidelines in the management of FBSS, the CBLP network chose to adhere to a consensus-based approach to achieve the set goals to define FBSS, design outlines for appropriate patient evaluation, and propose a treatment pathway. One limitation of the chosen method to achieve consensus in the present study is that it was based on round table discussions without involvement of ranking procedures that are used in the two most commonly utilized methods to reach consensus: the Delphi process and the nominal group technique [bib_ref] Qualitative Research: consensus methods for medical and health services research, Jones [/bib_ref]. Although not optimal, we consider the method we adopted to be appropriate based on the complexity of the set tasks which do not fit easily within an evidence-based treatment paradigm. Since personal contact with facilitated discussions among the network members was considered desirable, the Delphi method, the reliability of which rests on anonymity and increases with the size of the group, was not used. # Conclusions e complexity of FBSS suggests that a multidisciplinary strategy is most appropriate for patient assessment with the goal to optimize outcomes. is paper focuses on redefining FBSS taxonomy and clinical evaluation in order to improve patient assessment before adequate treatment options can be chosen. It is important for physicians and other healthcare professionals involved in the management of patients with FBSS to expand their knowledge of underlying aetiologies and use of appropriate diagnostic tools to adequately evaluate this difficult-to-treat group affected with chronic pain. In a second paper, a stratification and hierarchization of the various therapeutic options is constructed through a 4 level-approach with a proposal for a standardized treatment pathway for FBSS. e utilization of a MDT approach is emphasized to ensure that care is provided in a uniform manner for optimizing management and ultimately patient outcomes. Disclosure e funder did not provide input into the discussions or the consensus. Medtronic manufactures devices indicated for failed back surgery syndrome and may therefore gain from the implementation of the pathway described in this article. ## Conflicts of interest Philippe Rigoard, Kliment Gatzinsky, Jean-Philippe Deneuville, Wim Duyvendak, Nicolas Naiditch, Jean-Pierre Van Buyten, and Sam Eldabe treat patients with failed back surgery syndrome in the private an/or the public healthcare sectors and therefore may gain from the implementation of the pathway. Philippe Rigoard, Kliment Gatzinsky, Wim Duyvendak, Jean-Pierre Van Buyten, and Sam Eldabe were reimbursed for travel to Chronic Back and Leg Pain Network meetings and received honoraria for Chronic Back and Leg Pain Network meeting participation from Medtronic Inc., and may therefore have a preexisting relationship with Medtronic, the Funder, and may be influenced by beliefs associated with treatments recommended in the pathway. Philippe Rigoard, Kliment Gatzinsky, Sam Eldabe, and Wim Duyvendak have served as consultants to Medtronic Inc., and Boston Scientific and may therefore have a preexisting relationship with them and be influenced by beliefs associated with treatments recommended in the pathway. Kliment Gatzinsky and Sam Eldabe have served as consultants to Abbott and may therefore have a preexisting relationship with them and be influenced by beliefs associated with treatments recommended in the pathway. Sam Eldabe has served as a consultant to Mainstay Medical and may have a preexisting relationship with them and be influenced by beliefs associated with treatments recommended in the pathway. Philippe Rigoard, Wim Duyvendak, and Sam Eldabe have received research funding from Medtronic Inc., and may be influenced by beliefs Patient presents with ongoing back and/or leg pain that has persisted for >6 months following most recent spinal surgery Evaluation by an MDT to include orough somatic evaluation (i) (ii) (iii) (iv) (v) (vi) (vii) Spine and biomechanical assessment (including imaging) Psychosocial evaluation 1 Pain assessment: neuropathic/nociceptive/mixed pain Functional evaluation Confirmation of diagnosis of FBSS Determination of appropriate treatment MDT, multidisciplinary team. [bib_ref] From "mechanical" to "neuropathic" back pain concept in FBSS patients. A systematic..., Blond [/bib_ref] Best practice is for the psychosocial evaluation to be performed by a psychologist or psychiatrist with specific experience in the field of pain. Assessment should include the relevant tests and questionnaires that are able to identify patients with major psychological or psychiatric contraindications [fig_ref] Table 3: Instruments to assess psychological and social well-being among patients with failed back... [/fig_ref]. associated with treatments recommended in the pathway. Philippe Rigoard and Wim Duyvendak have received research funding from Boston Scientific and Abbott and may be influenced by beliefs associated with treatments recommended in the pathway. Sam Eldabe has received research funding from Nevro and may be influenced by beliefs associated with treatments recommended in the pathway. Nicolas Naiditch and Jean-Philippe Deneuville declare that there are no conflicts of interest regarding the publication of this paper. [fig] Figure 1: Schematic diagram of steps in the literatures searches: FBSS definition and evaluation. e electronic and hand literature searches yielded 1663 titles and 74 textbooks. Following a review of full-text versions of the 363 residual publications, after discarding duplicates and initial exclusion of 1300 titles/abstracts, 108 papers were finally selected, and 12 were retained for FBSS definition and MDT assessment and composition (Supplementary Material 1). [/fig] [fig] Figure 2: e initial stage of the proposed standardized multidisciplinary team failed back surgery syndrome care pathway, as recommended by the Chronic Back and Leg Pain Network. Clinical evaluation and confirmation of diagnosis. FBSS, failed back surgery syndrome; [/fig] [table] Table 1: Output of the review of publications with recommendations for specialties to be included in the multidisciplinary team management of failed back surgery syndrome. Pain History.e pain history must be carefully reviewed and pay specific attention to the following items:(i) New pain, persistent pain, and/or recurrent pain? (if yes, free interval needs to be quantified) (ii) Circumstances, positions, and movements that improve or exacerbate the symptoms[17] (iii) Any clinical sign that might be suspicious of underlying infection, neoplasm, and fracture, called "red flag" by the COST B13 group in available European guidelines[37] [/table] [table] Table 2: Validated questionnaires recommended for completion by patients to assess pain severity, function, and health-related quality of [/table] [table] Table 3: Instruments to assess psychological and social well-being among patients with failed back surgery syndrome (FBSS). [/table]	None	None	Failed back surgery syndrome (FBSS) is a controversial term for identifying patients affected by new, recurrent, or persistent pain in the low back and/or legs following spinal surgery. The lack of a comprehensive standardized care pathway compromises the appropriate management of FBSS patients, which is associated with a heavy financial burden. An international panel of spine surgeons, neurosurgeons, and pain specialists with a particular interest in FBSS established the chronic back and leg pain (CBLP) network with the aim of addressing the challenges and barriers in the clinical management of FBSS patients by building a common transdisciplinary vision. Based on literature reviews, additional input from clinical expertise of multiple professional disciplines, and consensus among its members, the network attempted to provide recommendations on the management of patients with FBSS utilizing a multidisciplinary team (MDT) approach. The presentation of this work has been divided in two separate parts to enhance its clarity. This first paper, in favour of selecting appropriate validated tools to improve the FBSS patient assessment, focuses on FBSS taxonomy and its clinical implications for evaluation. Concise recommendations for assessment, treatment, and outcome evaluation using a MDT approach would be an important resource for specialists and nonspecialist clinicians who manage patients with FBSS, to improve decision-making, reduce variation in practice, and optimize treatment outcomes in this difficult-to-treat population.
4e2992fc22f21f2b9f5c331578eda83501b8193c	pubmed	2014 KLCSG-NCC Korea Practice Guideline for the Management of Hepatocellular Carcinoma	2014 KLCSG-NCC Korea Practice Guideline for the Management of Hepatocellular Carcinoma # Introduction 1. introduction The guideline for the management of hepatocellular carcinoma (HCC) was first developed in 2003 and revised in 2009 by the Korean Liver Cancer Study Group (KLCSG) and the National Cancer Center (NCC), Korea. Since then, many studies on HCC have been carried out in Korea and other countries. In particular, a substantial body of knowledge has been accumulated on diagnosis, staging, and treatment specific to Asian characteristics, especially Koreans, prompting the proposal of new strategies. Accordingly, the new guideline presented herein was developed on the basis of recent evidence and expert opinions. ## Target population The primary targets of this guideline are patients with suspi-cious or newly diagnosed HCC. This guideline provides recommendations for the initial treatment of patients with newly diagnosed HCC. Moreover, this guideline includes some information about residual, progressed, and recurred tumors following initial treatment; however, it is not main topic of this guideline. Furthermore, preemptive antiviral therapies for underlying chronic hepatitis, management of cancer pain, and assessment of tumor response are also included to facilitate the use of the guideline in clinical practice. ## Intended users This revised guideline is intended to provide useful information and guidance for all Korean clinicians in charge of the diagnosis and treatment of HCC. It also provides trainee doctors and teachers practical information on the management of HCC. ## Developers and funding source The KLCSG proposed revising the KLCSG-NCC Korea Practice Guideline, and the NCC, Korea agreed. The KLCSG-NCC Korea Practice Guideline Revision Committee (KPGRC), which included hepatologists, oncologists, surgeons, radiologists, and radiation oncologists, was subsequently formed (Appendix 1). All required funding was provided by the NCC, Korea. Each member of the HCC-KPGRC collected and evaluated relevant evidence, and wrote the manuscript. Conflicts of interests of the HCC-KPGRC members are summarized in Appendix 2. ## Evidence collection The HCC-KPGRC collected and evaluated the literature relevant to HCC management by searching in using MEDLINE (up to 2014) for updated revisions. Only English and Korean literature was searched. The search term "hepatocellular carcinoma" and other keywords related to clinical questions shown were used (Appendix 3); these clinical questions contained a wide range of key topics including epidemiology, prevention, diagnosis, staging, treatment, and assessment of tumor response. ## Levels of evidence and grades of recommendation Relevant literature was systematically reviewed. The evidence and recommendations were graded according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system with minor modifications. The levels of evidence were assessed on the basis of the possibility of changes in the estimate of clinical impact by further research, and were categorized as high (A), moderate (B), or low (C). For example, A-level evidence is similar but not identical to that from one or more randomized controlled trials. If there is only a slight possibility of the level of evidence changing, because further randomized controlled trials are unlikely to be conducted, such evidence could be considered level A. According to the GRADE system, the grades of recommendation were classified as strong or weak , collectively considering the level of evidence, quality, patient-centered outcomes, and socioeconomic aspects of each study. Therefore, each recommendation was graded on the basis of the level of evidence (A-C) and grades of recommendation (1 or 2) as follows: A1, A2, B1, B2, C1, or C2 [fig_ref] Table 1: Grading of Recommendations, Assessment, Development, and Evaluation [/fig_ref]. This guideline avoided giving C2 grades. ## List of clinical questions The committee considered the following questions from four departments as key factors to be addressed in this guideline (Appendix 3). The committee reviewed the evidence and sug-gested recommendations through intra-and interdepartmental discussion. ## Manuscript review Drafts of the revised guideline were thoroughly reviewed at several intradepartmental, three interdepartmental, and four departmental head meetings. In addition to the contents, methodological validity was evaluated on the basis of the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. A revised draft of the manuscript was reviewed at an external review board meeting and an open symposium, and was modified further before publication. The external review board comprised eight specialists who are or were the head of the KLCSG or the Korean Association for the Study of the Liver (KASL). The final manuscript was endorsed by the board of executives of the KLCSG and the NCC, Korea. ## Guideline release The revised HCC guideline was presented at Liver Week 2014 (the Korean Association for the Study of the Liver-KLCSG-Korean Association of Hepato-biliary and Pancreas Surgery-Korean Liver Transplantation Society meeting) on June 14, 2014. The Korean edition is available at http://www.klcsg.or.kr or http:// ncc.re.kr. ## Plan for updates Updates will be planned when new major evidence regarding the diagnosis and/or treatment of HCC is accumulated. ## Epidemiology According to the central cancer registration statistics published in 2013, there were 218,017 cases of cancer in Korea in 2011. Among them, 7.6% [bib_ref] Metabolic syndrome increases the risk of primary liver cancer in the United..., Welzel [/bib_ref] [bib_ref] Preemptive use of lamivudine reduces hepatitis B exacerbation after allogeneic hematopoietic cell..., Lau [/bib_ref] of all malignancies were primary liver cancer cases, ranking fifth in incidence.Regarding sex, 12,189 cases were in men and 4,274 cases were in women, making primary liver cancer the fourth and sixth most Low (C) Further research is very likely to impact confidence on the estimate of clinical effect. ## Strength of recommendation criteria Strong Factors influencing the strength of the recommendation included the quality of the evidence, presumed patient-important outcomes, and cost. Weak Variability in preferences and values, or more uncertainty; recommendation is made with less certainty, higher cost or resource consumption. Among the quality levels of evidence originally included in the GRADE system, we excluded "very low quality" (D) (i.e., the estimate of the effect is very uncertain) from this guideline for convenience. common cancer in men and women in Korea, respectively; the male:female ratio was 2.85:1.Regarding age, primary liver cancer occurred most frequently in patients in their 50s (28.6%) followed by 60s (26.0%) and 70s (22.3%).The crude incidence rate, i.e., the number of newly occurring cancer patients during the observation period among the study population, was 32.9 (male, 48.6; female, 17.1) per 100,000 population. According to an annual report of the 2010 cancer registration statistics, the diagnostic code of HCC accounted for approximately.0% among all primary liver cancers. According to the age-standardized incidence rate, compensated with the mid-year population in 2000, the incidences of primary liver cancer occurrence were [bib_ref] Treatment of hepatitis C virus-related cirrhosis: a randomized, controlled trial of interferon..., Valla [/bib_ref] [bib_ref] Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and..., Lin [/bib_ref] , and the sex ratio was similar to that of recent data, whereas the total number of cases is less than that of the recent data . This may reflect the age structure of the Korean population, as the absolute number of liver cancer cases is increasing, whereas the age-standardized incidence is decreasing. Regarding regional distribution, in 1999, of HCC occurrence in Jeonnam, Gyeongbuk, and Gyeongnam was 28.9, 26.8, and 26.4 per 100,000 population, respectively. The occurrence of HCC was the lowest in Daejeon at 14.8 per 100,000 population; those in Gyeonggi and Seoul were 18.2 and 18.7 per 100,000 population, respectively. In 2010, the regional incidences of HCC in Jeonnam, Jeju, Busan, Gyeongnam, Gyeongbuk, and Gangwon were , and 19 per 100,000 population, respectively. Regions of relative low incidence were Jeonbuk, Chungnam, Chungbuk, with 14.9, 15.1, and 15.6, respectively, as well as Seoul, Daegu, and Daejeon, each with 15.9 per 100,000 population. In 2011, the national primary liver cancer prevalence was 47,697 (age-standardized prevalence, 67.1 per 100,000 population), ranking sixth after thyroid, stomach, colon, breast, and lung cancers. Regarding the sex-specific prevalence, primary liver cancer was ranked at fourth in men (prevalence, 35,689; age-standardized prevalence, 107.2/100,000) and ninth in women (prevalence, 12,009; age-standardized prevalence, 31.3/100,000); the male:female prevalence ratio was 2.97:1. Regarding 5-year prevalence, the age-standardized prevalence of primary liver cancer increased: [bib_ref] Cost effectiveness of alternative surveillance strategies for hepatocellular carcinoma in patients with..., Andersson [/bib_ref] The reason for the increasing prevalence of primary liver cancer despite its decreasing incidence is presumably because the survival rate of liver cancer patients is increasing. Liver cancer is the main cause of death of Korean men in their 50s. According to the National Statistics Office of Korea, 22.5 people (male, 33.7; female, 11.3) per 100,000 population die annually from liver cancer. While the most frequent cause of death in people after the age of 40 is malignancy, liver cancer is the top-ranked cause of death in people in their 40s and 50s.According to a recent report of 10 principal cancers, shows that the 5-year cancer relative survival rates for liver cancer were 10.7%, 13.2%, 20.2%, 27.3%, and 28.6% from , respectively, showing consistent improvement . However, the prognosis of liver cancer remains very poor compared to the 66.3% 5-year relative survival rates of all cancer patients from 2007 to 2011 in Korea. The prognosis of HCC is closely related to liver function. A report from Europe stated that a few patients excluded from curative treatment study (i.e., liver resection, liver transplantation , and percutaneous ethanol injection) showed a 3-year survival rate of 28% without any treatment for HCC. However, this could be considered to be a result of selection bias. In Korea, according to the 2003-2005 randomized registration of HCC (n=4,521), modified Union for International Cancer Control (mUICC) stages I, II, III, IVa, and IVb were 10.7%, 33.4%, 27.7%, 10.3%, and 7.9%, respectively; the 3-/5-year survival rates in these stages were 62.3%/52.0%, 48.1%/36.0%, .3%/15.5%, 8.0%/6.5%, and 8.0%/6.1%, respectively. 12 A recent single-center cohort study reports that 8.9%, 29.6%, 24.8%, 23.1%, and 13.6% of 1,972 patients with HCC from 2004 to 2009 were mUICC stage I, II, III, IVa, and IVb, respectively. The 5-year survival rates in stages I, II, III, IVa, and IVb were 71.1%, 59.8%, 25.0%, 4.6%, and 2.1%, respectively, showing improvement in overall survival rates compared with the previous 2000-2003 cohort study. Improved survival rates in hepatitis B-related advanced HCC highlights the importance of antiviral therapy for hepatitis B-positive patients. The risk factors for HCC are relatively well known and include chronic hepatitis B/C, liver cirrhosis, alcoholic liver disease, obesity-and fatty liver disease-related diabetes mellitus, [bib_ref] Metabolic syndrome increases the risk of primary liver cancer in the United..., Welzel [/bib_ref] and aflatoxin. [bib_ref] Curbing the liver cancer epidemic in Africa, Hainaut [/bib_ref] In Korea, one study reports that the underlying liver diseases of HCC patients included hepatitis B (72.3%), hepatitis C (11.6%), alcoholic liver disease in (10.4%), and non-B non-C hepatitis (0.7%).Another study reports that 74.6% of HCC patients were positive for hepatitis B virus (HBV), 9.3% were positive for hepatitis C virus (HCV), 7.4% were long-term alcohol abusers, and 8.7% had unidentified causes (probably metabolic liver disease). HCC develops in 1%-4% of cirrhotic patients annually and eventually develops in approximately one-third of cirrhotic patients. [bib_ref] The natural history of compensated cirrhosis due to hepatitis C virus: a..., Sangiovanni [/bib_ref] In Korea, the number of carriers of hepatitis B decreased markedly because of hepatitis B vaccination and prevention services in vertical transmission. Although antiviral therapy for chronic hepatitis B and C is expected to further decrease the incidence of HCC, metabolic liver disease may increase as a cause of HCC in the future. ## Prevention The primary, secondary, and tertiary prevention of HCC development are defined as follows. Primary prevention of HCC can be achieved by universal vaccination against HBV infection, 20 encouragement of healthy lifestyles preventing obesity and alcohol abuse, and controlling metabolic conditions. Secondary prevention is the prevention of HCC development in patients with chronic viral hepatitis through histologic improvement of inflammation and fibrosis by sustained suppression or eradication of hepatitis virus. Finally, tertiary prevention involves means to prevent recurrence in HCC patients after curative treatment. The World Health Organization recommends vaccination against HBV for all newborns and high-risk groups. As peri-natal or early postnatal transmission is an important cause of chronic HBV infection worldwide, the first dose of hepatitis B vaccine should be administered as soon as possible after birth. Vaccination is also recommended for age-specific cohorts (i.e., young adolescents) and people with risk factors for acquiring HBV infection, including healthcare workers, travelers to areas where HBV-infection is prevalent, intravenous drug users, people with multiple sex partners, and adult patients who do not have hepatitis B surface antigen or surface antibody. However, there is currently no vaccination against HCV. Antiviral therapies leading to sustained suppression of viral replication in chronic hepatitis B patients and inducing sustained virologic response in chronic hepatitis C patients are recommended because they prevent progression to cirrhosis and the development of HCC. Antiviral therapies should be administered according to the KASL guidelines for the management of chronic hepatitis B and C infections. Interferon and oral nucleos(t)ide analogues are now available for HBV treatment. Observational studies assessing the effect of interferon show a potential effect in the reduction of HCC incidence. Similarly, a randomized controlled trial assessing the effect of lamivudine shows a significant reduction in HCC incidence (32 months of follow-up; lamivudine vs placebo, 3.9% vs 7.4%; p=0.047). [bib_ref] Lamivudine for patients with chronic hepatitis B and advanced liver disease, Liaw [/bib_ref] Although HCC reduction after antiviral treatment remains controversial, 25 a recent study shows significant reduction in HCC incidence in patients treated with entecavir (5 years of followup; entecavir vs control, 3.7% vs 13.7%; p<0.001). [bib_ref] Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B..., Hosaka [/bib_ref] In chronic hepatitis C patients, whether interferon treatment reduces HCC risk (favors reducing; treated vs control, 4% vs 38%; p=0.002) is controversial. [bib_ref] Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in..., Nishiguchi [/bib_ref] However, others reported no significant difference in HCC incidence between treated and untreated controls. [bib_ref] Treatment of hepatitis C virus-related cirrhosis: a randomized, controlled trial of interferon..., Valla [/bib_ref] The results of a meta-analysis of 4,700 patients from 20 studies suggested the risk of HCC is reduced among interferon-treated patients (relative risk [RR], 0.43; 95% confidence interval [CI], 0.33 to 0.56). [bib_ref] A sustained viral response is associated with reduced liver-related morbidity and mortality..., Singal [/bib_ref] Furthermore, the risk of HCC is reduced among patients with HCV who achieve a sustained virological response with antiviral therapy compared with nonsustained virological response (RR, 0.35; 95% CI, 0.26 to 0.46). However, once cirrhosis is established, there is no conclusive evidence that antiviral therapy can prevent or delay the occurrence of HCC. Previous studies including Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) [bib_ref] Maintenance peginterferon therapy and other factors associated with hepatocellular carcinoma in patients..., Lok [/bib_ref] and Evaluation of PegIntron in Control of Hepatitis C Cirrhosis (EPIC) studies [bib_ref] Maintenance therapy with peginterferon alfa-2b does not prevent hepatocellular carcinoma in cirrhotic..., Bruix [/bib_ref] show that maintenance therapy with pegylatedinterferon in cirrhotic patients does not significantly decrease the incidence of HCC; the study populations included in these trials were patients with nonresponse to prior interferon treatment. Therefore, additional studies are required to determine the potential preventive effect of monotherapy or combinations of new direct-acting antivirals with interferon in cirrhotic patients. Regarding tertiary prevention for HCC, there is no conclusive evidence that antiviral therapy can prevent or delay HCC recur-rence after curative treatment. Yin et al. [bib_ref] Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis..., Yin [/bib_ref] reported oral antiviral treatment against HBV significantly decreased HCC recurrence and HCC-related death after resection, with hazard ratios (HRs) of 0.48 (95% CI, 0.32 to 0.70) and 0.26 (95% CI, 0.14 to 0.50), respectively. In a study by Chen et al.that enrolled 268 patients (133 in the interferon a-2b arm), the median recurrencefree survival in the interferon a-2b and control arms were 42.2 (95% CI, 28.1 to 87.1) and 48.6 (95% CI, 25.5 to infinity) months, respectively (p=0.828). A meta-analysis including 551 patients from nine cohortsshows a significant difference in the incidence of HCC recurrence in favor of the antiviral treatment group (55% vs 58%; odds ratio [OR], 0.59; p=0.04) after curative treatment of HBV related-HCC; the risk of HCC was reduced by 41% in the antiviral treatment group. There were also significant differences in favor of the antiviral treatment group with respect to liver-related mortality (0% vs 8%; OR, 0.13; p=0.02) and overall mortality (38% vs 42%; OR, 0.27; p<0.001). Miao et al. [bib_ref] Postoperative adjuvant antiviral therapy for hepatitis B/C virus-related hepatocellular carcinoma: a meta-analysis, Miao [/bib_ref] performed a meta-analysis of the impact of postoperative antiviral treatment on tumor recurrence and survival of patients with chronic HBV or HCV infection-related HCC after curative therapy; 1,224 patients were included in their analysis. The estimated ORs for the 1-, 3-, and 5-year recurrence in HBVrelated HCC were 0.59, 0.43, and 0.21, respectively. In HCV-related HCC patients, Shiratori et al. [bib_ref] Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma..., Shiratori [/bib_ref] report that the rates of second or third recurrence appeared to be lower in the interferon group than the untreated group. The 5-and 7-year survival rates of patients treated with interferon were of 68% and 53%, respectively; those of untreated patients were 48% and 23%, respectively. Mazzaferro et al. [bib_ref] Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV..., Mazzaferro [/bib_ref] recently reported that while no treatment effect was apparent on early recurrence in HCV-positive patients, there was a significant benefit on late recurrence (HR, 0.3; p=0.04). According to Miao et al., [bib_ref] Postoperative adjuvant antiviral therapy for hepatitis B/C virus-related hepatocellular carcinoma: a meta-analysis, Miao [/bib_ref] the estimated ORs for the 1-, 3-, and 5-year recurrence in HCV-related HCC were significantly reduced to 0.52, 0.23, and 0.37, respectively. In addition to HBV-, HCV-, and alcohol-related chronic liver disease, associations between diabetes and obesity, with HCC were recently reported. [bib_ref] Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma, El-Serag [/bib_ref] Policies for preventing HCV/HBV transmission encourage lifestyles that prevent obesity and alcohol abuse as well as the control of metabolic conditions such as diabetes. Bravi et al. [bib_ref] Coffee reduces risk for hepatocellular carcinoma: an updated metaanalysis, Bravi [/bib_ref] reported that coffee consumption reduced the RR of HCC compared to no coffee consumption: the summary RR was 0.72 for low consumption and 0.44 for high consumption. Their meta-analysis indicates the risk of HCC is reduced by 40% for any coffee consumption versus no consumption. Recommendations [fig_ref] Table 2: Summary of the Recommendations of the 2014 KLCSG-NCC Korea Practice Guidelines for... [/fig_ref] 1. Hepatitis B vaccination is recommended for all newborns (A1) and high-risk individuals (i.e., HBsAg-negative and anti-HBs-negative) (B1). 2. General preventive measures include the followings: pre-vention of HBV/HCV transmission (A1), avoidance of alcohol abuse, and control of metabolic disorders such as obesity and diabetes (C1). 3. Antiviral therapy as secondary prevention against HCC should follow the KASL guidelines for the management of chronic hepatitis B/C (A1). 4. Antiviral therapy should be considered after curative treatment for chronic viral hepatitis-related HCC to reduce the risk of recurrence (B1). ## Diagnosis The diagnosis of HCC is based on pathology or noninvasive criteria in high-risk groups. However, noninvasive criteria for HCC diagnosis vary greatly among guidelines. Most patients with HCC have definite risk factors such as HBV infection, HCV infection, and cirrhosis. Regular surveillance (i.e., abdominal ultrasound and serum a-fetoprotein [AFP]) is warranted in these high-risk groups. [bib_ref] Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis, Singal [/bib_ref] [bib_ref] Cost effectiveness of alternative surveillance strategies for hepatocellular carcinoma in patients with..., Andersson [/bib_ref] The cost-effectiveness and survival benefit of patients with early HCC detected in surveillance programs have been documented in previous studies. [bib_ref] Randomized controlled trial of screening for hepatocellular carcinoma, Zhang [/bib_ref] Dynamic contrast-enhanced computed tomography (CT), dynamic contrast-enhanced magnetic resonance imaging (MRI), or MRI using hepatocyte-specific contrast agent (i.e., gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid [Gd-EOB-DTPA]) are preferentially recommended if HCC is suspected in a surveillance program. Serum AFP has been traditionally and widely used as a tumor marker of HCC. However, serum AFP level is normal in up to 35% of cases of small HCC and can be nonspecifically elevated in patients with active hepatitis or active hepatocyte regeneration. Although the glycosylated AFP/total AFP ratio (AFP-L3), des-γ-carboxy prothrombin or protein induced by vitamin K absence-II (PIVKA-II) have been suggested as new tumor markers for the diagnosis of HCC, none have demonstrated a definite role in the diagnosis of HCC. A recent Japanese guideline indicates the combined use of tumor markers (AFP >200 ng/mL, AFP-L3 >15%, or PIVKA-II >40 mAU/mL) for the diagnosis of HCC. [bib_ref] Management of hepatocellular carcinoma in Japan: consensus-based clinical practice guidelines proposed by..., Kudo [/bib_ref] Several Korean retrospective studies also reported the clinical usefulness of these new tumor markers. [bib_ref] Clinical efficacy of serum PIVKA-II in the diagnosis and follow up after..., Yoon [/bib_ref] However, further well-designed studies are warranted to confirm their roles in the diagnosis of HCC. If serum AFP level increases steadily over time, especially in hepatitis B patients with fully suppressed viral activity, the development of HCC should be suspected, and a detailed imaging study is strongly recommended. [bib_ref] Management of hepatocellular carcinoma in Japan: consensus-based clinical practice guidelines proposed by..., Kudo [/bib_ref] [bib_ref] Asian Pacific Association for the Study of the Liver consensus recommendations on..., Omata [/bib_ref] [bib_ref] On-treatment alpha-fetoprotein is a specific tumor marker for hepatocellular carcinoma in patients..., Wong [/bib_ref] As the noninvasive diagnosis of HCC mostly depends on imaging studies, the sensitivity and specificity of imaging modalities are important for accurate diagnosis. Studies investigating the roles of imaging techniques in patients undergoing LT report that the diagnostic sensitivity of dynamic CT is 75.0%, while those of dynamic MRI are 100% for HCC ≥2 cm in diameter [bib_ref] Transplantation for hepatocellular carcinoma and cirrhosis: sensitivity of magnetic resonance imaging, Krinsky [/bib_ref] [bib_ref] Accuracy of multiphasic helical computed tomography and intraoperative sonography in patients undergoing..., Zacherl [/bib_ref] [bib_ref] Diagnostic accuracy of multi-/single-detector row CT and contrast-enhanced MRI in the detection..., Kim [/bib_ref] The overall sensitivities of ultrasound, dynamic CT, and dynamic MRI for the noninvasive diagnosis of HCC are 61%-67%, 68%-91%, and 81%-100%, respectively. [bib_ref] Development of evidencebased clinical guidelines for the diagnosis and treatment of hepatocellular..., Makuuchi [/bib_ref] [bib_ref] Accuracy of ultrasonography, spiral CT, magnetic resonance, and alpha-fetoprotein in diagnosing hepatocellular..., Colli [/bib_ref] [bib_ref] Recent advances in the diagnosis of hepatocellular carcinoma, Piscaglia [/bib_ref] If liver nodules are found during surveillance in high-risk groups, dynamic CT, dynamic MRI, or MRI using hepatocytespecific contrast agent should be performed. If the typical hallmark of HCC (i.e., hypervascularity in the arterial phase with washout in the portal or delayed phases) is identified by using the imaging techniques mentioned above, a nodule ≥1 cm in ## Systemic therapies 1. Sorafenib is indicated for HCC patients with very well-preserved liver function (Child-Pugh class A), good performance status, and regional lymph node or extrahepatic spread or for patients with tumor progression on other therapies (A1). 2. Sorafenib is recommended for HCC patients with very well-preserved liver function (Child-Pugh class A), good performance status, and vascular invasion (A2). 3. Sorafenib is considered for HCC patients with liver function Child-Pugh class superb B and good performance status if the above conditions 1 and 2 are satisfied (B1). 4. Cytotoxic chemotherapy can be considered for HCC patients with advanced tumors who have with well-preserved liver function and, with good performance status, in whom sorafenib therapy has failed (C1). 5. Adjuvant TACE, sorafenib, or cytotoxic chemotherapy are not recommended for HCC patients treated with curative resection (B1). Preemptive antiviral therapy 1. Patients should be tested for the HBsAg before starting cytotoxic chemotherapy or immunosuppressive therapy (A1). 2. Preemptive antiviral therapy is recommended for HBV carriers undergoing cytotoxic chemotherapy to prevent reactivation (A1). Preemptive antiviral therapy is considered for HBV-infected patients receiving TACE (B1), hepatic arterial infusion chemotherapy (C1), surgical resection (C1), or EBRT (C1) to prevent reactivation. 3. Antiviral treatment for HBV reactivation should follow the recommendations of the current KASL guidelines (A1). Drug treatment for cancer pain in HCC 1. Careful consideration is required for pain management with medication in patients with HCC and underlying liver disease. The dosage and dosing intervals of analgesics should be determined on the basis of liver functions (C1). 2. In patients with HCC and chronic liver disease, the dosage of acetaminophen should be lowered (C1) and NSAIDs should be used with caution (B1). 3. In patients with HCC and chronic liver disease, opioid analgesics and their dosage should be selected carefully on the basis of drug metabolism and liver function (C1). Assessment of tumor response and posttreatment follow-up diameter can be diagnosed as HCC. Low, medium, and high signal intensity in the hepatocyte phase, T2-weighted image, and diffusion-weighted image, respectively, have been suggested as additional findings to support the diagnosis of HCC by MRI using a hepatocyte-specific contrast agent. [bib_ref] Gadoxetic acidenhanced hepatobiliary phase MRI and high-b-value diffusionweighted imaging to distinguish well-differentiated..., Lee [/bib_ref] [bib_ref] Hypervascular hepatocellular carcinoma 1 cm or smaller in patients with chronic liver..., Kim [/bib_ref] However, further studies are required to confirm evidence on the role of these findings. The role of angiography in the diagnosis of HCC is quite limited owing to rapid advances in other noninvasive imaging techniques. Although contrast-enhanced ultrasonography has been introduced to characterize and localize small liver nodules (especially for radiofrequency ablation), its roles in the diagnosis and staging of HCC remain quite limited.Positron emission tomography-CT (PET-CT) is not recommended as a primary diagnostic imaging method, because its diagnostic accuracy is relatively low, especially in patients with small HCC. [bib_ref] A prospective evaluation of 18F-FDG and 11C-acetate PET/CT for detection of primary..., Park [/bib_ref] The accuracy of noninvasive diagnostic criteria largely depends on the size of the nodules. As the size of the nodules increases, their differentiation becomes poorer. [bib_ref] Early hepatocellular carcinoma and dysplastic nodules, Kojiro [/bib_ref] [bib_ref] Detection and characterization of hepatocellular carcinoma by imaging, Matsui [/bib_ref] As an HCC lesion grows, it begins to exhibit the typical hallmark of HCC, i.e., hypervascularity in the arterial phase with washout in the portal or delayed phases due to the gradual growth of tumor arteries and regression of portal flow. [bib_ref] Recent advances in the diagnosis of hepatocellular carcinoma, Piscaglia [/bib_ref] [bib_ref] Detection and characterization of hepatocellular carcinoma by imaging, Matsui [/bib_ref] Nowadays, small nodules <1 cm in diameter showing the typical hallmark of HCC are being detected more frequently because of recent advances in imaging technologies. Many guidelines from Asia allow the diagnosis of HCC on the basis of these small nodules. [bib_ref] Management of hepatocellular carcinoma in Japan: consensus-based clinical practice guidelines proposed by..., Kudo [/bib_ref] [bib_ref] Asian Pacific Association for the Study of the Liver consensus recommendations on..., Omata [/bib_ref] The pathologic diagnosis of HCC requires an adequate specimen through biopsy. However, biopsy is not always feasible because of the location of the target lesion and potential risk of complications such as bleeding and tumor seeding, especially in cirrhotic patients. The diagnostic sensitivity of fine-needle aspiration cytology, fine-needle aspiration biopsy, and core needle biopsy are reported to be 67% to 93% but much lower in patients with small HCC <2 cm or targeting problems. [bib_ref] Pathology of early hepatocellular carcinoma: conventional and molecular diagnosis, Roskams [/bib_ref] [bib_ref] Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective validation..., Forner [/bib_ref] As the risk of tumor seeding due to needle biopsy is reported to be 0.6% to 5.1%, the need for biopsy for patients with HCC curable by surgical resection is being challenged. [bib_ref] Seeding following percutaneous diagnostic and therapeutic approaches for hepatocellular carcinoma: what is..., Stigliano [/bib_ref] [bib_ref] Needle track seeding following biopsy of liver lesions in the diagnosis of..., Silva [/bib_ref] In addition, the false negativity of biopsy is reported to be approximately 33%. [bib_ref] Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective validation..., Forner [/bib_ref] The diagnosis of HCC for liver nodules detected by surveil-lance is based on noninvasive criteria or pathology , . Noninvasive criteria can only be applied to high-risk groups (i.e., HBV/HCV infection and liver cirrhosis) and are based on imaging including dynamic CT, dynamic MRI, and MRI using a hepatocyte-specific contrast agent. Diagnosis should be based on the identification of the typical hallmark of HCC (i.e., hypervascularity in the arterial phase and washout in the portal or delayed phase) for liver nodules ≥1 cm in diameter. [bib_ref] Management of hepatocellular carcinoma in Japan: consensus-based clinical practice guidelines proposed by..., Kudo [/bib_ref] [bib_ref] Comparison of usefulness of clinical diagnostic criteria for hepatocellular carcinoma in a..., Bae [/bib_ref] One or more imaging techniques are usually recommended for noninvasive diagnosis for these nodules; however, one or more imaging techniques are required in optimal settings (Appendices 5 and 6), whereas two or more are recommended in suboptimal settings for nodules 1-2 cm in diameter.In addition, stricter criteria are warranted for the diagnosis of HCC in cases of nodules <1 cm. Diagnosis should be based on the combination of the identification of the typical hallmark of HCC in two or more imaging modalities and increased serum AFP with an increasing trend over time for liver nodules <1 cm in patients with suppressed hepatitis activity. [bib_ref] Hypervascular hepatocellular carcinoma 1 cm or smaller in patients with chronic liver..., Kim [/bib_ref] Biopsy should be considered for atypical nodules not meeting the noninvasive criteria. Any changes in the size or characteristics of nodules or serum tumor markers should be monitored if noninvasive or pathologic diagnosis is unfeasible for liver nodules in high-risk patients. ## Diagnostic x-ray radiation exposure dose and risk of dynamic ct in hcc patients A study of low-dose radiation in atomic bomb survivors indicates a significant increase in cancer risk even from acute 10-50 mSv radiation exposure. [bib_ref] Radiation-related cancer risks at low doses among atomic bomb survivors, Pierce [/bib_ref] In addition, studies of occupational radiation exposure suggest protracted 50-100 mSv exposure can increase cancer risk in humans. [bib_ref] Report 13: solid cancer and noncancer disease mortality, Preston [/bib_ref] [bib_ref] First analysis of cancer incidence and occupational radiation exposure based on the..., Sont [/bib_ref] [bib_ref] Risk of cancer after low doses of ionising radiation: retrospective cohort study..., Cardis [/bib_ref] The International Commission on Radiological Protection (ICRP) reports that the cancer risk after radiation exposure exhibits a linear-nonthreshold dose-response relationship. [bib_ref] Invited commentary: studies of workers exposed to KLCSG and NCC: Practice Guideline..., Gilbert [/bib_ref] [bib_ref] National Coluncil on Radiation Protection and Measurements Scientific Committee 1-6. The state..., Upton [/bib_ref] However, there is no report on direct diagnostic X-ray radiation exposure-related cancer risk. The dose of radiation exposure of 4-phase liver dynamic CT is approximately 20-30 mSv. According to BEIR VII phase 2 trial by the Committee to Assess Heath Risks from Exposure to Low Levels of Ionizing Radiation, the additional lifetime attribut- . Diagnosis of Hepatocellular Carcinoma 1. Noninvasive diagnosis: in high-risk groups (i.e., HBV/HCV infection, liver cirrhosis) 1) For liver nodules 1 cm found by surveillance: If the typical hallmark of HCC* is identified on one or more (two or more † ) imaging techniques ‡ 2) For nodules <1 cm found by surveillance: If the typical hallmark of HCC* is identified in two or more imaging techniques ‡ and increased serum AFP with an increasing trend over time is noted in patients with suppressed hepatitis activity 2. Pathologic diagnosis HBV, hepatitis B virus; HCV, hepatitis C virus; HCC, hepatocellular carcinoma; AFP, a-fetoprotein. Hypervascularity in the arterial phase and washout in the portal or delayed phase; † For 1-2-cm nodules, the diagnosis should be based on the identification of the typical hallmark of HCC in one or more imaging techniques in optimal settings (Appendices 5 and 6) and in two or more imaging techniques in suboptimal settings; ‡ Dynamic computed tomography, dynamic magnetic resonance imaging, gadolinium-ethoxybenzyldiethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging magnetic resonance imaging. able solid cancer and leukemia incidence and mortality rates are 0.148% and 0.09%, respectively, in 50-year-old men with 25 mSv X-ray radiation exposure after a 4-phase liver dynamic CT. [bib_ref] Converting dose-length product to effective dose at CT, Huda [/bib_ref] The ICRP 2007 recommendations are as follows: "The limitation of the dose to the individual patient is not recommended because it may, by reducing the effectiveness of the patient's diagnosis or treatment, do more harm than good. The emphasis is then on the justification of the medical procedures and on the optimization of protection."Thus, considering the abovementioned factors, any limitation of the cumulative radiation dose from CT for the diagnosis and follow-up evaluation of HCC is invalid. Recommendations [fig_ref] Table 2: Summary of the Recommendations of the 2014 KLCSG-NCC Korea Practice Guidelines for... [/fig_ref] 1. HCC is diagnosed on the basis of either pathology or clinical criteria in case of the high-risk group (HBV/HCV positive or cirrhosis) (A1). 2. When HCC is suspected during surveillance in the highrisk group, dynamic contrast-enhanced CT/MRI or liver-specific contrast-enhanced MRI should be performed for diagnosis (B1). 3. In the high-risk group, HCC can be diagnosed for nodules ≥1 cm in diameter if one or two of the above-mentioned imaging techniques show typical features of HCC (for the diagnosis of nodules 1-2 cm in diameter, two or more imaging modalities are required if a suboptimal imaging technique is used). Typical features of HCC include arterial phase enhancement with washout in the portal or delayed phase (B1). 4. Nodules <1 cm in diameter can be diagnosed as HCC in high-risk patients when all of the following conditions are met: typical features of HCC in two or more of the above-mentioned imaging modalities and continuously rising serum AFP with hepatitis activity under control (C1). 5. Pathological diagnosis should be considered when the clinical criteria are not met or typical features of HCC are not present. The presence of indeterminate nodules despite imaging workups or pathologic examination needs to be followed up with repeated imaging and serum tumor marker analysis (B1). 6. Limitation of radiation exposure in diagnosis and staging is not considered relevant in patients with HCC. CT is essential for diagnosis and follow-up in HCC patients (C1). ## Staging Cancer staging plays a pivotal role in predicting prognosis as well as selecting the therapy to maximize survival potential. It also facilitates exchange of information and trial design. The prediction of prognosis in HCC patients is complex, because underlying liver function also affects prognosis. [bib_ref] Natural history and prognostic indicators of survival in cirrhosis: a systematic review..., D'amico [/bib_ref] Although several staging systems for patients with HCC have been devised, there is no worldwide consensus. [bib_ref] Clinical staging of hepatocellular carcinoma, Meier [/bib_ref] The American Joint Committee on Cancer (AJCC) has led a collaborative effort with the International Union for Cancer Control (UICC) to maintain a cancer staging system since 1959. This system classifies the extent of disease mostly on the basis of anatomic information on the extent of the primary tumor, regional lymph nodes, and distant metastases (i.e., TNM) and has been modified repeatedly. The Korean Liver Cancer Study Group and The Korea National Cancer Center have adopted the fifth version of the mUICC staging system as a primary staging system for HCC in 2003 [fig_ref] Table 4: Modified [/fig_ref].Thus, the continuous use of this staging system since then may facilitate consistency in the analyses of registry data.The mUICC staging system appears more advantageous for estimating the prognosis of small HCC because it sets the size criterion to 2 cm unlike the AJCC/ UICC, which used a criterion of 5 cm.sion of the mUICC staging system has limitations, particular its lack of extensive validation and different criteria compared with those of the current seventh AJCC/UICC TNM staging system. In addition to dynamic CT or MR imaging of the primary liver tumor, chest CT, bone, and PET-CT scans may be required to stage HCC. The risk of distant metastasis is low for patients with early-stage HCC; 82 therefore, tests for the evaluation of extrahepatic metastasis should be carefully selected. The direct or indirect evaluation of portal hypertension is also required, especially for patients who are being considered for surgical resection. The Barcelona Clinic Liver Cancer (BCLC) staging system includes factors for tumor stage, degree of liver function, and performance status of the patient. It suggests the most recommendable treatment modality for each stage and is being endorsed by the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), and the European Organisation for Research and Treatment of Cancer (EORTC). [bib_ref] Management of hepatocellular carcinoma, Bruix [/bib_ref] However, the use of the BCLC staging system is limited because it contains a subjective component (i.e., performance status), crude evaluation of liver function (i.e., Child-Pugh class), and unduly simplified recommendations for treatment modality. Recommendations [fig_ref] Table 2: Summary of the Recommendations of the 2014 KLCSG-NCC Korea Practice Guidelines for... [/fig_ref] 1. This guideline adopted the mUICC stages as a primary staging system, with the BCLC staging system serving as a complementary system (B1). [fig_ref] Table 1: Grading of Recommendations, Assessment, Development, and Evaluation [/fig_ref] Adapted from the Liver Cancer Study Group of Japan. ## Treatment overview The ultimate goal of treatment for HCC is improvement of patient survival. This requires multidisciplinary treatment planning including hepatology, oncology, surgery, diagnostic and interventional radiology, radiation oncology, and pathology. Therapies should be selected on the basis of strong evidence such as meta-analyses including randomized controlled trials (RCTs), prospective controlled studies, and prospective largescale cohort studies, all of which have survival as an endpoint. However, RCTs regarding HCC are limited. Therefore, currently available evidence should be interpreted cautiously. For balanced multidisciplinary treatment planning, objective evaluation is necessary in clinical practice. The recommendations in this guideline were derived from the current best available evidence. Prerequisites for the application of these recommendations include equipment, trained personnel, and financial resources; considering the varying levels of these prerequisites among facilities, best and alternative options are proposed herein . As the treatment options presented herein do not encompass all possible situations, specific treatments should be selected on the basis of tumor state, liver function, cirrhotic complications, and performance status. Recommendations for specific treatments are made on the basis of evidence and expert opinions, and are described in detail elsewhere in this guideline. This overview summarizes treatment options for patients in various mIUCC stages with well-preserved hepatic function (i.e., Child-Pugh class A) and good performance status, without any complications of portal hypertension. In addition, this guideline mainly includes initial treatment options for HCC at first diagnosis, without covering re-treatments for residual tumors or recurrence after initial treatment. ## Hepatic resection Hepatic resection is not only a primary treatment option for HCC unaccompanied by liver cirrhosis, 84 but should also be preferentially considered even for HCC with cirrhosis if the liver function is expected to be able to tolerate surgery. [bib_ref] Major liver resections for hepatocellular carcinoma on cirrhosis: early and long-term outcomes, Capussotti [/bib_ref] [bib_ref] Improving survival results after resection of hepatocellular carcinoma: a prospective study of..., Poon [/bib_ref] The results of hepatic resection for HCC have markedly improved thanks to recent advances in preoperative tests and surgical skills as well as accumulation of experience in postoperative management. [bib_ref] Improved long-term survival after major resection for hepatocellular carcinoma: a multicenter analysis..., Andreou [/bib_ref] Recent studies show that postoperative mortality after HCC resection is less than 1%-3%. In addition, the 5-year overall and disease-free survival rates are 46%-56% and 23%-32%, respectively. [bib_ref] Saftey and long-term outcome following major hepatectomy for hepatocellular carcinoma combined with..., Kim [/bib_ref] [bib_ref] A modified TNM-7 staging system to better predict the survival in patients..., Huang [/bib_ref] [bib_ref] A snapshot of the effective indications and results of surgery for hepatocellular..., Torzilli [/bib_ref] Child-Pugh classification is conventionally used to preoperatively assess the safety of hepatic resection [fig_ref] Table 5: Child-Pugh Classification [/fig_ref].Hepatic resection is commonly performed in patients with Child-Pugh class A with Eastern Cooperative Oncology Group (ECOG) performance status 0-2 [fig_ref] Table 6: Eastern Cooperative Oncology Group Performance Status* [/fig_ref]. However, Child-Pugh classification is an insufficient preoperative indicator of operability, because many patients can remain in Child-Pugh class A despite advanced cirrhosis. [bib_ref] Risk of major liver resection in patients with underlying chronic liver disease:..., Farges [/bib_ref] [bib_ref] Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the..., Belghiti [/bib_ref] Therefore, the indocyanine green 15-minute retention rate (ICG-R15), which was suggested in Japan, is evaluated at many Korean institutions as a preoperative test for the prediction of residual liver function. [bib_ref] The surgical approach to HCC: our progress and results in Japan, Makuuchi [/bib_ref] Although major hepatic resection is recommended only for patients with ICG-R15 ≤10%, some authors recently reported safely performing right hemihepatectomy even in patients with an ICG-R15 of 14%. [bib_ref] Hospital mortality of major hepatectomy for hepatocellular carcinoma associated with cirrhosis, Fan [/bib_ref] On the other hand, portal hypertension and serum bilirubin level have been suggested to be important indicators for the assessment of resectability in Europe and the USA. Portal hypertension is defined as a hepatic venous pressure gradient ≥10 mm Hg. [bib_ref] Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation, Llovet [/bib_ref] Esophageal varix and thrombocytopenia <100,000/ mm 3 accompanied by splenomegaly are also indicators of portal hypertension, and thrombocytopenia is considered the most clinically useful.The posthepatectomy complication rate is Class A ≤6 points, Class B=7-9 points, Class C ≥10 points. high and the long-term prognosis is poor in patients with portal hypertension. [bib_ref] Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation, Llovet [/bib_ref] [bib_ref] The adverse effect of indirectly diagnosed portal hypertension on the complications and..., An [/bib_ref] [bib_ref] Predictive factors for longterm survival in patients with clinically significant portal hypertension..., Choi [/bib_ref] However, some recent studies show comparable outcomes can be achieved even in patients with portal hypertension. [bib_ref] Portal hypertension: contraindication to liver surgery?, Capussotti [/bib_ref] [bib_ref] Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma, Ishizawa [/bib_ref] [bib_ref] Is portal hypertension a contraindication to hepatic resection?, Cucchetti [/bib_ref] Therefore, hepatic resection can also be considered the primary treatment option in patients with mild portal hypertension if LT is unavailable. Minor hepatic resection less than hemihepatectomy should be considered in patients with mild portal hypertension, because resection volume is closely associated with the risk of postoperative hepatic insufficiency. Assessment of future liver volume or remnant liver volume after resection is as important as the hepatic reservoir function test in order to predict postoperative hepatic insufficiency. HCC is accompanied by chronic liver disease in 80% of cases. Although 70%-80% of the liver's volume can be resected for normal livers, much less resection volume is allowed for diseased livers. There are few studies about the safe remnant liver volume in patients with cirrhosis. Nevertheless, a remnant liver volume ≥40% is generally recommended in cirrhotic patients for safety. [bib_ref] How much remnant is enough in liver resection, Guglielmi [/bib_ref] Several noninvasive tests to measure the severity of hepatic fibrosis have been developed. Among them, transient elastography was recently reported to be effective for predicting postoperative hepatic failure. [bib_ref] Liver stiffness measurement by transient elastography as a predictor on posthepatectomy outcomes, Wong [/bib_ref] [bib_ref] Value of transient elastography measured with FibroScan in predicting the outcome of..., Cescon [/bib_ref] In the near future, transient elastography is expected to play an important role in the preoperative assessment of hepatic functional reservoir. Dynamic contrast-enhanced CT is the basic test utilized as a preoperative radiologic study to assess the possibility of resection. MRI using a hepatic cell-specific contrast medium is superior to CT for HCC detection, especially for small HCCs <1 cm. [bib_ref] Diagnostic efficacy of gadoxetic acid (Primovist)-enhanced MRI and spiral CT for a..., Hammerstingl [/bib_ref] [bib_ref] Gadoxetic acid-enhanced MRI versus triple-phase MDCT for the preoperative detection of hepatocellular..., Kim [/bib_ref] Nevertheless, more studies are required to validate the value of MRI as the basic radiologic study for assessing resectability and formulating resection plans. Further postoperative examinations may be necessary to find extrahepatic metastases in patients with advanced HCC. 18 F-fluoro-2-deoxyglucose ( 18 F-FDG) PET-CT may be effective for investigating extrahepatic metastasis, although its sensitivity is very low for intrahepatic lesions. [bib_ref] A prospective evaluation of 18F-FDG and 11C-acetate PET/CT for detection of primary..., Park [/bib_ref] In addition, chest CT and bone scan may be helpful.Transarterial chemoembolization (TACE), performed before hepatic resection for the purpose of improving postoperative prognosis, is not recommended. [bib_ref] The effect of preoperative transarterial chemoembolization on the patient's outcome in resectable..., Kim [/bib_ref] [bib_ref] Preoperative transcatheter arterial chemoembolization for resectable large hepatocellular carcinoma: a reappraisal, Wu [/bib_ref] Some reports assert that portal vein embolization before extensive hepatic resection might induce compensatory hypertrophy of the residual liver and reduce the risk of surgery, especially in cases with liver cirrhosis; nonetheless, these are largely debatable. [bib_ref] Portal vein embolization before right hepatectomy: prospective clinical trial, Farges [/bib_ref] [bib_ref] Preoperative portal vein embolization improves prognosis after right hepatectomy for hepatocellular carcinoma..., Tanaka [/bib_ref] One reason why hepatic resection has recently become safer is the reduction in the amount of intraoperative hemorrhage, thus minimizing the amount of blood transfusion required. Blood transfusion compromises anticancer immunologic mechanisms and increases postoperative recurrence. A recent meta-analysis reports that intraoperative transfusion increases complication rates and reduces overall and disease-free survival rates after resection in HCC patients. [bib_ref] Perioperative allogenenic blood transfusion is associated with worse clinical outcomes for hepatocellular..., Liu [/bib_ref] Owing to selective hepatic blood flow occlusion, maintaining low central venous pressure, and precise transection of the hepatic parenchyma, the recent rate of transfusion in hepatic resection is ≤10%. [bib_ref] Selective hepatic vascular exclusion for the hepatic resection of HCC, Tsujita [/bib_ref] Although some reports suggest anatomical resection may be superior to nonanatomical resection by securing the resection margin and removing micro-metastases, [bib_ref] Comparison of the outcomes between an anatomical subsegmentectomy and a non-anatomical minor..., Eguchi [/bib_ref] further confirmation is required, because the results are inconsistent. [bib_ref] Anatomic versus limited nonanatomic resection for solitary hepatocellular carcinoma, Tanaka [/bib_ref] Surgery guaranteeing a tumorfree resection margin is absolutely critical for improving longterm prognosis. One prospective randomized trial shows that a resection margin >2 cm leads to better outcomes after HCC resection. [bib_ref] Partial hepatectomy with wide versus narrow resection margin for solitary hepatocellular carcinoma:..., Shi [/bib_ref] Meanwhile, another study reports that the resection margin width is not important so long as a tumor-negative margin is guaranteed. [bib_ref] Significance of resection margin in hepatectomy for hepatocellular carcinoma: a critical reappraisal, Poon [/bib_ref] Therefore, although sufficient margin from the tumor and anatomical resection are recommended during HCC resection if possible, considering patient safety is more important, because excessive hepatic resection can be fatal in patients with cirrhosis. [bib_ref] Comparison of the outcomes between an anatomical subsegmentectomy and a non-anatomical minor..., Eguchi [/bib_ref] [bib_ref] Systematic hepatectomy for small hepatocellular carcinoma in Korea, Suh [/bib_ref] [bib_ref] Anatomic resection independently improves long-term survival in patients with T1-T2 hepatocellular carcinoma, Wakai [/bib_ref] Laparoscopic hepatic resection has advanced rapidly, and its indications have been expanded. Many studies show that the efficacy and safety of laparoscopic hepatic resection is comparable to those of open hepatic resection for small HCCs located in the left lateral section or on the surface of the right liver.Although laparoscopic major hepatic resection is increasingly being performed as well, it is currently limited to only experienced surgeons. Accordingly, its efficacy and safety should be evaluated further. [bib_ref] World review of laparoscopic liver resection-2,804 patients, Nguyen [/bib_ref] Robotic hepatic resection has recently been tried in very select cases, and comparative studies between robotic hepatic resection and open or laparoscopic hepatic resection are expected. [bib_ref] Robot-assisted laparoscopic liver resection for hepatocellular carcinoma: short-term outcome, Lai [/bib_ref] The best prognosis after hepatic resection is generally expected in cases involving 1 or 2 small tumors. Larger tumors are associated with a high incidence of vascular invasion result in poor prognosis even after resection. However, a recent study shows that approximately one-third of large HCCs ≥10 cm have no vascular invasion and favorable results after resection in those cases. Therefore, the resectability for HCC should not be decided upon according to tumor size. [bib_ref] Simplified staging for hepatocellular carcinoma, Vauthey [/bib_ref] [bib_ref] Critical appraisal of the clinical and pathologic predictors of survival after resection..., Pawlik [/bib_ref] [bib_ref] Outcome of patients with huge hepatocellular carcinoma after primary resection and treatment..., Lee [/bib_ref] Recent advances in surgical techniques and improvements in patient management have enabled hepatic resection in elderly patients with comparable short-and long-term outcomes. Nevertheless, major hepatic resection should be considered with caution, because hepatic regeneration power gradually decreases with age. [bib_ref] Treatment for hepatocellular carcinoma in elderly patients: a literature review, Nishikawa [/bib_ref] [bib_ref] Aging reduces proliferative capacities of liver by switching pathways of C/EBPalpha growth..., Iakova [/bib_ref] [bib_ref] Hepatic insufficiency and mortality in 1,059 noncirrhotic patients undergoing major hepatectomy, Mullen [/bib_ref] Although some authors reported that one-stage hepatic resection was an effective method for ruptured HCC in patients with good liver function, 131 first hemostasis by TACE and subsequent elective surgery after accurate assessment of hepatic reservoir function would be safer and more effective in hemodynamically unstable patients. [bib_ref] Characteristics and prognosis after resection for ruptured hepatocellular carcinoma, Bae [/bib_ref] [bib_ref] Multidisciplinary management of ruptured hepatocellular carcinoma, Buczkowski [/bib_ref] However, ruptured cases have poorer long-term results than unruptured HCC cases. [bib_ref] Predictors and clinical outcomes for spontaneous rupture of hepatocellular carcinoma, Zhu [/bib_ref] Hepatic resection is generally contraindicated in cases with evident tumor invasion to major hepatic or portal veins. In patients with less hepatic fibrosis or those with a well-differentiated HCC of low Edmondson-Steiner grade, the 5-year survival rate after resection of HCC with major vascular invasion is reported to be ≥20%. [bib_ref] Hepatectomy for hepatocellular carcinoma with major portal or hepatic vein invasion: results..., Pawlik [/bib_ref] Nevertheless, surgical resection would be at least more effective than medical treatment. [bib_ref] Resection of hepatocellular carcinoma with macroscopic vascular invasion, Roayaie [/bib_ref] According to a Korean multicenter study, the 5-year survival rate after resection of HCC with bile duct invasion was satisfactory at 32%. [bib_ref] Surgical outcomes of hepatocellular carcinoma with bile duct tumor thrombus: a Korean..., Moon [/bib_ref] Hence, surgical resection can be considered even for HCC with major vascular invasion or bile duct invasion in select cases. The hanging maneuver is frequently used during hepatic resection. However, there is no report about the effect of the hanging maneuver on survival or recurrence after HCC resection. Nevertheless, the hanging maneuver can shorten operative time and reduce the amount of bleeding. [bib_ref] Liver hanging maneuver: a safe approach to right hepatectomy without liver mobilization, Belghiti [/bib_ref] The anterior approach, which is often used for the resection of large tumors, is associated with less bleeding, a lower transfusion rate, and better survival in one prospective study. [bib_ref] Anterior approach versus conventional approach right hepatic resection for large hepatocellular carcinoma:..., Liu [/bib_ref] However, its pathologic advantages require further evaluation. The 5-year recurrence rate after hepatic resection of HCC ranges from 58% to 81%, and 80% to 95% of postoperative recurrences are intrahepatic. [bib_ref] Selection criteria for repeat hepatectomy in patients with recurrent hepatocellular carcinoma, Minagawa [/bib_ref] Intrahepatic recurrences are divided into intrahepatic metastasis and de novo HCC by multicentric carcinogenesis. The two recurrence entities can be differentiated by means of genomic hybridization, DNA fingerprinting, DNA microarray, or HBV integration pattern. [bib_ref] Microdissectionbased allelotyping discriminates de novo tumor from intrahepatic spread in hepatocellular carcinoma, Finkelstein [/bib_ref] However, no clinical definition of either entity has been established. In general, late recurrence more than 2 years after primary resection is considered de novo HCC. [bib_ref] Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular..., Imamura [/bib_ref] Risk factors associated with recurrence after resection are classified as tumor-related factors and underlying disease-related factors. Tumor-related risk factors, which are usually related to early recurrence, include tumor size and number, microvascular invasion, poor tumor differentiation, high serum AFP and PIVKA-II levels, and positivity on 18 F-FDG PET. Meanwhile, underlying disease-related risk factors, which influence late recurrence, include cirrhosis, high serum HBV DNA level, and active hepatitis. [bib_ref] A prospective evaluation of 18F-FDG and 11C-acetate PET/CT for detection of primary..., Park [/bib_ref] [bib_ref] Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular..., Imamura [/bib_ref] [bib_ref] Prognostic factors of solitary large hepatocellular carcinoma: the importance of differentiation grade, Zhou [/bib_ref] [bib_ref] Predictors of survival after resection of early hepatocellular carcinoma, Nathan [/bib_ref] [bib_ref] Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and..., Portolani [/bib_ref] [bib_ref] Predictors of microvascular invasion before hepatectomy for hepatocellular carcinoma, Kaibori [/bib_ref] [bib_ref] Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma, Wu [/bib_ref] Nevertheless, no association between risk factors and recurrence time is evident in many cases, because this time-dependent classification does not actually reflect the tumor-pathologic mechanism of HCC recurrence. Imaging modalities such as CT and MRI as well as serum tumor markers are recommended surveillance tools during followup. Serum AFP, a traditional tumor marker of HCC, is not only useful for the diagnosis of HCC, but is also effective for checking for recurrence after resection. PIVKA-II is another HCC marker with increasing utility for diagnosis, follow-up, and prognostication of HCC. [bib_ref] Predictors of microvascular invasion before hepatectomy for hepatocellular carcinoma, Kaibori [/bib_ref] [bib_ref] PIVKA-II is a useful tumor marker for recurrent hepatocellular carcinoma after surgical..., Kim Do [/bib_ref] The 5-year survival rate of patients who undergo re-resection of intrahepatic recurrence after initial surgery ranges from 37% to 70%. [bib_ref] Selection criteria for repeat hepatectomy in patients with recurrent hepatocellular carcinoma, Minagawa [/bib_ref] [bib_ref] Prognostic factors and optimal treatment strategy for intrahepatic nodular recurrence after curative..., Choi [/bib_ref] [bib_ref] Efficacy of repeat hepatic resection for recurrent hepatocellular carcinomas, Nagano [/bib_ref] [bib_ref] Long-term outcomes of repeat hepatic resection in patients with recurrent hepatocellular carcinoma..., Huang [/bib_ref] Because the result of re-resection is excellent in cases with a long interval between initial surgery and tumor recurrence, re-resection can be recommended particularly for patients with late intrahepatic recurrence 1-2 years after initial resection as long as vascular invasion of the tumor is not evident and liver function is tolerable to re-operation. In addition, salvage transplantation could result in an excellent disease-free survival rate >60% if the conditions of the patient and recurrent tumors are suitable for transplantation. [bib_ref] Treatment strategy for recurrent hepatocellular carcinoma: salvage transplantation, repeated resection, or radiofrequency..., Chan [/bib_ref] [bib_ref] Systematic review of efficacy and outcomes of salvage liver transplantation after primary..., Chan [/bib_ref] Extrahepatic recurrence develops in 15%-37% of cases after HCC resection, most frequently in the lungs followed by the abdominal cavity and bones. [bib_ref] Extrahepatic metastases of hepatocellular carcinoma, Katyal [/bib_ref] Metastatectomy can also be considered when the liver function can tolerate surgery and intrahepatic HCCs have been clearly treated or are controllable. [bib_ref] Prognostic factors for pulmonary metastasectomy in hepatocellular carcinoma, Kuo [/bib_ref] [bib_ref] Pulmonary resection for metastases from hepatocellular carcinoma: factors influencing prognosis, Nakagawa [/bib_ref] Recommendations [fig_ref] Table 2: Summary of the Recommendations of the 2014 KLCSG-NCC Korea Practice Guidelines for... [/fig_ref] 1. Surgical resection is the first-line treatment for patients with intrahepatic single-nodular HCC and well-preserved liver function of Child-Pugh class A without portal hypertension or hyperbilirubinemia (A1). 2. Limited resection can be selectively applied to HCC patients with liver function Child-Pugh class A or superb B and with mild portal hypertension or mild hyperbilirubinemia (C1). 3. HCC Resection can be considered in patients with three or fewer intrahepatic tumors without macrovascular invasion if hepatic function is well preserved (C2). 4. Laparoscopy-assisted resection can be considered for HCC located in the lateral section of the left lobe or anterolateral segment of the right lobe (B2). ## Liver transplantation LT is the first choice of treatment for patients with single tumors ≤5 cm or those with small multinodular tumors (≤3 nodules ≤3 cm) and advanced liver dysfunction. LT involves complete removal of a diseased liver including HCC and replacement with another liver. It is theoretically the ideal treatment method. The application of broad selection criteria in the early history of LT resulted in very poor outcomes, with a 5-year survival less than 40%; there was even a time when LT was relatively contraindicated. [bib_ref] Liver transplantation for malignant tumors, Koneru [/bib_ref] [bib_ref] Hepatic resection versus transplantation for hepatocellular carcinoma, Iwatsuki [/bib_ref] However, this resulted in the identification of the best candidates, and subsequent studies with highly specific groups of patients report a 5-year disease-free survival rate of 74%. [bib_ref] Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients, Bismuth [/bib_ref] [bib_ref] Liver transplantation for hepatocellular carcinoma, Bismuth [/bib_ref] The Milan Group in Italy reports excellent results after LT, showing that patients with the following characteristics have 4-year survival and disease-free survival rates of 75% and 83%, respectively: (1) no extrahepatic metastasis or vascular infiltration in radiologic study before LT; (2) a single nodule ≤5 cm; (3) ≤3 nodules in cases of multiple nodules, with each nodule ≤3 cm. Accordingly, they suggest those criteria for LT in patients with HCC. [bib_ref] Liver transplantation for the treatment of small hepatocellular carcinomas in patients with..., Mazzaferro [/bib_ref] Since then, the Milan criteria have widely been applied for LT in patients with HCC. A recent systematic review of 90 studies including a total of 17,780 patients over 15 years identified the Milan criteria as an independent prognostic factor after LT. The overall 5-year survival rate of patients meeting the Milan criteria (65%-78%) is similar to that of non-HCC patients according to European and American transplant registries. [bib_ref] Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of..., Mazzaferro [/bib_ref] Recent advances in imaging technologies have enabled the noninvasive diagnosis of HCC with higher accuracy. However, small lesions that could not be detected by imaging studies when the Milan criteria were established can often be seen on imaging studies using current technologies, causing confusion as to whether a patient meets the Milan criteria or not. A recent meta-analysis including 22,392 patients concludes that the size of the largest tumor and total diameter of nodules are the best predictors of outcome but that there is insufficient evidence regarding the effect of nodule number on the outcome of LT. [bib_ref] Which matters most: number of tumors, size of the largest tumor, or..., Germani [/bib_ref] Sugimachi et al.also report poor diagnostic accuracy of radiologic imaging for small (<1 cm) HCCs and their small effect on prognosis after LT. Therefore, lesions ≤10 mm or showing atypical imaging features should not be considered when deciding upon LT. Before LT, patients with HCC undergo tests for staging in addition to general whole-body examination. Dynamic contrastenhanced CT or MRI is performed as a radiologic assessment of the liver itself. Extrahepatic staging should include chest CT, and abdominal and pelvic CT or MRI. [bib_ref] Imaging diagnosis and staging of hepatocellular carcinoma, Lee [/bib_ref] Brain imaging and bone scintigraphy can also be performed. Moreover, 18 F-FDG PET-CT can help clarify the biologic characteristics of HCC, because PET-positive tumors exhibit unfavorable histological features more frequently (e.g., high cellular dedifferentiation and microvascular invasion), resulting in worse recurrence-free survival after LT. [bib_ref] The role of (18)F-FDG-PET imaging for the selection of liver transplantation candidates..., Yang [/bib_ref] [bib_ref] 18F-FDG-uptake of hepatocellular carcinoma on PET predicts microvascular tumor invasion in liver..., Kornberg [/bib_ref] Although there is neither a specific study nor consensus on the optimal timing or modality of evaluation of wait-listed patients to ensure they continue to meet the acceptability criteria for LT, re-evaluation with a 3-month interval is commonly performed with dynamic CT or MRI and AFP measurement. [bib_ref] Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report, Clavien [/bib_ref] ## Deceased donor liver transplantation Deceased liver donors are always in shortage. Accordingly, many patients are waiting for LT at any given time. Patients with HCC must undergo a long waiting period from registration to LT. The American United Network for Organ Sharing (UNOS) introduced the Model for End-stage Liver Disease (MELD) scoring system in order to decide on the priority order for LT. Patients with HCC involving a single nodule between 2 and 5 cm or multinodular tumors (≤3 nodules ≤3 cm) are given the priority MELD score of 22 points as well as 10% additional points for every 3 months waiting for LT; thus, similar risks of dropout from the waiting-list can be expected between HCC patients and non-HCC candidates. [bib_ref] The new liver allocation system: moving toward evidence-based transplantation policy, Freeman [/bib_ref] [bib_ref] Report of a national conference on liver allocation in patients with hepatocellular..., Pomfret [/bib_ref] Meanwhile, Korean the National Organ Transplantation Management Center operates the Korean Network for Organ Sharing (KONOS) grading system.In this system, no additional points are given to patients with HCC. The provision in the KONOS grading system regarding patients with HCC specifies that cases with a Child-Turcott-Pugh score ≥7 points and simultaneously meeting the Milan criteria belong to KONOS grade 2B. Patients with KONOS grade 2B are pushed back in the priority order, and will not be able to undergo LT in a short time. [bib_ref] Liver transplantation for adult patients with hepatocellular carcinoma in Korea: comparison between..., Hwang [/bib_ref] According to a recent multicenter study in Korea (n=1,101; mean follow-up, 349 days), 23.5% of waitlisted patients with HCC dropped out. The most frequent reason for dropping out was aggravation of liver function (46.7%), followed by aggravation of HCC (36.3%). Aggravation of HCC was observed in 44.8% (241/538) of patients while on the waiting list; 14.2% and 48.1% of aggravations occurred within 1 year and between 1 and 2 years after listing, respectively. [bib_ref] Comparison between Status with CTP score and MELD score in allocation of..., Kim [/bib_ref] The overall survival of patients with HCC was significantly worse than that of patients without HCC. The impact of HCC on the LT waiting list drop-out rate was significant only in patients with a MELD score <20. [bib_ref] Comparison between Status with CTP score and MELD score in allocation of..., Kim [/bib_ref] If the cutoff for the definition of a cure is a 5-year survival rate of 50% after LT in patients with HCC, the indications for LT could be expanded beyond the Milan criteria. [bib_ref] Novel advancements in the management of hepatocellular carcinoma in 2008, Llovet [/bib_ref] Some studies chose a 5-year survival rate cutoff of 70%, because it is similar to the rate expected for patients undergoing LT for noncancerous conditions and liver grafts from deceased donors. [bib_ref] Toward optimizing the indications for orthotopic liver transplantation in hepatocellular carcinoma, Samuel [/bib_ref] [bib_ref] Liver transplantation for hepatocellular carcinoma: impact of the MELD allocation system and..., Ioannou [/bib_ref] [bib_ref] A novel model measuring the harm of transplanting hepatocellular carcinoma exceeding Milan..., Volk [/bib_ref] The University of California, San Francisco (UCSF) Group reports a 5-year survival rate of 75% for patients meeting the following criteria: (1) a single tumor ≤6.5 cm; (2) <3 nodules in multiple HCC cases, with the longest diameter <4.5 cm and the sum of diameters <8 cm. [bib_ref] Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does..., Yao [/bib_ref] In addition, the "up-to-seven criteria," (i.e., the number 7 as the sum of the largest tumor diameter plus the number of tumors) have also been suggested; the 5-year survival rate of patients meeting these criteria is 71.2%.Microvascular invasion in pretransplant biopsy, tumor volume, and AFP levels are also considered in the expanded indications for LT. [bib_ref] Progression of alphafetoprotein before liver transplantation for hepatocellular carcinoma in cirrhotic patients:..., Vibert [/bib_ref] [bib_ref] Total tumor volume predicts risk of recurrence following liver transplantation in patients..., Toso [/bib_ref] ## Bridging therapy The actuarial probability of dropping due to tumor progression while waiting for LT for 1 year is reported to range from 15% to 30%. [bib_ref] Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does..., Yao [/bib_ref] Locoregional therapies are reported to reduce the dropout rate to 0%-25%. 173,187 TACE or radiofrequency ablation (RFA) can be performed to prevent tumor progression. [bib_ref] Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list..., Llovet [/bib_ref] [bib_ref] Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an..., Yao [/bib_ref] Markov-based cost-effectiveness analysis indicates benefits for neo-adjuvant treatments when waiting times exceed 6 months. [bib_ref] Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list..., Llovet [/bib_ref] AFP increasing >15 μg/L/mo while waiting for LT is the most relevant preoperative prognostic factor for low overall survival and disease-free survival. [bib_ref] Progression of alphafetoprotein before liver transplantation for hepatocellular carcinoma in cirrhotic patients:..., Vibert [/bib_ref] The effects of neoadjuvant treatments on survival after LT are even more difficult to assess. Many studies report survival rates similar to those of untreated individuals; [bib_ref] Impact of pretransplantation transarterial chemoembolization on survival and recurrence after liver transplantation..., Decaens [/bib_ref] [bib_ref] Lack of benefit of pretransplant locoregional hepatic therapy for hepatocellular cancer in..., Porrett [/bib_ref] [bib_ref] Transarterial chemoembolization as a bridge to liver transplantation for hepatocellular carcinoma: an..., Lesurtel [/bib_ref] [bib_ref] An intention-to-treat analysis of liver transplantation for hepatocellular carcinoma using organ procurement..., Pelletier [/bib_ref] however, the major limitation of these studies is shorter waiting times (<6 months) for LT. [bib_ref] Impact of pretransplantation transarterial chemoembolization on survival and recurrence after liver transplantation..., Decaens [/bib_ref] [bib_ref] Lack of benefit of pretransplant locoregional hepatic therapy for hepatocellular cancer in..., Porrett [/bib_ref] The response to bridging therapy significantly affects both tumor recurrence and overall survival rate. This result suggests that HCC candidates should be prioritized with respect to their response to bridging therapy 195 that improved overall survival after LT is expected. [bib_ref] Transarterial chemoinfusion for hepatocellular carcinoma as downstaging therapy and a bridge toward..., Luna [/bib_ref] The Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients data regarding LT for HCC show a higher 3-year post-LT survival rate in patients who received ablative procedures before LT than those who did not regardless of pre-LT treatment modality. [bib_ref] Liver and intestine transplantation in the United States, Freeman [/bib_ref] Radiation as a bridge to LT for advanced HCC is feasible, and well-selected patients are expected to achieve improved overall survival if HCC responds. [bib_ref] Long-term outcomes of stereotactic body radiation therapy in the treatment of hepatocellular..., O'connor [/bib_ref] [bib_ref] The safety and efficacy of high-dose proton beam radiotherapy for hepatocellular carcinoma:..., Bush [/bib_ref] [bib_ref] Stereotactic hypofractionated radiation therapy as a bridge to transplantation for hepatocellular carcinoma:..., Katz [/bib_ref] 3. Downstaging Regarding downstaging, there are no randomized controlled trials, large case-control studies, or large well-designed cohort studies in which patients were treated consistently and properly followed up. Some prospective studies suggest downstaging according to the Milan or UCSF criteria as a result of locoregional therapies achieves 5-year survival outcomes similar to those within the Milan or UCSF criteria. [bib_ref] Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an..., Yao [/bib_ref] [bib_ref] Liver transplantation for hepatocellular carcinoma: results of down-staging in patients initially outside..., Ravaioli [/bib_ref] However, it is unclear if downstaging therapies yield measurable anticancer effects. Downstaging of HCC with TACE may be possible in 24%-63% of cases. [bib_ref] Transarterial chemoinfusion for hepatocellular carcinoma as downstaging therapy and a bridge toward..., Luna [/bib_ref] [bib_ref] Outcomes of neoadjuvant transarterial chemoembolization to downstage hepatocellular carcinoma before liver transplantation, Chapman [/bib_ref] [bib_ref] A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation, Yao [/bib_ref] Downstaging is more effective in cases in which tumor size is <7 cm or there are fewer than 3 tumors, [bib_ref] A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation, Yao [/bib_ref] but there is no clear upper limit for the eligibility of downstaging. [bib_ref] The challenges of liver transplantation for hepatocellular carcinoma on cirrhosis, Bhoori [/bib_ref] Downstaging is possible with RFA or hepatic resection, but the efficacy of both remains inconclusive. [bib_ref] Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting liver transplantation:..., Mazzaferro [/bib_ref] Transarterial radioembolization (TARE) using 90 Y appears to outperform TACE for downstaging HCC from UNOS T3 to T2, and downstaged patients show a statistically insignificant trend toward improved overall survival after LT. [bib_ref] A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization, Lewandowski [/bib_ref] ## Living donor liver transplantation Patients with HCC in Korea have a very low probability of receiving deceased donor liver transplantation (DDLT) before tumor progression.According to the KONOS regulation for registration and allocation in Korea, LT recipient candidates with HCC cannot gain higher priority on the waiting list.These findings suggest DDLT is not a feasible treatment modality for patients with HCC in Korea. Therefore, living donor liver transplantation (LDLT) from a healthy donor has emerged as an alternative to DDLT as a treatment modality for HCC. In fact, a significant proportion of the LT recipients with HCC received transplantations from live donors in Korea. The proportion of adult LDLT recipients with HCC has recently increased to 30%-40% in Korea, suggesting LDLT is now one of the main treatment modalities for HCC. [bib_ref] Liver transplantation for HCC: its role: Eastern and Western perspectives, Hwang [/bib_ref] The outcome of LDLT versus DDLT for patients with HCC is controversial. A meta-analysis of 633 LDLTs and 1,232 DDLTs 208 indicates LDLT is an acceptable option that does not compromise survival rates. However, the disease-free survival rate is worse after LDLT than DDLT. The higher recurrence observed after LDLT is likely due to differences in tumor characteristics, pretransplant HCC management, and waiting time. [bib_ref] Outcomes of living and deceased donor liver transplant recipients with hepatocellular carcinoma:..., Kulik [/bib_ref] [bib_ref] Living donor liver transplantation for hepatocellular carcinoma, Kulik [/bib_ref] [bib_ref] Living donor liver transplantation for early hepatocellular carcinoma: a life-expectancy and cost-effectiveness..., Sarasin [/bib_ref] The recurrence rate with respect to stage is higher in recipients whose transplants were accelerated (i.e., "fast-tracked") by performing LDLT, especially in the era in which patients with HCC are disadvantaged by the allocation algorithm. [bib_ref] Living donor liver transplantation for hepatocellular carcinoma, Kulik [/bib_ref] Cost-effectiveness studies suggest LDLT can be offered to patients with HCC if the waiting list exceeds 7 months. [bib_ref] Living donor liver transplantation for early hepatocellular carcinoma: a life-expectancy and cost-effectiveness..., Sarasin [/bib_ref] Some authors recommend an observation period, e.g., 3 months prior to LT, in order to avoid transplantation in cases with potentially aggressive tumors. [bib_ref] Living donor liver transplantation for hepatocellular carcinoma, Kulik [/bib_ref] However, these propositions require further investigation. Furthermore, future studies must have better study design and reporting in order to accurately describe the observed difference in disease-free survival due to inappropriate study design or biological risk specifically associated with LDLT. [bib_ref] Living vs. deceased donor liver transplantation for hepatocellular carcinoma: a systematic review..., Grant [/bib_ref] Several eligibility criteria besides the Milan criteria for LDLTs have been adopted by many high-volume LDLT centers. At Asan Medical Center, patients with ≤6 HCCs ≤5 cm and without gross vascular invasion are considered eligible for LT; such patients have a 5-year survival rate of 81.6% at this center. [bib_ref] Expanded indication criteria of living donor liver transplantation for hepatocellular carcinoma at..., Lee [/bib_ref] At Seoul Catholic Medical Center, LDLT is considered the preferred therapeutic option in patients with an AFP level <100 ng/mL and a tumor diameter <5 cm. The 5-year disease-free survival and overall survival rates after LDLT in all patients with HCC are 80.9% and 76.4%, respectively. [bib_ref] Clinical outcome in patients with hepatocellular carcinoma after livingdonor liver transplantation, Choi [/bib_ref] At Seoul National University Hospital, the 3-year survival rate is reported to be 86.2% if vascular invasion was absent in preoperative radiological studies and preoperative AFP was <400 ng/mL. [bib_ref] Liver transplantation for hepatocellular carcinoma in patients who do not meet the..., Suh [/bib_ref] At Samsung Medical Center, patient selection according to tumor size <5 cm and AFP <400 ng/mL without limitation of tumor number expanded patient selection; 1-, 3-, and 5-year survival rates are reported to be 92.2, 82.6, and 79.9%, respectively. [bib_ref] HCC in living donor liver transplantation: can we expand the Milan criteria?, Kwon [/bib_ref] In the selection of HCC patients for LT, the University of Tokyo has adopted the 5-5 rule, i.e., HCC ≤5 cm and ≤5 in number, and a recurrencefree survival rate of 94% after LT was achieved.Kyoto University further extended the number of tumors to 10 with serum PIVKA-II levels ≤400 mAU/mL; the resultant 5-year survival rate was 86.7%. [bib_ref] Expansion of selection criteria for patients with hepatocellular carcinoma in living donor..., Ito [/bib_ref] At Kyushu University, a 5-year survival rate of 82.7% was achieved in patients with HCCs ≤5 cm and serum PIVKA-II levels <300 mAU/mL. [bib_ref] Impact of des-gammacarboxy prothrombin and tumor size on the recurrence of hepatocellular..., Taketomi [/bib_ref] In a study involving 49 centers and 653 patients in Japan, patients with HCCs beyond the Milan criteria but with serum AFP levels ≤200 ng/mL and serum PIVKA-II levels ≤100 mAU/mL had a 5-year disease-free survival rate of 84.3%. [bib_ref] Extending indication: role of living donor liver transplantation for hepatocellular carcinoma, Todo [/bib_ref] LDLT has been proposed as an ideal setting for exploring expanded indications for HCC, considering a lack of graft allocation and priority policies. Moreover, the graft of a live donor is a personal gift. If the posttransplant outcomes of several eligible criteria beyond the Milan criteria for LDLTs are comparable to those with the Milan criteria, expanded indications can be accepted as long as the safety of the live donor is ensured. The 5-year overall and disease-free survival rates of expanded indications beyond the Milan criteria for LDLTs exceed 80% and 70%, respectively. [bib_ref] Recipient deaths during donor surgery: a new ethical problem in living donor..., Siegler [/bib_ref] [bib_ref] Donor morbidity after living donation for liver transplantation, Ghobrial [/bib_ref] [bib_ref] Live donors in liver transplantation, Brown [/bib_ref] The outcomes of live donors (n=2,872 published cases) from Korea are excellent. [bib_ref] Three-quarters of right liver donors experienced postoperative complications, Yi [/bib_ref] [bib_ref] Comparison of open and laparoscopic live donor left lateral sectionectomy, Kim [/bib_ref] [bib_ref] Lessons learned from 1,000 living donor liver transplantations in a single center:..., Hwang [/bib_ref] [bib_ref] Surgical outcome of right liver donors in living donor liver transplantation: singlecenter..., Kim [/bib_ref] [bib_ref] Improving outcomes of living-donor right hepatectomy, Kim [/bib_ref] [bib_ref] Donor morbidity including biliary complications in living-donor liver transplantation: single-center analysis of..., Shin [/bib_ref] The risks and benefits of LDLT should take into account both the donor and recipient; this concept is known as "double equipoise." The associated probabilities of death and life-threatening complications in LDLT for healthy donors are reported to be 0.3% and <2%, respectively. [bib_ref] Recipient deaths during donor surgery: a new ethical problem in living donor..., Siegler [/bib_ref] [bib_ref] Donor morbidity after living donation for liver transplantation, Ghobrial [/bib_ref] [bib_ref] Live donors in liver transplantation, Brown [/bib_ref] Because of the complexity of the procedure, LDLT must be restricted to centers of excellence in hepatic surgery and LT to minimize donor risk and maximize recipient outcome. Careful attention should be given to the psychosocial aspects of live donors. ## Salvage liver transplantation Salvage liver transplantation (SLT) is promoted as a potential curative treatment strategy for HCC recurrence following primary liver resection with curative intent. [bib_ref] Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma..., Poon [/bib_ref] This strategy may reduce disease progression in patients waiting for LT and may also reduce the number of transplants required. An intentionto-treat analysis shows that LT for patients with small resectable HCCs yields survival outcomes superior to those of liver resection. [bib_ref] Benefit of initial resection of hepatocellular carcinoma followed by transplantation in case..., Fuks [/bib_ref] [bib_ref] Single HCC in cirrhotic patients: liver resection or liver transplantation? Long-term outcome..., Sapisochin [/bib_ref] [bib_ref] Harm and benefits of primary liver resection and salvage transplantation for hepatocellular..., Cucchetti [/bib_ref] Nevertheless, patients with small resectable HCCs are offered liver resection rather than LT because of the aforementioned organ shortage. [bib_ref] Recipient outcomes of salvage liver transplantation versus primary liver transplantation: a systematic..., Hu [/bib_ref] Patients with HCCs beyond as well as within the Milan criteria should be initially treated with liver resection and can later be salvaged with LT if they develop recurrent HCC within the Milan criteria and is not too aggressive. [bib_ref] Treatment strategy for recurrent hepatocellular carcinoma: salvage transplantation, repeated resection, or radiofrequency..., Chan [/bib_ref] The selection criteria for SLT are same as those for primary LT. [bib_ref] Treatment strategy for recurrent hepatocellular carcinoma: salvage transplantation, repeated resection, or radiofrequency..., Chan [/bib_ref] [bib_ref] Systematic review of efficacy and outcomes of salvage liver transplantation after primary..., Chan [/bib_ref] [bib_ref] Single HCC in cirrhotic patients: liver resection or liver transplantation? Long-term outcome..., Sapisochin [/bib_ref] [bib_ref] Salvage liver transplantation for recurrent hepatocellular carcinoma within UCSF criteria after liver..., Liu [/bib_ref] [bib_ref] Primary versus salvage living donor liver transplantation for patients with hepatocellular carcinoma:..., Moon [/bib_ref] [bib_ref] Salvage living donor liver transplantation after prior liver resection for hepatocellular carcinoma, Hwang [/bib_ref] [bib_ref] Living donor liver transplantation for recurrent hepatocellular carcinoma after liver resection, Kaido [/bib_ref] This is because the risk factors for HCC recurrence after SLT are similar to those of primary LT. [bib_ref] Primary versus salvage living donor liver transplantation for patients with hepatocellular carcinoma:..., Moon [/bib_ref] [bib_ref] Salvage liver transplantation for patients with recurrent hepatocellular carcinoma after curative resection, Wu [/bib_ref] Significant independent risk factors for HCC recurrence after SLT include microscopic vascular invasion, poor differentiation, satellite nodules, high AFP level, and tumor size and number. Extension beyond the Milan criteria and avoiding risk factors are also important issues regarding SLT. Furthermore, prophylactic or preemptive SLT before HCC recurrence for patients with risk factors for recurrence after hepatic resection remains controversial in light of the organ shortage. Another concern is the potential for surgical difficulty following prior resection and postoperative complications, which may negate the benefit of an SLT. Meta-analyses and systemic reviews [bib_ref] Systematic review of efficacy and outcomes of salvage liver transplantation after primary..., Chan [/bib_ref] [bib_ref] Recipient outcomes of salvage liver transplantation versus primary liver transplantation: a systematic..., Hu [/bib_ref] [bib_ref] Salvage liver transplantation in the treatment of hepatocellular carcinoma: a meta-analysis, Li [/bib_ref] show that the recipient outcomes of SLT are similar to those of primary LT with respect to overall and disease-free survival. For patients who develop recurrent HCC after primary hepatic resection but have a very low probability of receiving DDLT before tumor progression, salvage LDLT could be a curative treatment option like primary LT. The indications and selection criteria for salvage LDLT are same as those for primary LDLT. 153,236-239 ## Posttransplantation immunosuppression A calcineurine inhibitor-based immunosuppressant is generally administered in HCC patients after LT. [bib_ref] How should patients with hepatocellular carcinoma recurrence after liver transplantation be treated?, Schwartz [/bib_ref] Sirolimus was recently reported to suppress HCC recurrence via an antiprolifera-tion effect [bib_ref] Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma, Zimmerman [/bib_ref] [bib_ref] De novo sirolimus-based immunosuppression after liver transplantation for hepatocellular carcinoma: long-term outcomes..., Toso [/bib_ref] contributing to improved survival. [bib_ref] Sirolimus-based immunosuppression in liver transplantation for hepatocellular carcinoma: a meta-analysis, Liang [/bib_ref] However, this finding must be corroborated by additional studies. Recommendations [fig_ref] Table 2: Summary of the Recommendations of the 2014 KLCSG-NCC Korea Practice Guidelines for... [/fig_ref] 1. DDLT is the first-line treatment for patients with singlenodular HCC <5 cm in diameter or 3 or fewer ≤3 nodules ≤3 cm in diameter (Milan criteria), which are not indicated for resection (A1). 2. Locoregional therapies (local ablation or TACE) are recommended if the timing of transplantation is not predictable (B1). 3. Downstaging (e.g., with TACE) can be considered for HCCs exceeding the criteria for transplantation (C2). 4. LDLT is an effective alternative to deceased donor transplantation (B1). 5. An expanded indication for transplantation beyond the Milan criteria can be considered in HCC cases without definitive vascular invasion or extrahepatic spread, if other effective treatment options are not inapplicable (C2). 6. Salvage transplantation can be indicated for recurrent HCC after resection according to the same criteria as for first-line transplantation (B1). ## Locoregional therapies Locoregional therapies are widely performed as nonsurgical treatments for HCC because of their convenience and relatively lower invasiveness. Although TACE can be considered a locoregional therapy in a broad sense, it will not be discussed here. RFA and percutaneous ethanol injection therapy (PEIT) are the current standard local therapies, while others such as microwave ablation, laser ablation, cryoablation, acetic acid injection therapy, and high-intensity focused ultrasound are currently undergoing clinical trials. The indications for locoregional therapies include patients with a single HCC nodule ≤5 cm or up to 3 nodules ≤3 cm, although they vary among studies. The effectiveness of local therapies depends on tumor size, while complete tumor necrosis rates are reported to exceed 80% for tumors <3 cm. [bib_ref] Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma, Sala [/bib_ref] Predictors of survival include initial complete tumor necrosis, Child-Pugh score, tumor size and number, and baseline serum AFP level. In particular, local therapies are very effective for Child-Pugh class A patients with single small HCC nodules <2 cm, although surgical resection is the standard treatment for such tumors.Some researchers assert local therapies should be the primary treatments for these tumors because of the favorable tumor response; however, this remains controversial. [bib_ref] Sustained complete response and complications rates after radiofrequency ablation of very early..., Livraghi [/bib_ref] Local therapies are less effective for larger tumors, but efforts to improve them are being made. Contraindications for local therapies include corrected platelet count <50×10 3 /mm 3 and low prothrombin time (≤50%). ## Radiofrequency ablation RFA is currently the most widely used ablation technique for the treatment of HCC. Very fast alternating currents (460 to 500 kHz) flow in the vicinity of radiofrequency electrodes, inducing internal friction among molecules. The internal heat generated by the internal friction can evoke tissue necrosis. Heating to 60 o C can cause almost immediate protein denaturation and destruction of cell membranes followed by coagulative necrosis. Heating to 45 o C-50 o C for ≥3 minutes can also cause similar necrotic effects. The main advantage of RFA is that fewer treatment sessions are required to achieve complete tumor necrosis. For HCC nodules >2 cm, RFA results in a higher complete tumor necrosis rate than PEIT; 248-251 most procedures were performed via a percutaneous approach, although a laparoscopic or open surgical approach may be required in some instances. Initial complete tumor necrosis rates on imaging studies are reported to exceed 96% and if RFA procedures are repeated for residual viable tumors, a complete tumor necrosis rate of almost 100% can be achieved. [bib_ref] A randomized controlled trial of radiofrequency ablation with ethanol injection for small..., Shiina [/bib_ref] However, the estimated 3-year local tumor progression rate after RFA ranges widely from 0.9% to 21.4%. [bib_ref] Sustained complete response and complications rates after radiofrequency ablation of very early..., Livraghi [/bib_ref] [bib_ref] Ten-year outcomes of percutaneous radiofrequency ablation as first-line therapy of early hepatocellular..., Kim [/bib_ref] [bib_ref] Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors, Shiina [/bib_ref] Despite these favorable outcomes, RFA has some disadvantages. First, the risk of major adverse events is usually higher than that with PEIT, particularly when the tumors are located near the liver hilum or a major abdominal organ such as the large intestine. In addition, the heat sink effect may hinder effective transmission of heat energy to the tumor in cases in which the tumors are adjacent to relatively large intrahepatic vessels. [bib_ref] Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus..., Lencioni [/bib_ref] [bib_ref] Adverse events during radiofrequency treatment of 582 hepatic tumors, De Baère [/bib_ref] [bib_ref] Major complications after radiofrequency thermal ablation of hepatic tumors: spectrum of imaging..., Rhim [/bib_ref] However, the risk of thermal injury to the adjacent abdominal organs can be overcome by inducing artificial ascites. [bib_ref] Percutaneous radiofrequency ablation of hepatocellular carcinoma abutting the diaphragm and gastrointestinal tracts..., Song [/bib_ref] Another major limitation of RFA is that HCC nodules <2 cm may not be visible on conventional ultrasonography. However, recent applications of ultrasound contrast agents and fusion imaging techniques have broadened the indications for RFA to such cases. [bib_ref] Planning US for percutaneous radiofrequency ablation of small hepatocellular carcinomas (1-3 cm):..., Lee [/bib_ref] [bib_ref] Newly developed novel ultrasound technique, defect reperfusion ultrasound imaging, using sonazoid in..., Kudo [/bib_ref] The mortality rate due to procedure-related complications after RFA is reported to be 0.1%-0.5%, and the major complication rate after RFA is <5%. [bib_ref] Sustained complete response and complications rates after radiofrequency ablation of very early..., Livraghi [/bib_ref] [bib_ref] Adverse events during radiofrequency treatment of 582 hepatic tumors, De Baère [/bib_ref] [bib_ref] Major complications after radiofrequency thermal ablation of hepatic tumors: spectrum of imaging..., Rhim [/bib_ref] Major complications include needle tract seeding, hemoperitoneum, hemothorax, liver abscess, massive infarction of liver parenchyma, intestinal perforation, pneumoperitoneum, etc. [bib_ref] Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors, Shiina [/bib_ref] The long-term survival outcomes of HCC patients can vary after RFA with respect to tumor size. For Child-Pugh class A cirrhotic patients with tumors <2 cm, the 3-and 5-year overall survival rates after RFA are reported to be approximately 90% and 65%-70%, respectively; 247,252,253 meanwhile, those for tumors 2-5 cm are 65%-75% and 50%, respectively. [bib_ref] Ten-year outcomes of percutaneous radiofrequency ablation as first-line therapy of early hepatocellular..., Kim [/bib_ref] [bib_ref] Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors, Shiina [/bib_ref] The 10-year overall survival rate of Child-Pugh class A patients with single HCC <3 cm is 41.3%. [bib_ref] Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors, Shiina [/bib_ref] In four RCTs comparing RFA and PEIT for patients with HCC, [bib_ref] Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma <..., Lin [/bib_ref] [bib_ref] A randomized controlled trial of radiofrequency ablation with ethanol injection for small..., Shiina [/bib_ref] [bib_ref] Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus..., Lencioni [/bib_ref] [bib_ref] Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and..., Lin [/bib_ref] [bib_ref] Radiofrequency ablation versus ethanol injection for early hepatocellular carcinoma: a randomized controlled..., Brunello [/bib_ref] patients treated with RFA showed better local tumor response and overall survival outcomes than those treated with PEIT. A meta-analysis of these four RCTs also demonstrates that the 3-year overall survival rate of RFA is significantly higher than that of PEIT. [bib_ref] Systematic review of randomized trials for hepatocellular carcinoma treated with percutaneous ablation..., Cho [/bib_ref] Nevertheless, for patients with HCC <2 cm, there is no significant difference in survival outcomes between RFA and PEIT. Therefore, further prospective controlled studies are required. As it is difficult to compare observational studies evaluating the long-term survival outcomes of RFA and surgical resection, it is not adequate to draw a definite conclusion regarding the superiority of either treatment. Three RCTs have recently been published on this topic. There were no significant differences in the survival outcomes between the two treatments in one RCT for solitary HCC <5 cm and another RCT for single or double HCCs <4 cm. [bib_ref] A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy..., Chen [/bib_ref] [bib_ref] A randomized controlled trial of radiofrequency ablation and surgical resection in the..., Feng [/bib_ref] However, the other RCT for HCC diagnosed according to the Milan criteria indicates the superiority of surgical resection over RFA with respect to 3-and 5-year overall survival rates (p<0.001). [bib_ref] A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming..., Huang [/bib_ref] Nevertheless, such results should be interpreted cautiously, as RFA is most effective for tumors <3 cm. A meta-analysis of these three RCTs shows that the complication rate was usually higher in the resection group than the RFA group (p=0.002) and that hospitalization duration was significantly longer in the resection group than the RFA group (p<0.001). [bib_ref] Radiofrequency ablation versus hepatic resection for small hepatocellular carcinoma: a meta-analysis of..., Qi [/bib_ref] Nevertheless, it is not possible to draw a definite conclusion about the overall or disease-free survival rate of HCC patients on the basis of a meta-analysis of the three RCTs mentioned above, because the indications differed substantially among studies. [bib_ref] Radiofrequency ablation versus hepatic resection for small hepatocellular carcinoma: a meta-analysis of..., Qi [/bib_ref] In contrast, RFA may be unfeasible because of the tumor location in some cases, making surgical resection more useful. [bib_ref] A randomized controlled trial of radiofrequency ablation and surgical resection in the..., Feng [/bib_ref] As a strategy combining the advantages of these treatment modalities for small HCCs, i.e., the lower invasiveness of RFA and better curative potential of hepatic resection, primary RFA and subsequent resection in cases of failed RFA can be considered. A recent decision model analysis shows there was no difference in the survival outcomes of patients with single HCC smaller than 2 cm between the combined strategy and resection monotherapy. [bib_ref] Hepatic resection versus radiofrequency ablation for very early stage hepatocellular carcinoma: a..., Cho [/bib_ref] For intermediate-sized HCCs (i.e., 3-5 cm), the local recurrence rates after RFA are reported to range from 30% to 50%, [bib_ref] Ten-year outcomes of percutaneous radiofrequency ablation as first-line therapy of early hepatocellular..., Kim [/bib_ref] and combined treatment of TACE and RFA can be considered for these tumors. The difference in the 3-year overall survival rates between combined treatment and RFA monotherapy is <10% for tumors smaller than 3 cm 267,268 but is much greater for HCCs 3-5 cm in diameter. [bib_ref] Midterm outcomes in patients with intermediate-sized hepatocellular carcinoma: a randomized controlled trial..., Morimoto [/bib_ref] Meta-analyses of RCTs also show similar results. [bib_ref] Radiofrequency ablation plus chemoembolization versus radiofrequency ablation alone for hepatocellular carcinoma: a..., Lu [/bib_ref] [bib_ref] Meta-analysis of radiofrequency ablation in combination with transarterial chemoembolization for hepatocellular carcinoma, Ni [/bib_ref] No RCT has compared re-resection and RFA for recurrent HCC following hepatic resection. However, a recent retrospective analysis shows that the 2-and 5-year overall survival rates after re-resection and RFA are 90% vs 96% and 72% vs 83%, respectively; the differences are not statistically significant. [bib_ref] Survival in patients with recurrent hepatocellular carcinoma after primary hepatectomy: comparative effectiveness..., Ho [/bib_ref] Another retrospective study shows similar results. [bib_ref] Percutaneous radiofrequency ablation versus repeat hepatectomy for recurrent hepatocellular carcinoma: a retrospective..., Liang [/bib_ref] In those studies, baseline liver functional status might have been unfavorable in the RFA group compared to the surgical group. Consequently, RFA appears comparable to re-resection for the treatment of recurrent HCC following hepatic resection, although further investigation is necessary to confirm this. [bib_ref] Survival analysis of re-resection versus radiofrequency ablation for intrahepatic recurrence after hepatectomy..., Chan [/bib_ref] ## Percutaneous ethanol injection PEIT is widely used in the treatment of HCC because it is relatively convenient to perform and adverse reactions are infrequent. However, PEIT has been largely supplanted by RFA recently, mainly because PEIT should be performed repetitively in contrast to RFA and it is difficult to obtain complete necrosis for tumors larger than 3 cm. PEIT is now usually reserved for patients with ≤3 nodules ≤3 cm in diameter. As a special consideration, PEIT can be performed to treat peri vascular tumors to reduce the heat sink effect of RFA. However, the risk of biliary stricture is not eliminated by PEIT if the tumors are located in the liver hilum. [bib_ref] Therapeutic efficacy and safety of percutaneous ethanol injection with or without combined..., Cha [/bib_ref] The reported rates of tumor necrosis after PEIT range between 66% and 100%. [bib_ref] Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma <..., Lin [/bib_ref] [bib_ref] A randomized controlled trial of radiofrequency ablation with ethanol injection for small..., Shiina [/bib_ref] [bib_ref] Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus..., Lencioni [/bib_ref] [bib_ref] Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and..., Lin [/bib_ref] In particular, the therapeutic efficacy of PEIT largely depends on the tumor size; the rate of tumor necrosis decreases with increasing tumor size. A rate of tumor necrosis ≥90% is reported for tumors smaller than 2 cm, but the rate decreases to approximately 50% for 3-5-cm tumors. Local tumor progression rates after PEIT range between 24% and 34%, although there is no consensus on the definition of local tumor progression. [bib_ref] Local recurrence of hepatocellular carcinoma after percutaneous ethanol injection, Ishii [/bib_ref] [bib_ref] Tumor size determines the efficacy of percutaneous ethanol injection for the treatment..., Vilana [/bib_ref] [bib_ref] Percutaneous ethanol injection in the treatment of hepatocellular carcinoma in cirrhosis: a..., Livraghi [/bib_ref] For Child-Pugh class A patients with solitary tumors smaller than 2 cm, the 3-and 5-year overall survival rates are 70%-80% and ≥50%, respectively. For tumors 2-3 cm in diameter, the 3-year overall survival rate ranges from 47% to 64%. [bib_ref] Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma <..., Lin [/bib_ref] [bib_ref] Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and..., Lin [/bib_ref] For cirrhotic patients with Child-Pugh class A or B and a solitary tumor smaller than 3 cm, several comparative studies show no definite differences in the survival outcomes between PEIT and surgical resection. [bib_ref] Hepatic resection and percutaneous ethanol injection as treatments of small hepatocellular carcinoma:..., Daniele [/bib_ref] [bib_ref] Percutaneous ethanol injection versus surgical resection for the treatment of small hepatocellular..., Huang [/bib_ref] In particular, an RCT comparing PEIT and surgical resection targeting 76 patients who had one or two HCC nodules ≤3 cm reports no difference in the survival rates or local recurrence rates between treatment groups. [bib_ref] Percutaneous ethanol injection versus surgical resection for the treatment of small hepatocellular..., Huang [/bib_ref] However, it is very difficult to reach a definite conclusion based on a single RCT. Furthermore, the sample size of that RCT was calculated on the basis of the tumor recurrence rate and not the survival rate. The 5-year survival rates differed greatly-46% and 81.8% in the PEIT and resection groups, respectivelyeven though there was no significant difference in the overall survival rates of the two treatments. Therefore, additional welldesigned prospective controlled studies are necessary to reach a definite conclusion. ## Other locoregional therapies Other local therapies are currently under investigation, including microwave ablation, cryoablation, high-intensity focused ultrasound, laser ablation, and holmium injection therapy among others. An important advantage of microwave ablation over RFA is that treatment efficacy is less affected by vessels lo-cated near the tumor. In addition, effective ablation can be expected even for tissues with low electrical conductivity, and the simultaneous application of multiple electrodes is technically feasible with this technique. [bib_ref] Radiofrequency versus microwave ablation in a hepatic porcine model, Wright [/bib_ref] [bib_ref] Microwave tumor ablation: mechanism of action, clinical results, and devices, Lubner [/bib_ref] Despite its potential advantages, no RCT has compared microwave ablation and RFA with respect to clinical usefulness. Furthermore, no RCTs have evaluated the other ablation techniques mentioned above; even single-arm studies do not demonstrate any additional benefits over RFA with respect to response or survival outcomes. Therefore, clinical indications for these various ablation techniques are currently uncertain. Recommendations [fig_ref] Table 2: Summary of the Recommendations of the 2014 KLCSG-NCC Korea Practice Guidelines for... [/fig_ref] 1. RFA provides survival comparable to that of resection in patients with single-nodular HCCs ≤3 cm in diameter (A2). 2. RFA is superior to PEIT in terms of anticancer effect and survival (A1). For HCCs ≤2 cm in diameter, PEIT can be considered if RFA is unfeasible, because the outcomes of both modalities are similar (A2). 3. Survival outcomes can be improved by combining TACE and RFA compared to RFA alone in patients with tumors 3-5 cm in diameter if resection is unfeasible (A2). ## Tace and other transarterial therapies Most HCC patients are unresectable at the time of diagnosis because of portal hypertension, poor liver functional status, multiplicity of tumors, portal vein tumor invasion, inability to secure sufficient resection margin around the tumors, old age, and severe comorbidities. [bib_ref] Resectability of hepatocellular carcinoma: evaluation of 333 consecutive cases at a single..., Sotiropoulos [/bib_ref] TACE is the most commonly used nonsurgical treatment modality for these patients; meanwhile, tumor necrosis can be achieved by the combined effects of antitumor chemotherapy and selective ischemia of tumor tissue. [bib_ref] Resectability of hepatocellular carcinoma: evaluation of 333 consecutive cases at a single..., Sotiropoulos [/bib_ref] [bib_ref] Trends in utilization of transarterial treatments for hepatocellular carcinoma: results of a..., Bargellini [/bib_ref] TACE is the most widely practiced primary treatment modality for HCC in Asia and North America. [bib_ref] Observations of hepatocellular carcinoma (HCC) management patterns from the global HCC bridge..., Park [/bib_ref] TACE can be classified as conventional TACE using lipiodol and drug-eluting bead TACE (debTACE). [bib_ref] Chemoembolization practice patterns and technical methods among interventional radiologists: results of an..., Gaba [/bib_ref] It is important to note that TACE should be distinguished from transarterial embolization, which uses only embolic material, and HAIC, which uses only antitumor chemotherapeutic agents. 287,288 ## Conventional tace The TACE procedure involves mixing chemotherapeutic agents such as doxorubin, cisplatin, and mitomycin with iodized oil and injecting the mixture into the feeding artery as an emulsion. This is followed by arterial embolization using gelatin sponge particles, polyvinyl alcohol particles, or microspheres, which induce selective tumor ischemia. The most important technique for maximizing the antitumor effect and minimizing liver toxicity when performing TACE is to superselect the feeding arteries of tumors as distal as possible. [bib_ref] Small hepatocellular carcinoma: treatment with subsegmental transcatheter arterial embolization, Matsui [/bib_ref] Regarding the repetition strategy of TACE, on-demand repetitions to treat the residual or recurrent tumors can minimize the incidence of procedure-related liver toxicity, which is therefore preferable to on-schedule regular repetitions every 1-2 months. Several RCTs and meta-analyses confirm compared to supportive treatments, TACE results in more favorable tumor response, time to progression, and survival outcomes in patients with unresectable HCC. [bib_ref] Natural history and prognostic indicators of survival in cirrhosis: a systematic review..., D'amico [/bib_ref] [bib_ref] Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular..., Llovet [/bib_ref] [bib_ref] Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma, Lo [/bib_ref] A recent prospective cohort study by the Japanese Liver Cancer Study Group reports that the 1-, 3-, 5-, and 7-year survival rates of 8,510 patients who underwent TACE were 82%, 47%, 26%, and 16%, respectively; for tumors larger than 5 cm, the 1-, 3-, and 5-year survival rates were 63%, 30%, and 16%, respectively. [bib_ref] Prospective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510..., Takayasu [/bib_ref] In a recent prospective multicenter study performed in 27 Japanese and South Korean centers, the complete or partial remission rate according to the modified Response Evaluation Criteria in Solid Tumors (mRE-CIST) criteria was 73% and the 2-year overall survival rate was 75%; these figures are higher than those previously reported in the literature. [bib_ref] Prospective study of transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: an Asian..., Ikeda [/bib_ref] In that study, grade 3-4 severe toxicities after TACE included elevated serum alanine aminotransferase level in 36% of patients, thrombocytopenia in 12%, and abdominal pain in 4%, while mild fever occurred in 57%. In another retrospective analysis, postembolization fever >38.0 o C occurred after TACE in 20% of patients; it occurred more frequently in patients with tumors >5 cm and was a poor prognostic factor for survival. [bib_ref] Does postembolization fever after chemoembolization have prognostic significance for survival in patients..., Shim [/bib_ref] Even though TACE can be performed safely in general, severe complications such as irreversible hepatic failure occur in 3% of patients and postembolization syndrome, which is characterized by transient fever and abdominal pain, occurs more frequently, affecting 60%-80% of patients. [bib_ref] A prospective study regarding the complications of transcatheter intraarterial lipiodol chemoembolization in..., Chan [/bib_ref] The best tumor response and the lowest complication rates after TACE can be expected for patients with favorable performance status, with nodular HCCs, and without traces of vascular invasion. Future RCTs should evaluate the survival benefits of TACE for patients with unfavorable prognostic factors such as poor performance status, major portal vein tumor invasion, Child-Pugh class C, and extrahepatic metastasis. Local tumor response after TACE can vary substantially according to the size and number of tumors as well as patterns of tumor growth, such as tumor encapsulation and vascular invasion. The complete remission rate is quite low for large or multiple tumors despite multiple TACE sessions. However, in cases with small tumors, complete tumor necrosis can be obtained in more than 50% of cases after superselective TACE. [bib_ref] Ultraselective transcatheter arterial chemoembolization with a 2-f tip microcatheter for small hepatocellular..., Miyayama [/bib_ref] For patients with Child-Pugh class A and surgically resectable HCC <4 cm, the 5-year overall survival rate after subsegmental TACE is reported to exceed 50%. [bib_ref] Small hepatocellular carcinoma: treatment with subsegmental transcatheter arterial embolization, Matsui [/bib_ref] [bib_ref] Prospective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510..., Takayasu [/bib_ref] A prospective cohort study from Korea comparing surgical resection after primary TACE with TACE monotherapy published a decade ago reports that the survival rates were similar between the two treatment groups in cases in stage T3. In addition, the survival rate of the TACE group in stage T1 and T2 cases was similar to that of the surgical resection group if iodized oil was compactly retained within the tumor. [bib_ref] Therapeutic efficacy of transcatheter arterial chemoembolization as compared with hepatic resection in..., Lee [/bib_ref] In a recent prospective cohort study on BCLC stage A patients for whom resection or ablation could not be performed, the 1-month complete remission rate according to the mRECIST criteria were 67% and the 3-year overall survival rate was 80%. In another recent retrospective study comparing resection, RFA, and TACE as initial treatments for single small HCC <3 cm in diameter, the unadjusted 5-year overall survival rate of the TACE group was the lowest at 74.2%. However, after adjusting for liver functional status, thrombocytopenia, varix, etc., the differences in the survival outcomes among the groups lost statistical significance. [bib_ref] Small single-nodule hepatocellular carcinoma: comparison of transarterial chemoembolization, radiofrequency ablation, and hepatic..., Yang [/bib_ref] Taking the potential selection bias of the abovementioned studies into account, TACE can be considered an alternative treatment with curative intent if a patient rejects surgical treatment, is high risk for surgery, or is contraindicated for RFA. Portal vein tumor invasion occurs in approximately 30% of HCC patients in Korea. According to the AASLD practice guidelines, systemic chemotherapy with sorafenib is the standard primary treatment for HCC invading the portal vein. [bib_ref] Hypervascular hepatocellular carcinoma 1 cm or smaller in patients with chronic liver..., Kim [/bib_ref] However, in practice, this recommendation is not routinely followed by physicians, because the expected survival benefits are modest. [bib_ref] Observations of hepatocellular carcinoma (HCC) management patterns from the global HCC bridge..., Park [/bib_ref] Therefore, further investigations of effective alternative treatments are required. When TACE is performed for HCC patients with good hepatic functions but portal vein tumor invasion, the risk of hepatic functional deterioration after TACE is reported to be acceptably low. [bib_ref] Transarterial chemoembolization can be safely performed in patients with hepatocellular carcinoma invading..., Chung [/bib_ref] [bib_ref] Safety and efficacy of transarterial chemoembolization in patients with unresectable hepatocellular carcinoma..., Georgiades [/bib_ref] [bib_ref] The safety and efficacy of transcatheter arterial chemoembolization in the treatment of..., Lee [/bib_ref] The 1-and 3-year overall survival rates of such patients after repeated TACE range from 25%-35% and 9%-10%, respectively. [bib_ref] Prospective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510..., Takayasu [/bib_ref] [bib_ref] Hepatocellular carcinoma and portal vein invasion: results of treatment with transcatheter oily..., Chung [/bib_ref] [bib_ref] Transarterial chemoembolization for unresectable hepatocellular carcinoma with portal vein tumor thrombosis: a..., Luo [/bib_ref] In a prospective study targeting HCCs invading the major portal vein, the median survival period of the TACE-treated group (5.0 to 5.1 months) was 2 to 2.5 months longer than those of the supportively treated group; however, the difference was not statistically significant probably because of the small number of patients included. [bib_ref] Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma, Lo [/bib_ref] [bib_ref] The safety and efficacy of transcatheter arterial chemoembolization in the treatment of..., Lee [/bib_ref] However, a recent study from Korea reports that the median survival rate of TACE-treated HCC invading the major portal vein is 22 to 30 months for a subgroup of patients with nodular tumor growth or limited tumor extent. [bib_ref] The safety and efficacy of transcatheter arterial chemoembolization in the treatment of..., Lee [/bib_ref] [bib_ref] Hepatocellular carcinoma and portal vein invasion: results of treatment with transcatheter oily..., Chung [/bib_ref] A recent prospective nonrandomized study on unresectable HCC patients with portal vein invasion shows more favorable survival outcomes for the TACEtreated group than the supportive treatment group. [bib_ref] Transarterial chemoembolization for unresectable hepatocellular carcinoma with portal vein tumor thrombosis: a..., Luo [/bib_ref] However, the lack of randomization in that study limits the validity of this finding. Therefore, additional well-designed RCTs are required to confirm the survival benefits of TACE over supportive treatment in HCC patients with portal vein invasion. Future investigations are also required to compare the clinical effectiveness of TACE monotherapy with other monotherapies (i.e., radiation therapy, systemic sorafenib, hepatic arterial infusion chemotherapy, etc.) and combined treatments of those therapies and TACE while considering liver functional status, tumor extent, and the extent of portal vein invasion. ## Drug-eluting bead tace Drug-eluting beads, which are microspheres loaded with highdose doxorubicin, represent a newly developed embolic agent for tumor feeders. The major theoretical advantage of debTACE is the higher intratumor drug concentration and lower serum drug concentration due to the slow release of doxorubicin from the microspheres after embolization of the tumor feeders. In prospective clinical trials, liver toxicities and systemic adverse effects occur less frequently after debTACE than conventional TACE. [bib_ref] Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics, Varela [/bib_ref] In contrast, a phase II RCT on 212 HCC patients demonstrates no additional benefit of debTACE over conventional TACE with respect to 6-month complete or partial remission rate.However, subgroup analyses show that debTACE was superior to conventional TACE in patients with Child-Pugh class B, ECOG performance status 1, bilobar disease, or recurrent HCCs.In another RCT, there was no significant difference between the two treatments with respect to tumor response, time to progression, or survival period. [bib_ref] Conventional versus doxorubicin-eluting bead transarterial chemoembolization for hepatocellular carcinoma, Sacco [/bib_ref] The 5-year overall survival rates of HCC patients after debTACE and conventional TACE were 38.3% and 22.5%, respectively. [bib_ref] Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using..., Burrel [/bib_ref] [bib_ref] Chemoembolization with doxorubicin-eluting beads for unresectable hepatocellular carcinoma: five-year survival analysis, Malagari [/bib_ref] When debTACE is performed by experienced interventional radiologists, postembolization syndrome or systemic adverse effects occur less frequently. [bib_ref] Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics, Varela [/bib_ref] [bib_ref] Safety and efficacy of doxorubicin drug-eluting bead transarterial chemoembolization in patients with..., Prajapati [/bib_ref] However, there is a lack of evidence confirming the long-term survival benefits of debTACE compared to conventional TACE, thus warranting further phase III RCTs. ## Transarterial radioembolization TARE involves the injection of implantable radioactive microspheres into tumor-feeding arteries in order to expose the tumor to highly concentrated radiation while protecting the normal parenchyma. Yttrium-90 ( 90 Y) is the most commonly used radioisotope and emits high-energy and pure β-rays with a halflife of 64.2 hours, and mean and maximum tissue penetration of 2.5 and 11 mm, respectively. The microspheres available for [bib_ref] A snapshot of the effective indications and results of surgery for hepatocellular..., Torzilli [/bib_ref] Y infusion are about 35 μm in diameter and are made of resin or glass. The small size of the injected microspheres and their concentration at the hypervascular HCC minimize the embolic effect on surrounding tissue. Preprocedural angiography and [bib_ref] Portal hypertension: contraindication to liver surgery?, Capussotti [/bib_ref] mTc-labeled macroaggregated albumin scan are required to decide on the treatment site, determine the radiation dose, and detect and calculate the degree of shunting to the lungs and any other extrahepatic organs. In a prospective single-arm phase II study of 52 patients with intermediate or advanced HCC treated with TARE, the objective tumor response rate (i.e., complete or partial remission rate) was 40.4%, and the median survival period was 15 months. [bib_ref] Yttrium-90 radioembo-KLCSG and NCC: Practice Guideline for Hepatocellular Carcinoma 305 lization for..., Mazzaferro [/bib_ref] In another large retrospective cohort study, the median survival periods of patients with and without portal vein invasion were 10 and 15.3 months, respectively; the difference was statistically significant. The median survival periods of patients with Child-Pugh class A and B were 17.2 and 7.7 months, respectively; the difference was also statistically significant. [bib_ref] Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term..., Salem [/bib_ref] [bib_ref] Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic..., Sangro [/bib_ref] In a recent prospective multicenter study performed in Korea on 40 HCC patients in BCLC stage B or C, the 3-month tumor response rate was 57.5% and the 3-year overall survival rate was 75%. [bib_ref] Radioembolization with Yttrium-90 resin microspheres in hepatocellular carcinoma: a multicenter prospective study, Kim [/bib_ref] The most frequent adverse effect after 90 Y TARE is transient fatigue. However, postembolization syndrome is less likely to occur than in conventional TACE, because the embolic effect of 90 Y TARE is not as strong. Therefore, 90 Y TARE can be performed safely for patients with portal vein tumor thrombosis. Elevated serum bilirubin levels occur in 20% of patients, and the mortality rate within 1 month ranges from 0% to 3%. [bib_ref] Yttrium-90 radioembo-KLCSG and NCC: Practice Guideline for Hepatocellular Carcinoma 305 lization for..., Mazzaferro [/bib_ref] [bib_ref] Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term..., Salem [/bib_ref] [bib_ref] Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic..., Sangro [/bib_ref] Severe complications such as radiation pneumonitis and gastroduodenal ulcer can occur in the event of inadvertent embolization into the extrahepatic organs. Therefore, 90 Y TARE requires meticulous precautions and experience performing radioembolization. In summary, no RCT has compared 90 Y TARE with other standard treatments with respect to long-term survival outcomes and complication rates. Therefore, it is difficult to suggest indications for 90 Y TARE in HCC patients. However, the incidence of postembolization syndrome and systemic adverse effects with [bib_ref] A snapshot of the effective indications and results of surgery for hepatocellular..., Torzilli [/bib_ref] Y TARE are relative low, and the tumor response rates are similar to those of conventional TACE. Accordingly, a phase III RCT is required to determine the indications, cost-effectiveness, and survival outcomes for this new type of treatment. Recommendations [fig_ref] Table 2: Summary of the Recommendations of the 2014 KLCSG-NCC Korea Practice Guidelines for... [/fig_ref] 1. TACE is recommended for patients with good performance status without major vascular invasion or extrahepatic spread who are ineligible for surgical resection, liver transplantation, RFA, or PEIT (A1). 2. TACE should be performed through tumor-feeding vessels using selective/superselective techniques to maximize antitumor activity and minimize hepatic damage (B1). 3. Chemoembolization using drug-eluting beads results in less systemic adverse events and has similar therapeutic efficacy compared with conventional TACE (B2). 4. In case of portal vein invasion, TACE can be considered for patients with localized tumors and well-preserved liver function (B2). ## External-beam radiation therapy External-beam radiation therapy (EBRT) for the treatment of HCC is commonly used for lesions that are surgically unresectable and not amendable with other local modalities. Child-Pugh class A or upper B are criteria for EBRT. The reported overall response rates and median survival after EBRT are 40%-90% and 10-25 months, respectively. [bib_ref] Radiation therapy for hepatocellular carcinoma: from palliation to cure, Hawkins [/bib_ref] EBRT requires computerized radiation therapy planning by CT, and the liver volume receiving ≥30 Gy must be limited to ≤60% of the total liver volume in three-dimensional radiotherapy planning-based dose-volume analysis. [bib_ref] Dose-volumetric parameters predicting radiation-induced hepatic toxicity in unresectable hepatocellular carcinoma patients treated..., Kim [/bib_ref] For hypofractionated EBRT consisting of ≤10 fractions, the normal liver volume receiving <15 Gy must be ≥700 mL [bib_ref] A phase I trial of stereotactic body radiation therapy (SBRT) for liver..., Schefter [/bib_ref] and the dose to the normal liver volume excluding the tumor must be limited to ≤28 Gy (corrected to 2 Gy per fractionequivalent dose). [bib_ref] Radiation-associated liver injury, Pan [/bib_ref] EBRT can be used for patients with HCC who are unsuitable for surgical resection, LT, RFA, PEIT, or TACE. In most centers, hypofractionated radiotherapy including stereotactic ablative radiation therapy is used to treat patients with Child-Pugh A or superb B liver function and adequate normal liver volume; the 2-year local control and survival rates are reported to range from 70% to 100% and 50% to 75%, respectively. [bib_ref] Stereotactic body radiotherapy for primary hepatocellular carcinoma, Andolino [/bib_ref] [bib_ref] Sequential phase I and II trials of stereotactic body radiotherapy for locally..., Bujold [/bib_ref] [bib_ref] Stereotactic body radiation therapy combined with transcatheter arterial chemoembolization for small hepatocellular..., Honda [/bib_ref] [bib_ref] Stereotactic body radiation therapy in recurrent hepatocellular carcinoma, Huang [/bib_ref] [bib_ref] Stereotactic body radiation therapy for inoperable hepatocellular carcinoma as a local salvage..., Kang [/bib_ref] [bib_ref] Stereotactic body radiotherapy for small hepatocellular carcinoma: a retrospective outcome analysis in..., Sanuki [/bib_ref] [bib_ref] Stereotactic body radiation therapy as an alternative treatment for small hepatocellular carcinoma, Yoon [/bib_ref] In particular, stereotactic ablative radiation therapy for the treatment of ≤3 lesions and lesions with a cumulative diameter ≤6 cm results in local control rates exceeding 90%. [bib_ref] Stereotactic body radiotherapy for primary hepatocellular carcinoma, Andolino [/bib_ref] [bib_ref] Stereotactic body radiation therapy for inoperable hepatocellular carcinoma as a local salvage..., Kang [/bib_ref] [bib_ref] Stereotactic body radiotherapy for small hepatocellular carcinoma: a retrospective outcome analysis in..., Sanuki [/bib_ref] [bib_ref] Stereotactic body radiation therapy as an alternative treatment for small hepatocellular carcinoma, Yoon [/bib_ref] Proton therapy for HCC results in a 2-year local control rate from 75% to 96% and a 5-year survival rate from 23% to 44%. [bib_ref] The safety and efficacy of high-dose proton beam radiotherapy for hepatocellular carcinoma:..., Bush [/bib_ref] [bib_ref] A prospective study of hypofractionated proton beam therapy for patients with hepatocellular..., Fukumitsu [/bib_ref] [bib_ref] Phase II study of radiotherapy employing proton beam for hepatocellular carcinoma, Kawashima [/bib_ref] [bib_ref] Clinical results and risk factors of proton and carbon ion therapy for..., Komatsu [/bib_ref] [bib_ref] Proton beam therapy for hepatocellular carcinoma: the University of Tsukuba experience, Nakayama [/bib_ref] An advantage of EBRT is that it can be performed safely regardless of the presence of portal vein invasion by the tumor. [bib_ref] Feasibility and efficacy of stereotactic ablative radiotherapy for Barcelona Clinic Liver Cancer-C..., Bae [/bib_ref] [bib_ref] The feasibility of combined transcatheter arterial chemoembolization and radiotherapy for advanced hepatocellular..., Cho [/bib_ref] [bib_ref] The retrospective cohort study for survival rate in patients with advanced hepatocellular..., Eun [/bib_ref] [bib_ref] Intra-arterial 5-fluorouracil/interferon combination therapy for advanced hepatocellular carcinoma with or without three-dimensional..., Katamura [/bib_ref] [bib_ref] Three-dimensional conformal radiotherapy for portal vein thrombosis of hepatocellular carcinoma, Kim [/bib_ref] [bib_ref] Stereotactic ablative radiotherapy for unresectable hepatocellular carcinoma patients who failed or were..., Lo [/bib_ref] [bib_ref] Accelerated treatment using intensity-modulated radiation therapy plus concurrent capecitabine for unresectable hepatocellular..., Mcintosh [/bib_ref] [bib_ref] Feasibility and efficacy of single photon emission computed tomography-based three-dimensional conformal radiotherapy..., Shirai [/bib_ref] [bib_ref] Radiation treatment outcomes for unresectable hepatocellular carcinoma, Skinner [/bib_ref] [bib_ref] Proton-beam therapy for hepatocellular carcinoma associated with portal vein tumor thrombosis, Sugahara [/bib_ref] [bib_ref] vessels: efficacy and outcomes, Tanaka [/bib_ref] [bib_ref] Effectiveness of stereotactic body radiotherapy for hepatocellular carcinoma with portal vein and/or..., Xi [/bib_ref] [bib_ref] Prospective trial of combined transcatheter arterial chemoembolization and three-dimensional conformal radiotherapy for..., Yamada [/bib_ref] [bib_ref] Radiotherapy plus transarterial chemoembolization for hepatocellular carcinoma invading the portal vein: long-term..., Yoon [/bib_ref] [bib_ref] Prognostic index for portal vein tumor thrombosis in patients with hepatocellular carcinoma..., Yu [/bib_ref] One study reports that when EBRT was used for patients unsuitable for TACE owing to severe tumor-induced arteriovenous shunts, 20% of these patients were able to undergo TACE successfully after radiation therapy-induced vascular occlusion. [bib_ref] Three-dimensional conformal radiotherapy for the treatment of arteriovenous shunting in patients with..., Hsu [/bib_ref] A meta-analysis reports that the use of TACE in combination with EBRT improves the 3-year survival rate by 10%-28% compared to TACE monotherapy.Meanwhile, the results of controlled studies comparing combination treatments are anticipated. Moreover, the addition of EBRT for HCC after incomplete TACE is reported to result in a complete response rate of 20.9%. [bib_ref] Early three-dimensional conformal radiotherapy for patients with unresectable hepatocellular carcinoma after incomplete..., Oh [/bib_ref] In a Korean multicenter retrospective cohort analysis, 78.4% of patients received TACE before receiving EBRT. [bib_ref] A multicenter retrospective cohort study of practice patterns and clinical outcome on..., Seong [/bib_ref] Another recent study shows that TACE combined with EBRT for resectable HCC with portal vein invasion resulted in a superior median survival of 12.3 months versus 10.0 months for the surgical group. [bib_ref] Surgical resection versus conformal radiotherapy combined with TACE for resectable hepatocellular carcinoma..., Tang [/bib_ref] Furthermore, combined treatment for HCC patients with inferior vena cava invasion also resulted in a superior median survival period of 11.7 months in comparison with the historical cohort who received TACE alone. [bib_ref] Combination of transarterial chemoembolization and three-dimensional conformal radiotherapy for hepatocellular carcinoma with..., Koo [/bib_ref] The sequential combination of EBRT 2 weeks after TACE may be complicated by liver dysfunction; however, Common Terminology Criteria of Adverse Events grade ≥3 liver dysfunction is reported in only 2.5% of all patients. [bib_ref] Scheduled interval trans-catheter arterial chemoembolization followed by radiation therapy in patients with..., Yu [/bib_ref] In one study, regional chemotherapy with 5-fluorouracil and cisplatin combined with EBRT for locally advanced HCC resulted in a 3-year survival rate of 24.1% and a median survival period of 13.1 months. [bib_ref] Pilot clinical trial of localized concurrent chemoradiation therapy for locally advanced hepatocellular..., Han [/bib_ref] The same institution reports a median progression-free survival of 4.5 months and overall survival of 9.8 months after TACE followed by EBRT and concurrent intraarterial 5-fluorouracil for locally advanced HCC with portal vein invasion and intrahepatic metastases. [bib_ref] Combination treatment of localized concurrent chemoradiation therapy and transarterial chemoembolization in locally..., Park [/bib_ref] In another study, the addition of EBRT to intra-arterial 5-fluorouracil and sub-cutaneous interferon treatment for 40 patients with advanced HCC and portal vein invasion significantly improved the time to progression from 4.0 to 6.9 months and the median survival from 9.1 to 12.0 months. [bib_ref] Efficacy of therapy for advanced hepatocellular carcinoma: intra-arterial 5-fluorouracil and subcutaneous interferon..., Chuma [/bib_ref] EBRT can also be considered a local neoadjuvant treatment for large HCCs with the aim of improving resectability. Accordingly, it has been reported that surgery can be performed safely post-EBRT, resulting in an effective response to neoadjuvant radiotherapy. [bib_ref] The efficacy of hepatic resection after neoadjuvant transarterial chemoembolization (TACE) and radiation..., Choi [/bib_ref] In addition, EBRT can be considered a bridging treatment for patients awaiting liver transplantation. [bib_ref] The safety and efficacy of high-dose proton beam radiotherapy for hepatocellular carcinoma:..., Bush [/bib_ref] [bib_ref] Stereotactic hypofractionated radiation therapy as a bridge to transplantation for hepatocellular carcinoma:..., Katz [/bib_ref] [bib_ref] Stereotactic body radiotherapy for primary hepatocellular carcinoma, Andolino [/bib_ref] Nevertheless, a controlled prospective comparative study is required to establish the role of EBRT as a new adjuvant treatment. EBRT can also be used as a secondline treatment for recurrent HCC after various nonsurgical treatments including TACE. [bib_ref] A multicenter retrospective cohort study of practice patterns and clinical outcome on..., Seong [/bib_ref] [bib_ref] Three-dimensional conformal radiotherapy of unresectable hepatocellular carcinoma patients for whom transcatheter arterial..., Kim [/bib_ref] [bib_ref] Local radiotherapy for patients with unresectable hepatocellular carcinoma, Park [/bib_ref] EBRT is also effective for relieving symptoms such as cancer pain. [bib_ref] Radiation therapy for hepatocellular carcinoma: from palliation to cure, Hawkins [/bib_ref] [bib_ref] Conformal chemoradiation for primary and metastatic liver malignancies, Dawson [/bib_ref] In patients with jaundice presenting with biliary obstructions due to the progression of HCC, EBRT has been demonstrated to successfully reduce tumor size and relieve symptoms; accordingly, EBRT is also expected to improve the survival in these patients. [bib_ref] A pilot study of three-dimensional conformal radiotherapy in unresectable hepatocellular carcinoma, Cheng [/bib_ref] [bib_ref] Incidence and clinical outcome of icteric type hepatocellular carcinoma, Huang [/bib_ref] In HCC patients with abdominal lymph node metastases, EBRT results in response rates of approximately 80% 361-364 with improved median survival time. [bib_ref] Consideration of role of radiotherapy for lymph node metastases in patients with..., Zeng [/bib_ref] In HCC patients with symptomatic bone metastases, EBRT is reported to relieve pain in 75%-99% of patients 366-370 as well as symptoms in patients with brain metastases from HCC. [bib_ref] Brain metastases from hepatocellular carcinoma: prognostic factors and outcome: brain metastasis from..., Choi [/bib_ref] Moreover, in a previous study, EBRT doses from 30 to 50.7 Gy for spinal cord compression from vertebral metastases resulted in ambulatory rates of 85% and 63% at 3 and 6 months, respectively. [bib_ref] A retrospective study of radiotherapy for spinal bone metastases from hepatocellular carcinoma..., Nakamura [/bib_ref] In two other studies, EBRT for lung metastases resulted in response rates from 60% to 70% while symptom relief was observed in 90% of symptomatic patients. [bib_ref] Simultaneous multitarget irradiation using helical tomotherapy for advanced hepatocellular carcinoma with multiple..., Jang [/bib_ref] [bib_ref] Palliative radiation therapy for pulmonary metastases from hepatocellular carcinoma, Jiang [/bib_ref] Recommendations [fig_ref] Table 2: Summary of the Recommendations of the 2014 KLCSG-NCC Korea Practice Guidelines for... [/fig_ref] 1. EBRT can be performed in HCC patients if liver functions are Child-Pugh class A or superb B and the irradiated total liver volume receiving ≥30 Gy is ≤60% (B1). 2. EBRT can be considered for HCC patients ineligible for surgical resection, liver transplantation, RFA, PEIT, or TACE (C1). 3. EBRT can be considered for HCC patients who show incomplete response to TACE when the dose-volume criteria in Recommendation 1 are met (B2). 4. EBRT can be considered for HCC patients with portal vein invasion when the dose-volume criteria in Recommendation 1 are met (C1). 5. EBRT is performed to alleviate symptoms caused by primary HCC or its metastases (B1). ## Systemic therapies 1. sorafenib Sorafenib is a multi-tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor, Raf-1, and c-kit. Sorafenib was the first approved molecular targeted agent for the treatment of HCC. In the SHARP study, a global phase III trial, the median survival of HCC patients with portal vein tumor invasion or extrahepatic metastasis treated with sorafenib was 10.7 months, which was significantly longer than 7.9 months in patients who received placebo (HR, 0.69; 95% CI, 0.55 to 0.87; p=0.00058). [bib_ref] Sorafenib in advanced hepatocellular carcinoma, Llovet [/bib_ref] The time to progression in the sorafenib group was 5.5 months, which was also significantly longer than 2.8 months in the control group. [bib_ref] Sorafenib in advanced hepatocellular carcinoma, Llovet [/bib_ref] In an Asia-Pacific phase III trial that included Korean patients with unresectable HCC, patients who received sorafenib had a significantly longer median survival (6.5 months) than that of the control group (4.2 months; HR, 0.68; 95% CI, 0.50 to 0.93; p=0.014). [bib_ref] Efficacy and safety of sorafenib in patients in the Asia-Pacific region with..., Cheng [/bib_ref] The median survival of patients treated with sorafenib was consistently reported to be approximately 10 months in the following 3 randomized controlled phase III trials testing novel molecular targeted agent in which sorafenib treatment was the control group. [bib_ref] Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase..., Cheng [/bib_ref] [bib_ref] Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular..., Johnson [/bib_ref] [bib_ref] Phase III trial of linifanib versus sorafenib in patients with advanced hepatocellular..., Cainap [/bib_ref] On the basis of the results of clinical trials, sorafenib is currently the only molecular targeted agent proven to prolong survival in advanced HCC patients. The abovementioned two phase III trials for sorafenib (i.e., the SHARP and Asia-Pacific trials) recruited HCC patients with Child-Pugh class A and ECOG performance status 0-2. In clinical practice, the safety and efficacy of sorafenib are reported to be comparable between Child-Pugh class A and B patients; [bib_ref] Practical efficacy of sorafenib monotherapy for advanced hepatocellular carcinoma patients in a..., Shim [/bib_ref] [bib_ref] Sorafenib for hepatocellular carcinoma according to Child-Pugh class of liver function, Kim [/bib_ref] [bib_ref] Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment..., Lencioni [/bib_ref] however, the prognosis is reported to differ with respect to the presence of ascites and Child-Pugh score. [bib_ref] Worse outcome of sorafenib therapy associated with ascites and Child-Pugh score in..., Kim [/bib_ref] Thus, although sorafenib can be used cautiously in patients with decreased liver function, more controlled studies are necessary. The most common adverse event related to sorafenib treatment is hand-foot syndrome reaction (HFSR), followed by fatigue, skin rash, anorexia, weight loss, hypertension, and alopecia. As HFSR tends to be decreasing sptontaneously after 3 months of treatment, it is important to continue therapy through patient education and proper management; for example, creams containing urea may be helpful for preventing dryness of the hands and feet. Furthermore, it is recommended to remove thick calluses, wear comfortable shoes with cushioning, avoid hot water, and take analgesics if necessary. [bib_ref] Management of sorafenib-related adverse events: a clinician's perspective, Brose [/bib_ref] Sorafenib is primarily used in advanced HCC patients with vascular invasion (i.e., the portal vein, hepatic vein, or inferior vena cava) or extrahepatic metastasis. It can also be used in HCC patients in whom locoregional therapies have failed or are not indicated. Although there is no clear definition of TACE failure or refractoriness, if HCC progresses and the tumor stage advances despite repeated applications of TACE (i.e., 3 times within 6 months) for residual or recurrent tumors after the initial TACE, sorafenib might be indicated on the basis of the concept of TACE failure or refractoriness. [bib_ref] Consensus recommendations and review by an International Expert Panel on Interventions in..., Park [/bib_ref] [bib_ref] Re-evaluating transarterial chemoembolization for the treatment of hepatocellular carcinoma: consensus recommendations and..., Cheng [/bib_ref] [bib_ref] Severity and timing of progression predict refractoriness to transarterial chemoembolization in hepatocellular..., Kim [/bib_ref] Regarding combination therapy with TACE and sorafenib in intermediate-stage HCC, a single-center phase II study shows longer survival and time to progression in combination therapy than a historic control group treated with TACE monotherapy; 388 while another phase II study, the SPACE trial, does not show the beneficial outcomes of combination therapy; 389 the former has the limitation of being a single-arm study, while the latter has drawbacks of study design, specifically not "on-demand" TACE but "scheduled" TACE and an endpoint of overall survival in patients with intermediate-stage HCC, who are expected to have favorable long-term prognosis. On the basis of the proven safety of combination therapies in both of these trials, there is an ongoing phase III trial of combination therapy with TACE and sorafenib in advanced HCC. Recommendations [fig_ref] Table 2: Summary of the Recommendations of the 2014 KLCSG-NCC Korea Practice Guidelines for... [/fig_ref] 1. Sorafenib is indicated for HCC patients with very wellpreserved liver function (i.e., Child-Pugh class A), good performance status, and regional lymph node or extrahepatic spread or patients with tumor progression on other therapies (A1). 2. Sorafenib is recommended for HCC patients with very wellpreserved liver function (i.e., Child-Pugh class A), and good performance status, and vascular invasion (A2). 3. Sorafenib is considered for HCC patients with preserved liver function (i.e., Child-Pugh class superb B) and good performance status if the above conditions (1 and 2) are satisfied (B1). ## Cytotoxic chemotherapy Sorafenib is recommended as a first-line systemic agent; however, despite several clinical trials, no second-line agent is proven to be effective in cases in which sorafenib fails or intolerance. Cytotoxic chemotherapy can be considered in cases of HCC progression on sorafenib or drug intolerance. [bib_ref] Metronomic capecitabine in advanced hepatocellular carcinoma patients: a phase II study, Brandi [/bib_ref] [bib_ref] Gemcitabine and oxaliplatin as second-line treatment in patients with hepatocellular carcinoma pre-treated..., Mir [/bib_ref] [bib_ref] Epirubicin, cisplatin, 5-FU combination chemotherapy in sorafenib-refractory metastatic hepatocellular carcinoma, Lee [/bib_ref] Most cytotoxic chemotherapeutics have shown poor response and no survival benefit through RCTs. Even though some agents result in a relatively good antitumor response, it is unrealistic to perform a multicenter prospective RCT evaluating efficacy and safety because of lack of study funding/sponsership. Despite the widespread use of doxorubicin, the response rate is less than 20%. [bib_ref] Doxorubicin (75 mg/m2) for hepatocellular carcinoma: clinical and pharmacokinetic results, Chlebowski [/bib_ref] [bib_ref] Chemotherapy for advanced hepatocellular carcinoma: adriamycin versus quadruple chemotherapy, Choi [/bib_ref] [bib_ref] Adriamycin treatment for hepatocellular carcinoma: experience with 109 patients, Sciarrino [/bib_ref] Satisfactory results have not been obtained with single agents such as 5-fluorouracil, [bib_ref] 5-Fluorouracil and highdose calcium leucovorin for hepatocellular carcinoma: a phase II trial, Tetef [/bib_ref] gemcitabine, 397,398 oxaliplatin, [bib_ref] Phase II study of oxaliplatin in patients with unresectable, metastatic, or recurrent..., Yen [/bib_ref] capecitabine, [bib_ref] Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma, Patt [/bib_ref] and irinotecan. [bib_ref] Irinotecan as first-line chemotherapy in patients with advanced hepatocellular carcinoma: a multicenter..., Boige [/bib_ref] In addition, octreotide, [bib_ref] A randomized placebo-controlled study of long-acting octreotide for the treatment of advanced..., Yuen [/bib_ref] interferon, [bib_ref] Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma, Llovet [/bib_ref] and tamoxifen [bib_ref] Randomized controlled trial of tamoxifen in advanced hepatocellular carcinoma, Barbare [/bib_ref] have not shown any survival benefit for HCC. Several combination regimens have been tried because of the modest efficacy of monotherapy. The PIAF regimen (cisplatin/ interferon a-2b/doxorubicin/fluorouracil) shows better objective response rates (20.9% vs 10.5%, p=0.058) and median overall survival (8.67 months vs 6.83 months; RR, 0.97; p=0.830), although the difference failed to reach statistical significance. Meanwhile, hematologic toxicities were significantly more frequent in PIAF group. [bib_ref] A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/ fluorouracil (PIAF)..., Yeo [/bib_ref] Another combination regimen, FOLFOX (oxaliplatin/fluorouracil/leucovorin) was compared with doxorubicin monotherapy. Patients receiving FOLFOX had significantly better progression-free survival (2.93 months vs 1.77 months, p<0.01) and disease control rate (52.17% vs 31.55%, p<0.001) but a nonsignificant trend toward better survival (6.4 months vs 4.97 months, p=0.07). [bib_ref] Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative..., Qin [/bib_ref] Some results of cisplatin-containing regimens (e.g., in combination with doxorubicin,capecitabine, [bib_ref] Efficacy of combination chemotherapy with capecitabine plus cisplatin in patients with unresectable..., Shim [/bib_ref] [bib_ref] Combination chemotherapy with capecitabine and cisplatin for patients with metastatic hepatocellular carcinoma, Lee [/bib_ref] or 5-fluorouracil 411 ) or oxaliplatincontaining regimens (e.g., in combination with gemcitabine 412 or capecitabine 413 ) for HCC have been reported, but the benefits of these regimens compared to monotherapy are still lacking. Most patients with HCC are accompanied by chronic liver disease or liver cirrhosis, which can alter the metabolism of chemotherapeutics and increase their toxicity. [bib_ref] Systemic therapy for hepatocellular carcinoma, Thomas [/bib_ref] Therefore, systemic chemotherapy should be reserved for patients with good performance status and liver function. In addition, great care is required to maintain the quality of life of patients receiving chemotherapeutics. ## Hepatic arterial infusion chemotherapy HAIC can directly deliver high concentrations of chemotherapeutic agents via the hepatic artery with low systemic toxicities. HAIC is usually performed for HCC with portal vein invasion and can be considered for TACE-refractory cases. Recent reports demonstrate that HAIC can also be tried for sorafenib-refractory or intolerant HCCs, although further studies are warranted. [bib_ref] Feasibility and efficacy of hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma..., Terashima [/bib_ref] [bib_ref] The efficacy of hepatic arterial infusion chemotherapy as an alternative to sorafenib..., Jeong [/bib_ref] The most widely used agent in HAIC is 5-fluorouracil, which is either administered alone or with cisplatin, showing response rates from 3.8% to 38.5% and median survival from 5 to 19.5 months. [bib_ref] Hepatic arterial infusion chemotherapy with use of an implanted port system in..., Hamada [/bib_ref] [bib_ref] Hepatic arterial infusion chemotherapy using low-dose 5-fluorouracil and cisplatin for advanced hepatocellular..., Ueshima [/bib_ref] HAIC can be administered in combination with systemic interferon. [bib_ref] Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma: is the addition of..., Takaki-Hamabe [/bib_ref] [bib_ref] Randomized, phase II study comparing interferon combined with hepatic arterial infusion of..., Yamashita [/bib_ref] The implantable device required for HAIC can sometimes cause complications such as infection and occlusion. Nevertheless, further studies are warranted, because there is insufficient evidence demonstrating that HAIC improves survival compared to systemic chemotherapy or best supportive care. Recommendations [fig_ref] Table 2: Summary of the Recommendations of the 2014 KLCSG-NCC Korea Practice Guidelines for... [/fig_ref] 1. Cytotoxic chemotherapy can be considered for HCC patients with advanced tumors who have well-preserved liver function and good performance status in whom sorafenib therapy has failed (C1). ## Adjuvant therapy Adjuvant therapy usually refers to an additional treatment after definitive or curative therapy to prevent recurrence. As there recurrence rate 5 years after curative resection for HCC is very high at 70% (see "Liver Resection" section), [bib_ref] Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular..., Imamura [/bib_ref] [bib_ref] A system of classifying microvascular invasion to predict outcome after resection in..., Roayaie [/bib_ref] [bib_ref] Intrahepatic recurrence after resection of hepatocellular carcinoma complicating cirrhosis, Belghiti [/bib_ref] an effective adjuvant therapy is urgently required. There is currently no proven modality; 58 neither sorafenib nor cytotoxic chemotherapy is recommended as an adjuvant therapy. Furthermore, there is no evidence that TACE prevents HCC recurrence after curative resection. [bib_ref] Lipiodolized transarterial chemoembolization in hepatocellular carcinoma patients after curative resection, Chen [/bib_ref] Although one study reports that 131 I infusion via the hepatic artery after curative resection reduces the recurrence of HCC, no validation study was performed. [bib_ref] Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial, Lau [/bib_ref] [bib_ref] Adjuvant intra-arterial injection of iodine-131-labeled lipiodol after resection of hepatocellular carcinoma, Boucher [/bib_ref] Thus, this radionuclide therapy is not recommended at present. A study of activated immune cells derived from patients shows a 15% decrease in the 3-year recurrence rate compared to that of the control group. [bib_ref] Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised..., Takayama [/bib_ref] However, there has been no reliable study to corroborate this. TACE can result in the downstaging of HCC, enabling curative resection. Even for resectable HCC, TACE can be applied prior to resection as a neoadjuvant therapy. However, there is no evidence that TACE followed by resection increases diseasefree survival compared with resection only in resectable HCC. [bib_ref] Preoperative transarterial chemoembolization and resection for hepatocellular carcinoma: a nationwide Taiwan database..., Shi [/bib_ref] Recommendations [fig_ref] Table 2: Summary of the Recommendations of the 2014 KLCSG-NCC Korea Practice Guidelines for... [/fig_ref] 1. Adjuvant TACE, sorafenib, and cytotoxic chemotherapy are not recommended for HCC patients treated with curative resection (B1). ## Preemptive antiviral treatment ## Hbv carriers The rate of HBV reactivation in HCC patients after cytotoxic chemotherapy varies widely from 30% to 60%, [bib_ref] Hepatitis B reactivation in patients with hepatocellular carcinoma undergoing systemic chemotherapy, Yeo [/bib_ref] [bib_ref] Prophylactic lamivudine administration prevents exacerbation of liver damage in HBe antigen positive..., Nagamatsu [/bib_ref] and the subsequent mortality rate is reported to be approximately 30% of all deaths resulting from HBV reactivation. HBV reactivation with concomitant elevation of serum HBV DNA level or abnormality of biochemical liver function is observed in 20%-50% of total HBV carriers who receive immunosuppressants or cytotoxic chemotherapy for the treatment of malignancies other than HCC (e.g., breast cancer, hematologic malignancies, and other solid cancers). [bib_ref] Hepatitis B reactivation in patients with hepatocellular carcinoma undergoing systemic chemotherapy, Yeo [/bib_ref] [bib_ref] Screening, prevention and treatment of viral hepatitis B reactivation in patients with..., Lalazar [/bib_ref] [bib_ref] Hepatitis B virus reactivation after cytotoxic chemotherapy: the disease and its prevention, Mindikoglu [/bib_ref] [bib_ref] Preemptive use of lamivudine reduces hepatitis B exacerbation after allogeneic hematopoietic cell..., Lau [/bib_ref] [bib_ref] Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy:..., Yeo [/bib_ref] Therefore, the test for hepatitis B surface antigen (HBsAg) must be performed in patients at high risk for HBV infection prior to immunosuppressive therapy or cytotoxic chemotherapy. [bib_ref] Chronic hepatitis B, Lok [/bib_ref] Antiviral drugs should be preemptively administered in HBV carriers at the onset of the cytotoxic chemotherapy or immunosuppressant administration and must be continued for at least 6 months. Although further research is required to clarify the adequate serum HBV DNA level, recurrence is more likely after the discontinuation of antiviral drugs in patients with high HBV DNA levels prior to cytotoxic chemotherapy. Therefore, in patients with HBV DNA levels >2,000 IU/mL prior to cytotoxic chemotherapy, continuation of antiviral treatment should be considered until the treatment goal of chronic hepatitis B is reached. [bib_ref] Chronic hepatitis B, Lok [/bib_ref] Most studies on preemptive antiviral treatment are limited to lamivudine, but other recently developed antiviral drugs can be used. In cases of lamivudine resistance, antiviral drugs should be replaced according to the treatment guidelines for resistance. [bib_ref] An optimized antiviral modification strategy for prevention of hepatitis B reactivation in..., Wu [/bib_ref] [bib_ref] Adefovir added to lamivudine for hepatitis B recurrent infection in refractory Bcell..., Cortelezzi [/bib_ref] In cases in which antiviral therapy is expected to continue for more than 12 months in particular, the antiviral drug with the minimum resistance profile should be selected. [bib_ref] Antiviral therapy decreases viral reactivation in patients with hepatitis B virus-related hepatocellular..., Huang [/bib_ref] [bib_ref] Posthepatectomy HBV reactivation in hepatitis B-related hepatocellular carcinoma influences postoperative survival in..., Huang [/bib_ref] Interferon is not recommended as a preemptive treatment because of the risk of bone marrow suppression and transient aggravation of hepatitis. In the HBsAg-negative, anti-HBc-positive, and anti-HBs-positive patients, HBV reactivation can develop very rarely, and there is little evidence to recommend uniform preemptive treatment owing to a lack of research. [bib_ref] Chronic hepatitis B, Lok [/bib_ref] Comparatively many studies have evaluated HBV reactivation during TACE for the treatment of HCC; HBV reactivation is reported to occur in 4%-40% of patients. [bib_ref] Hepatitis B reactivation in patients with hepatocellular carcinoma undergoing systemic chemotherapy, Yeo [/bib_ref] [bib_ref] Effects of antiviral therapy on hepatitis B virus reactivation and liver function..., Lao [/bib_ref] [bib_ref] Changes in hepatitis B virus DNA levels and liver function after transcatheter..., Lao [/bib_ref] [bib_ref] Management of viral hepatitis in hematologic malignancies, Firpi [/bib_ref] [bib_ref] A randomized controlled study of preemptive lamivudine in patients receiving transarterial chemo-lipiodolization, Jang [/bib_ref] [bib_ref] Risk of hepatitis B exacerbation is low after transcatheter arterial chemoembolization therapy..., Park [/bib_ref] According to a study comparing preemptive lamivudine treatment to a nonadministered control group during TACE, 444 significant differences were observed with respect to HBV reactivation (2.8% and 40.5%) as well as the consequent occurrence of hepatitis (2.8% and 19.7%) and liver failure (0% and 8.1%). Hence, preemptive antiviral treatment can be considered for HBV-positive HCC patients undergoing TACE. However, differences in chemotherapeutic agents, and treatment interval and frequency may have resulted in discordant HBV reactivation rates. [bib_ref] A randomized controlled study of preemptive lamivudine in patients receiving transarterial chemo-lipiodolization, Jang [/bib_ref] [bib_ref] Risk of hepatitis B exacerbation is low after transcatheter arterial chemoembolization therapy..., Park [/bib_ref] [bib_ref] Risk of HBV reactivation according to viral status and treatment intensity in..., Jang [/bib_ref] Therefore, additional research is required to determine the serum HBV DNA levels and biochemical liver function test levels that require preemptive antiviral treatment. HBV reactivation rates after HAIC for HCC (24%-67%) are reported to be higher than those after TACE possibly because of the higher dose of chemotherapeutic agents, as HAIC is carried out in shorter intervals. [bib_ref] Prophylactic lamivudine administration prevents exacerbation of liver damage in HBe antigen positive..., Nagamatsu [/bib_ref] [bib_ref] Lamivudine therapy for hepatitis B virus reactivation in a patient receiving intra-arterial..., Tamori [/bib_ref] [bib_ref] Investigation of associating factors in exacerbation of liver damage after chemotherapy in..., Nagamatsu [/bib_ref] However, more research is needed to support the claim that HAIC has a higher reactivation rate than TACE, as only a few studies with a limited number of subjects have been reported and no comparative study with TACE has been performed. Following the surgical resection of HCC, HBV reactivation with concomitant elevation in the HBV DNA level or abnormal biochemical liver function test is observed in 14%-32% of patients. [bib_ref] Reactivation of viral replication after liver resection in patients infected with hepatitis..., Kubo [/bib_ref] In a prospective study comparing preemptive telbivudine administration to a nonadministered control group from the day of resection, the HBV reactivation rates were 2.5% and 31.8%, respectively. While 57.1% of the control group showed HBV reactivation within 1 week following surgical resection, only 2.5% of the telbivudine-administered group showed reactivation within 4 weeks. [bib_ref] Antiviral therapy decreases viral reactivation in patients with hepatitis B virus-related hepatocellular..., Huang [/bib_ref] The authors of that study recommend preemptive antiviral treatment before the surgical resection of HCC; however, that study involved only few patients at a single institution in China. Therefore, a large-scale multicenter study should be performed to determine a universal preemptive antiviral treatment before the surgical resection of HCC. A study comparing preemptive lamivudine administration and a nonadministered control group following radiotherapy for HCC reports the HBV reactivation rates to be 0% and 21.8%, respectively; meanwhile, alanine transaminase elevation occurred in 2.3% and 12.5% of patients, respectively. [bib_ref] Hepatitis B virus reactivation after three-dimensional conformal radiotherapy in patients with hepatitis..., Kim [/bib_ref] Another recent report suggests concurrent TACE and external radiotherapy may double the HBV reactivation rate compared to TACE alone. [bib_ref] Risk of HBV reactivation according to viral status and treatment intensity in..., Jang [/bib_ref] However, it is difficult to recommend preemptive antiviral treatment before external radiotherapy for HCC because of the lack of controlled prospective studies. There are limited studies regarding HBV reactivation from PEIT or RFA; nonetheless, the HBV reactivation rates for these therapies are reported to be 0% and 5.6%-9.1%, respectively. [bib_ref] Hepatitis B virus reactivation after radiofrequency ablation or hepatic resection for HBV-related..., Dan [/bib_ref] [bib_ref] Safety and efficacy of lamivudine after radiofrequency ablation in patients with hepatitis..., Yoshida [/bib_ref] Meanwhile, no HBV reactivation was observed after sorafenib administration in a retrospective study. [bib_ref] Practical efficacy of sorafenib monotherapy for advanced hepatocellular carcinoma patients in a..., Shim [/bib_ref] Regardless, more observations and research are required. ## Hcv carriers Regarding HCV-related HCC, there are almost no reported cases of HCV reactivation or aggravation of hepatitis after HCC treatment. In a recent retrospective study on hepatitis virus reactivation comparing HCV-and HBV-related HCC after TACE, the rates of HCV and HBV reactivation, hepatitis, and liver failure were 26.5% and 32.5%, 10.2% and 34.8%, and 0% and 10.9%, respectively. [bib_ref] Differences in the patterns and outcomes of enhanced viral replication between hepatitis..., Sung [/bib_ref] No significant difference was observed between the HCV and HBV groups with respect to the reactivation rate, but the development of hepatitis and liver failure were significantly lower in the HCV-related HCC group. Hepatitis C treatments can be considered in patients with active chronic hepatitis C and completely eradicated HCC. As interferon and ribavirin administration may cause bone marrow suppression and transient aggravation of hepatitis, they are not recommended as preemptive treatments before cytotoxic chemotherapy in HCC patients. Recommendations [fig_ref] Table 2: Summary of the Recommendations of the 2014 KLCSG-NCC Korea Practice Guidelines for... [/fig_ref] 1. Patients should be tested for hepatitis B surface antigen before starting cytotoxic chemotherapy or immunosuppressive therapy (A1). 2. Preemptive antiviral therapy is recommended for HBV carriers undergoing cytotoxic chemotherapy to prevent reactivation (A1). Preemptive antiviral therapy is considered for HBV infected patients receiving TACE (B1), hepatic arterial infusion chemotherapy (C1), surgical resection (C1), or EBRT (C1) to prevent reactivation. 3. Antiviral treatment for HBV reactivation should follow the recommendations of the current KASL guidelines (A1). ## Drug treatment for cancer pain in hcc Pain is one of the most troublesome symptoms in cancer patients. The prevalence of pain in cancer patients ranges from 45% to 53%, [bib_ref] Change in cancer pain management in Korea between 2001 and 2006: results..., Hong [/bib_ref] [bib_ref] Prevalence of pain in patients with cancer: a systematic review of the..., Van Den Beuken-Van Everdingen [/bib_ref] and early aggressive palliative care including pain management could improve survival in lung cancer patients. [bib_ref] Early palliative care for patients with metastatic non-small-cell lung cancer, Temel [/bib_ref] A few studies have investigated the prevalence of pain in HCC patients, which is reported to range from 22% to 66.8%. [bib_ref] Pain at presentation and survival in hepatocellular carcinoma, Carr [/bib_ref] [bib_ref] Symptom clusters and quality of life in Korean patients with hepatocellular carcinoma, Ryu [/bib_ref] Therefore, pain management should be considered an important aspect of palliative care for HCC patients. As most HCC patients have chronic liver disease and/or liver cirrhosis, their drug metabolism may be altered according to the degree of liver dysfunction. [bib_ref] Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction, Verbeeck [/bib_ref] Furthermore, HCC patients receiving analgesics may suffer from more frequent and severe side effects. However, there is a paucity of studies on pain man-agement for patients with HCC and liver disease.Therefore, drug treatment for cancer pain in HCC patients should generally follow the principles of pain management for general solid tumors.However, drug selection, dosage, and administration interval might need to be adjusted according to the degree of liver function impairment. The universal strategy for cancer pain treatment is based on a sequential three-step analgesics ladder approach from nonopioids to weak opioids and finally to strong opioids according to pain intensity and the efficacy of pain control.The main nonopioid analgesics such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are indicated for the treatment of mild pain (numerical rating scale, 1-3). Meanwhile, weak opioids such as codeine, hydrocodone, and tramadol are indicated for mild to moderate pain (numerical rating scale, 4-6). Finally, strong opioids such as morphine, oxycodone, hydromorphone, fentanyl, and their analogues are the mainstay of analgesics for treating moderate to severe cancer-related pain (numerical rating scale, 7-10). Acetaminophen is the most common cause of fulminant hepatic failure, [bib_ref] Use of over-the-counter analgesics in patients with chronic liver disease: physicians' recommendations, Rossi [/bib_ref] [bib_ref] Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study, Larson [/bib_ref] but clinically significant hepatic injury is very rare when the dosage is limited to 4 g/day.Although one case report demonstrates that even therapeutic doses of acetaminophen less than 4 g/day in alcoholic patients without liver cirrhosis can result in acute liver failure, [bib_ref] Hepatotoxicity caused by therapeutic doses of paracetamol in alcoholics: report of 2..., Mofredj [/bib_ref] other studies show 4 g/day in alcoholic patients is not associated with a significant increase in liver toxicity. [bib_ref] Does therapeutic use of acetaminophen cause acute liver failure?, Dart [/bib_ref] [bib_ref] The effect of acetaminophen (four grams a day for three consecutive days)..., Kuffner [/bib_ref] Moreover, one study shows a significant increase in the liver enzymes of alcoholic patients taking acetaminophen 4 g/day. [bib_ref] A randomized trial to determine the change in alanine aminotransferase during 10..., Heard [/bib_ref] In patients with cirrhosis, acetaminophen 2-3 g/day is not associated with acute hepatic decompensation. [bib_ref] Use of over-thecounter analgesics is not associated with acute decompensation in patients..., Khalid [/bib_ref] Even though the half-life of oral acetaminophen is twice as long in patients with cirrhosis compared to healthy controls, 473 significant hepatic injury is rare in patients with liver disease and/or cirrhosis at a dosage of less than 4 g/ day. [bib_ref] Pomier-Layrargues G. Pharmacokinetics and metabolism of acetaminophen in normal, alcoholic and cirrhotic..., Villeneuve [/bib_ref] [bib_ref] Preventative hepatology: minimising symptoms and optimising care, Hirschfield [/bib_ref] Nonetheless, most experts recommend lowering the dosage of acetaminophen to 2-3 g/day in patients with liver cirrhosis because of the inevitable possibility of altered drug metabolism and increased half-life. [bib_ref] The therapeutic use of acetaminophen in patients with liver disease, Benson [/bib_ref] [bib_ref] Pain management in the cirrhotic patient: the clinical challenge, Chandok [/bib_ref] The unbound drug concentrations of NSAIDs are generally elevated in liver disease patients, which can lead to more severe side effects and toxicity. [bib_ref] Naproxen disposition in patients with alcoholic cirrhosis, Williams [/bib_ref] Indeed, roughly 10% of total druginduced hepatotoxicity cases are related to NSAIDs, [bib_ref] Non-steroidal anti-inflammatory drugs: what is the actual risk of liver damage?, Bessone [/bib_ref] and NSAID-induced liver injury is well documents. [bib_ref] Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study, Larson [/bib_ref] [bib_ref] Ibuprofen-induced hepatotoxicity in patients with chronic hepatitis C: a case series, Riley Tr 3rd [/bib_ref] Moreover, NSAIDs can cause nephrotoxicity, 480 gastric ulcer, hemorrhage, 481,482 decompensation of liver function, etc. [bib_ref] Use of over-thecounter analgesics is not associated with acute decompensation in patients..., Khalid [/bib_ref] As the liver is the major site of metabolism for most opioids, impaired metabolism and excretion of opioids due to underlying liver disease in HCC patients can lead to increased side effects. Moreover, opioids are a well-known major precipitants of hepatic encephalopathy. [bib_ref] Preventative hepatology: minimising symptoms and optimising care, Hirschfield [/bib_ref] Therefore, careful selection, and dosage and interval adjustment of drugs are required according to the liver metabolism of each opioid. [bib_ref] Pain management in the cirrhotic patient: the clinical challenge, Chandok [/bib_ref] [bib_ref] Opioid metabolism, Smith [/bib_ref] Morphine is an active analgesic compound by itself, and more than 90% of metabolites are excreted renally after glucuronidation in the liver. The half-life of morphine is approximately twice as long in cirrhotic patients as that in healthy controls. [bib_ref] The metabolism and bioavailability of morphine in patients with severe liver cirrhosis, Hasselström [/bib_ref] [bib_ref] Pharmacokinetics of opioids in liver disease, Tegeder [/bib_ref] Furthermore, its bioavailability is 4-fold greater in patients with HCC (68%) as that in healthy controls (17%). [bib_ref] Pharmacokinetics of controlled release morphine (MST) in patients with liver carcinoma, Kotb [/bib_ref] As the analgesic effect of codeine is presumed to be secondary following its conversion to morphine, serum levels are not expected. The ceiling effect of codeine may cause side effects before achieving a sufficient analgesic effect. Similarly, hydrocodone is metabolized to hydromorphone before producing an analgesic effect, which results in variable serum levels. Meanwhile, tramadol has 10-fold less affinity for opioid receptors than codeine and exerts its analgesic effect via the peripheral pain pathway, which may result in fewer side effects in patients with liver disease. However, its elimination half-life is up to 3-fold greater in patients with primary liver carcinoma than that in controls. [bib_ref] Abd El-Rahman AM. Pharmacokinetics of oral tramadol in patients with liver cancer, Kotb [/bib_ref] Oxycodone is converted to various metabolites including oxymorphone (an active metabolite), which may result in variable serum levels of metabolites and an unpredictable analgesic effect. The elimination half-life of oxycodone is prolonged, while its clearance is diminished with significant ventilation depression in pretransplantation liver cirrhosis patients compared to posttransplantation patients. [bib_ref] Pharmacokinetics and ventilatory effects of oxycodone before and after liver transplantation, Tallgren [/bib_ref] Hydromorphone is an active analgesic compound by itself and is metabolized and excreted after glucuronidation. Liver dysfunction does not have a relatively substantial effect on hydromorphone; the half-life of hydromorphone does not differ significantly in patients with moderate hepatic impairment compared to controls. [bib_ref] Pharmacokinetics of oral immediate-release hydromorphone (Dilaudid IR) in subjects with moderate hepatic..., Durnin [/bib_ref] Although fentanyl is metabolized by cytochrome, its metabolism does not yield toxic metabolites, significantly alter serum levels in cirrhotic patients. [bib_ref] Fentanyl pharmacokinetics in anaesthetized patients with cirrhosis, Haberer [/bib_ref] Furthermore, it is not influenced by renal dysfunction. [bib_ref] Pain management in the cirrhotic patient: the clinical challenge, Chandok [/bib_ref] [bib_ref] Opioid metabolism, Smith [/bib_ref] Recommendations [fig_ref] Table 2: Summary of the Recommendations of the 2014 KLCSG-NCC Korea Practice Guidelines for... [/fig_ref] 1. Careful consideration is required for pain management with medication in patients with HCC and underlying liver disease. The dosage and dosing intervals of analgesics should be determined on the basis of liver functions (C1). 2. In patients with HCC and chronic liver disease, the dosage of acetaminophen should be lowered (C1) and NSAIDs should be used with caution (B1). 3. In patients with HCC and chronic liver disease, opioid analgesics and their dosage should be selected carefully on the basis of drug metabolism and liver function (C1). ## Assessment of tumor response and posttreat-ment follow-up ## Tumor response The main endpoint in cancer research is overall survival. Nonetheless, tumor response and time to progression are also considered pivotal for the surrogate assessment of efficacy. In oncology, tumor response was initially measured according to the 1979 World Health Organization (WHO) criteria as follows: [bib_ref] Reporting results of cancer treatment, Miller [/bib_ref] (1) Complete response (CR): Complete disappearance of all known disease and no new lesions determined by two observations not less than 4 weeks apart. (2) Partial response (PR): 50% reduction in total tumor load of all measurable lesions determined by two observations not less than 4 weeks apart. (3) Progressive disease (PD): 25% increase in the size of one or more measurable lesions or the appearance of new lesions. (4) Stable disease (SD): Cases not belonging to CR, PR, or PD. However, several problems arose when applying these definitions to clinical practice. For example, there were discrepancies in the criteria for measuring tumor size among researchers. Furthermore, some researchers define progressive disease on the basis of the change in the size of one tumor, while others define it on the basis of the sum of the changes in the sizes of all tumors. Another limitation of the WHO criteria is properly reflecting the changes in tumor volume determined by recent advanced CT and MRI technologies. In order to overcome these problems, the Response Evaluation Criteria in Solid Tumors (RECIST) criteria and RECIST version 1.1 were developed and released in 2000 and 2009, respectively. In these criteria, overall responses are determined after evaluating the treatment responses for all lesions that are targeted or nontargeted. [bib_ref] Individual patient data analysis to assess modifications to the RECIST criteria, Bogaerts [/bib_ref] The criteria used to determine objective tumor responses for targeted lesions (or an index lesion) are as follows: (1) Complete response (CR): Disappearance of all targeted lesions. Any pathologic lymph nodes must have reduction in short axis to <10 mm. (2) Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions with respect to baseline sum diameter. (3) Progressive disease (PD): At least a 20% increase in the sum of the diameter of the target lesion. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (4) Stable disease: Cases not belonging to CR, PR, or PD. Meanwhile, the criteria for the evaluation of nontargeted lesions are as follows:(1) Complete response: Disappearance of all nontargeted lesions and normalization of tumor marker levels. All lymph nodes must be nonpathologic in size (i.e., <10 mm short axis). (2) Noncomplete response/nonprogressive disease: Persistence of one or more on-target lesions and/or maintenance of tumor marker levels above the normal limits. (3) Progressive disease: Progression of existing nontargeted lesions or appearance of new lesions. However, these criteria were primarily designed to evaluate cytotoxic agents. Therefore, they do not address measures of antitumor activity besides tumor shrinkage; thus, the best response in these criteria might be stable disease. As acknowledged in the original RECIST publication, assessments based solely on changes in tumor size can be misleading when applied to other anticancer drugs such as molecular targeted therapies or other therapeutic interventions.Therefore, these determinations may be inaccurate. Several clinical studies on HCC demonstrate that the RECIST criteria do not mirror the extent of tumor necrosis induced by interventional therapies or new molecular targeted drugs. [bib_ref] Sorafenib in advanced hepatocellular carcinoma, Llovet [/bib_ref] [bib_ref] Evaluation of tumor response after locoregional therapies in hepatocellular carcinoma: are response..., Forner [/bib_ref] In theory, viable tumor formation should be assessed by CT or MRI studies, and tumor viability should be defined according to the uptake of contrast agent in the arterial phase of dynamic imaging studies. In fact, extensive tumor necrosis, which develops after local treatment, may not be paralleled by a decrease in lesion diameter. [bib_ref] Sorafenib in advanced hepatocellular carcinoma, Llovet [/bib_ref] [bib_ref] Evaluation of tumor response after locoregional therapies in hepatocellular carcinoma: are response..., Forner [/bib_ref] To overcome these limitations, the EASL developed new criteria for HCC treatment response that take into account the degree of necrosis. [bib_ref] Clinical management of hepatocellular carcinoma: conclusions of the Barcelona-2000 EASL conference. European..., Bruix [/bib_ref] Furthermore, mRECIST criteria were first proposed by a panel of experts; [bib_ref] Design and endpoints of clinical trials in hepatocellular carcinoma, Llovet [/bib_ref] [bib_ref] Modified RECIST (mRECIST) assessment for hepatocellular carcinoma, Lencioni [/bib_ref] this proposal is based on the fact that the diameter of the target lesions with viable tumors should guide all assessments. Specific modifications to the original criteria regarding the assessment of vascular invasion, lymph nodes, ascites, pleural effusion, and new lesions are summarized in [fig_ref] Table 7: Assessment of Tumor Response* RECIST mRECIST Target lesion response CR Disappearance of... [/fig_ref]. However, a limitation that should be noted is that the assessment of response to treatment based on the mRECIST criteria can be influenced by the image quality of CT/MRI as well as the subjective decisions of radiologists. Because there is no solid evidence indicating which set of criteria is superior, the panel of experts recommends determining whether a set of criteria outperforms the conventional RECIST criteria as well as correlations with pathologic studies and outcome prediction. Recommendations [fig_ref] Table 2: Summary of the Recommendations of the 2014 KLCSG-NCC Korea Practice Guidelines for... [/fig_ref] 1. Assessment of response should follow both the RECIST and mRECIST criteria (B1). ## Follow-up after complete response Follow-up data after complete response in HCC are very limited. In cases of complete response after hepatic resection, transplantation, or percutaneous local ablation, follow-up intervals are determined on the basis of pretreatment risk factors and the treatment-specific risk of recurrence. The 5-year recurrence rate following hepatic resection is up to 70% and is due to intrahepatic metastases and/or de novo carcinogenesis. [bib_ref] Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation, Llovet [/bib_ref] [bib_ref] A system of classifying microvascular invasion to predict outcome after resection in..., Roayaie [/bib_ref] [bib_ref] Predictive factors for postoperative recurrence of hepatocellular carcinoma, Okada [/bib_ref] [bib_ref] Factors linked to early recurrence of small hepatocellular carcinoma after hepatectomy: univariate..., Shirabe [/bib_ref] Postoperative recurrence is usually classified as early (i.e., <2 years postoperatively) or late (i.e., >2 years postoperatively). [bib_ref] Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular..., Imamura [/bib_ref] [bib_ref] Design and endpoints of clinical trials in hepatocellular carcinoma, Llovet [/bib_ref] Risk factors for recurrence are related to the tumor or underlying chronic liver disease. Tumor-related risk factors for recurrence are associated with early recurrence and include tumor size and number, degree of differentiation, vascular invasion, serum AFP (if elevated preoperatively), insufficient resection margin, and nonanatomical resection. [bib_ref] Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular..., Imamura [/bib_ref] [bib_ref] Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and..., Portolani [/bib_ref] [bib_ref] Predictive factors for postoperative recurrence of hepatocellular carcinoma, Okada [/bib_ref] [bib_ref] Factors linked to early recurrence of small hepatocellular carcinoma after hepatectomy: univariate..., Shirabe [/bib_ref] [bib_ref] Intrahepatic recurrence after curative resection of hepatocellular carcinoma: long-term results of treatment..., Poon [/bib_ref] [bib_ref] Risk factors for intrahepatic recurrence in human small hepatocellular carcinoma, Adachi [/bib_ref] Meanwhile, late recurrence risk factors are related to underlying liver disease and include elevated serum HBV DNA during the perioperative period in cases of chronic hepatitis B, 148,503-505 and persistent active inflammation and advanced degree of fibrosis in cases of chronic hepatitis C. [bib_ref] Clinicopathological criteria for multicentricity of hepatocellular carcinoma and risk factors for such..., Kubo [/bib_ref] The 5-year survival rate of liver transplantation exceeds 70% and the recurrence rate is less than 15% in patients meeting Mi-lan criteria. [bib_ref] Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of..., Mazzaferro [/bib_ref] Major risk factors for recurrence after transplantation are tumor size and vascular invasion; other risk factors include tumor number, degree of differentiation, serum AFP level, and bilobar location of tumors. [bib_ref] Living donor liver transplantation for adult patients with hepatocellular carcinoma: experience in..., Todo [/bib_ref] [bib_ref] Liver transplantation for hepatocellular carcinoma validation of present selection criteria in predicting..., Shetty [/bib_ref] [bib_ref] Tumour size is an important predictor for the outcome after liver transplantation..., Löhe [/bib_ref] Recurrence occurs in more than 90% of patients within 2 years, 35% of which occur in the liver if the abovementioned risk factors are present. A recent multicenter study from Korea reports that the recurrence-free survival was significantly lower in living donor than DDLT. [bib_ref] Living-donor liver transplantation associated with higher incidence of hepatocellular carcinoma recurrence than..., Park [/bib_ref] Thus, follow-up after LDLT should be emphasized, especially in countries where most liver transplants are cases are from living donors, such as Korea. Local recurrence rates up to 2 years after treatment are higher after RFA (2%-18%) or PEIT (11%-45%) than after surgery, respectively. [bib_ref] Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma <..., Lin [/bib_ref] [bib_ref] A randomized controlled trial of radiofrequency ablation with ethanol injection for small..., Shiina [/bib_ref] [bib_ref] Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus..., Lencioni [/bib_ref] [bib_ref] Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and..., Lin [/bib_ref] [bib_ref] Radiofrequency ablation versus ethanol injection for early hepatocellular carcinoma: a randomized controlled..., Brunello [/bib_ref] The 4-year cumulative recurrence rate after RFA for single tumors <3 cm is 57%. Meanwhile, the 3-/5-year cumulative recurrence rates after RFA or PEIT for ≤3 tumors <3 cm in diameter are 57%/72% and 64%/77%, respectively. [bib_ref] Long-term effectiveness of resection and radiofrequency ablation for single hepatocellular carcinoma </=3..., Pompili [/bib_ref] [bib_ref] Comparison of resection and ablation for hepatocellular carcinoma: a cohort study based..., Hasegawa [/bib_ref] Incomplete tumor necrosis often occurs after PEIT, and the local recurrence rate is up to 43% for large tumors >3 cm. [bib_ref] Prospective analysis of risk factors for early intrahepatic recurrence of hepatocellular carcinoma..., Khan [/bib_ref] RFA for patients with a single nodular tumor <2 cm results in a 5-year survival rate of 70%. [bib_ref] Sustained complete response and complications rates after radiofrequency ablation of very early..., Livraghi [/bib_ref] Improved survival is anticipated when complete response after retreatment with RFA is achieved for local recurrence after RFA. Thus, early detection of local recurrence after RFA is of the utmost importance. [bib_ref] Repeated radiofrequency ablation for management of patients with cirrhosis with small hepatocellular..., Rossi [/bib_ref] Recurrence usually develops within 2 years after potentially curative treatments. Because early detection of recurrence allows the possibility of reapplication of curative treatment modalities, posttreatment monitoring should be performed frequently enough to detect recurrence as early as possible. However, the ideal monitoring intervals and methods require further research. Therefore, we recommend follow-up with dynamic enhanced imaging (i.e., CT or MRI) or MRI with liver-specific contrast agent every 2-6 months for the first 2 years after curative treatment. After 2 years without recurrence, follow-up can be performed at less frequent intervals. In addition, the monitoring interval should be individualized on the basis of patient-specific risk factors according to tumor biology and underlying liver diseases. [bib_ref] Model to estimate survival in ambulatory patients with hepatocellular carcinoma, Yang [/bib_ref] [bib_ref] Validation of a model to estimate survival in ambulatory patients with hepatocellular..., Kim [/bib_ref] Recommendations [fig_ref] Table 2: Summary of the Recommendations of the 2014 KLCSG-NCC Korea Practice Guidelines for... [/fig_ref] 1. Patients with complete response after treatment should be followed up with imaging studies (i.e., dynamic contrastenhanced CT/MRI or MRI with liver-specific contrast agents) and serum tumor markers every 2-6 months in the first 2 years; thereafter, patients should be followed by regular checkups at individualized intervals (B1). ## Conflicts of interest Conflicts of interests of the HCC-KPGRC members are summarized in Appendix 2. [fig] Figure 1, Figure 2: Annual cases and incidence rate of hepatocellular carcinoma. Changes in the 5-year survival rates of overall cancers and hepatocellular carcinoma (HCC). [/fig] [table] Table 1: Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) [/table] [table] Table 2: Summary of the Recommendations of the 2014 KLCSG-NCC Korea Practice Guidelines for the Management of Hepatocellular Carcinoma Topic Recommendation but only 52% for HCC <2 cm in diameter. [/table] [table] Table 4: Modified [/table] [table] Table 5: Child-Pugh Classification [/table] [table] Table 6: Eastern Cooperative Oncology Group Performance Status* [/table] [table] Table 7: Assessment of Tumor Response* RECIST mRECIST Target lesion response CR Disappearance of all target lesions Disappearance of any intratumor arterial enhancement in all target lesions PR At least a 30% decrease in the sum of the diameters of target lesions, taking the baseline sum of the diameters of target lesions as a reference At least a 30% decrease in the sum of the diameters of viable (enhancement in the arterial phase) target lesions, taking the baseline sum of the diameters of target lesions as a reference SD Any case that does not qualify for either PR or PD Any case that does not qualify for either PR or PD PD An increase of at least 20% in the sum of the diameters of target lesions, taking the smallest sum of the diameters of target lesions recorded since treatment started as a reference An increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking the smallest sum of the diameters of viable (enhancing) target lesions recorded since treatment started as a reference Nontarget lesions response CR Disappearance of all nontarget lesions Disappearance of any intratumor arterial enhancement in all nontarget lesions IR/SD Persistence of one or more nontarget lesions Persistence of intratumor arterial enhancement in one or more nontarget lesions PD Appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions Appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions mRECIST recommendations Pleural effusion and ascites Cytopathologic confirmation of the neoplastic nature of any effusion that appears or worsens during treatment is required to declare PD Porta hepatis lymph node Lymph nodes detected at the portal hepatitis can be considered malignant if the lymph node short axis is at least 2 cm Portal vein invasion Malignant portal vein invasion should be considered a nonmeasurable lesion and thus included in the nontarget lesion group New lesion A new lesion can be classified as HCC if its longest diameter is at least 1 cm and the enhancement pattern is typical of HCC. A lesion with an atypical radiological pattern can be diagnosed as HCC by evidence of at least 1-cm interval growth Overall response assessment in mRECIST RECIST, Response Evaluation Criteria in Solid Tumors; mRECIST, modified RECIST; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; IR, incomplete response; HCC, hepatocellular carcinoma. *Adapted from J Hepatol 2012;56:908-943 58 and Semin Liver Dis 2010;30:52-60. 498 [/table]	None	https://www.gutnliver.org/journal/download_pdf.php?doi=10.5009/gnl14460	The guideline for the management of hepatocellular carcinoma (HCC) was first developed in 2003 and revised in 2009 by the Korean Liver Cancer Study Group and the National Cancer Center, Korea. Since then, many studies on HCC have been carried out in Korea and other countries. In particular, a substantial body of knowledge has been accumulated on diagnosis, staging, and treatment specific to Asian characteristics, especially Koreans, prompting the proposal of new strategies. Accordingly, the new guideline presented herein was developed on the basis of recent evidence and expert opinions. The primary targets of this guideline are patients with suspicious or newly diagnosed HCC. This guideline provides recommendations for the initial treatment of patients with newly diagnosed HCC.
8dd74ac61420dd6eefe47d38797f8ab5fbd54499	pubmed	Use of Chest Imaging in the Diagnosis and Management of COVID-19: A WHO Rapid Advice Guide	Use of Chest Imaging in the Diagnosis and Management of COVID-19: A WHO Rapid Advice Guide # Introduction A cluster of pneumonia cases in Wuhan, China was first reported to the World Health Organization (WHO) Country Office in China on 31 st of December 2019. Soon thereafter, a novel coronavirus was identified as the causative agent . This virus was named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the associated disease was named coronavirus disease 2019 (COVID-19) . Since December 2019, COVID-19 has rapidly spread from Wuhan to other parts of China and throughout the world. On 30 January 2020, WHO declared the outbreak a public health emergency of international concern and on 11 March 2020, WHO characterized the outbreak as a pandemic . The diagnosis of COVID-19 is currently confirmed by identification of viral RNA in reverse transcriptase polymerase chain reaction (RT-PCR). Chest imaging has been considered as part of the diagnostic workup of symptomatic subjects with suspected COVID-19 in settings where laboratory testing (RT-PCR) is not available or results are delayed or are initially negative in the presence of symptoms attributable to COVID-19. COVID-19 manifests with non-respiratory symptoms as well as respiratory symptoms which are nonspecific and of variable severity, ranging from mild to life threatening, which may demand advanced respiratory assistance and artificial ventilation. Imaging has been also considered to complement clinical evaluation and laboratory parameters in the management of patients already diagnosed with COVID-19 (1). A recent international survey conducted by the International Society of Radiology and the European Society of Radiology found important variations in imaging practices related to COVID-19 . Several countries requested WHO's advice on the role of chest imaging in the diagnostic workup of subjects with suspected or probable COVID-19 disease and in the clinical management of patients with confirmed COVID-19. As a consequence, WHO undertook the development of a rapid guide on the use of chest imaging in the diagnosis and management of COVID-19 . # Methods ## I n p r e s s The development of this rapid advice guide followed the process outlined in the WHO handbook for guideline development , which used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology . Given the nature of the emergency, the process was implemented within a time frame of two months. The reporting of this guide followed the Reporting Items for practice Guidelines in HealThcare (RIGHT) checklist . The main target audience of the guidance are health professionals involved in the diagnosis and management of COVID-19. ## Group composition In conformity with the WHO process, the following bodies were established: a core group (coordination role), a steering group (advisory role), a guideline development group (GDG; the expert panel) and an external review group (peer review role). Membership of the GDG and the external review group included experts from 10 high income countries and 14 low-and middle-income countries (LMICs). In addition, a systematic review team was contracted to conduct a rapid systematic review for each of the guidance's questions. Appendix E1 provides the details on group composition and roles and list of contributors. ## Management of declaration of interests All experts declared their interests prior to participation in the guideline development processes and meetings. All declarations were managed following WHO regulations, on a case-by-case basis and communicated to the experts at the start of the first GDG meeting. A summary was included in Appendix E2. All authors have completed the ICMJE uniform disclosure form at ww.icmje.org/coi_disclosure.pdf and declare no conflicts. ## Identification of the key questions The core group reviewed formal consensus statements from professional bodies and/or national health authorities on the use of chest imaging in COVID-19, with the assistance of the GDG and the International Society of Radiology. Informed by these statements , the core group formulated the key questions using the PICO format (Population, Intervention, Comparator, Outcomes), with the help of the steering group, the GDG and the systematic review team (see Appendix E3). The intended I n P r e s s PICO 2: The systematic review identified 23 studies that evaluated the diagnostic accuracy of three imaging modalities in symptomatic patients with suspected COVID-19, against a reference standard, chest radiography (n=3), chest CT (n=19) and lung ultrasound (n=1). None of these studies compared two imaging modalities against each other. The systematic review team judged those studies to be at either high risk of bias (n=17) or moderate risk of bias (n=6). The studies provided limited information regarding clinical presentation (e.g. the severity of symptoms at presentation) and few reported specific criteria for a positive imaging test for COVID-19. Eleven studies did not describe a reference standard to diagnose COVID-19 that included serial RT-PCR or clinical follow-up. The median sensitivity and specificity reported by the included studies were 0.64 and 0.82 for chest radiography; 0.92 and 0.56 for chest CT; and 0.95 and 0.83 for lung ultrasound. The systematic review team judged the certainty of this evidence to be low for chest radiography, chest CT and lung ultrasound. The corresponding evidence-to-decision table available in Appendix E4 provides the counts for true positives, true negatives, false positives and false negatives for four hypothetical prevalence values of COVID-19 infection which were assumed to be 20%, 40%, 60% and 80% among symptomatic patients with suspected COVID-19. The update of the review conducted before the publication of the guide identified five new studies that evaluated the diagnostic accuracy of chest radiography, chest CT and lung ultrasound in symptomatic patients with suspected COVID-19. The synthesized evidence as well as its associated certainty were judged to remain unchanged. PICO 3: The systematic review identified no eligible study that evaluated any chest imaging modality in patients with suspected or confirmed COVID-19 not yet hospitalized to support decisions on hospital admission versus home discharge on health outcomes. PICO 4: The systematic review identified no eligible study that evaluated any chest imaging modality in patients with suspected or confirmed COVID-19 not yet hospitalized to support decisions on regular admission versus intensive care unit admission on health outcomes. The update of the review conducted before the publication of the guide identified one new study that evaluated the use of chest imaging in patients with suspected or confirmed COVID-19 not yet hospitalized. The certainty of the evidence was judged as very low. I n P r e s s PICO 5: The systematic review team identified three studies that evaluated chest imaging in patients currently hospitalized with moderate or severe symptoms and suspected or confirmed COVID-19, for predicting mortality or admission at the intensive care unit. The certainty of evidence was judged to be very low. PICO 7: The systematic review team identified no study that evaluated any chest imaging modality to support the decision on discharge home. Refer to the full guideline publication for the citations of studies referred in the summary of evidence . The GDG developed one recommendation for each PICO question with two exceptions: it developed two recommendations for PICO 2 and developed no recommendation for PICO 6 (due to lack of evidence and the rapidly evolving knowledge related to that question). The recommendations for which no evidence meeting inclusion criteria was identified were labelled as based on expert opinion. presents a summary of the recommendations. All developed recommendations are conditional, which means that the desirable effects were judged to likely outweigh the undesirable effects under certain conditions. One set of these conditions relates to the characteristics of patients who are likely to benefit from the recommended interventions (listed in for each recommendation). Another set of conditions relates the factors to consider when choosing a specific imaging modality (included in for all recommendations). Appendix E5 provides implementation considerations, monitoring and evaluation considerations, and research priorities for the different recommendations. lists only those implementation considerations that are common across all recommendations. The evidence-to-decision tables for the different recommendations are included in Appendix E4. # Discussion The purpose of the guide is to support WHO Member States in their response to the COVID-19 pandemic by providing up-to-date guidance on use of chest imaging in adult patients with suspected or confirmed COVID-19, including chest radiography, computed tomography and lung ultrasound. It covers the care pathway from outpatient facility or hospital entry to home discharge. The guidance is I n P r e s s provided for patients with different levels of disease severity, from asymptomatic individuals to critically ill patients. Additional guidance on infection prevention and control (IPC) in medical imaging procedures for COVID-19 management is provided in Appendix E6. The IPC guidance addresses both general measures for all imaging procedures and specific precautions for chest radiography, chest CT and lung ultrasound. The guide also promotes quality and safety of radiation use in health facilities, thus enhancing protection and safety of patients and health workers (Appendix E6). The guide has a number of strengths including its development based on standard methodology [20], the consideration of contextual factors , its reporting according the RIGHT statement, and the consideration of stakeholders views . Limitations include that the evidence on which the recommendations are based is either lacking or at best of low certainty, and that scope is relatively narrow (e.g., excluded children, did not address the systemic aspects of the disease). However, the latter was necessary to allow the rapid development of recommendations addressing the most pressing questions. The recommendations address chest imaging in general, but not specific imaging modalities. While there is accumulating evidence about typical findings with each imaging modality , evidence about comparative diagnostic and prognostic value of the different modalities is still lacking. The experience indicates that in most cases chest radiography with portable equipment can provide the information needed at the point of care. In addition to limiting patient transfers it gives the possibility of adapting procedures to reduce staff exposure and increase operational efficiencies (e.g. portable chest radiography obtained through the glass of an isolation room door) . Preliminary studies on lung ultrasound seem promising, in particular for use of portable ultrasound scanners at the point of care, but further evidence still needs to be generated. A CT scan may be the indicated modality for particular patient groups (e.g. those with suspected thrombotic/thromboembolic disease, multisystemic disease). In health facilities, particularly in LMICs, where CT scans are not available for those patients, policy makers should consider provisions to facilitate patient transfer to reference hospitals where CT scans can be performed. In the long-term, the assessment of clinical, social, I n P r e s s economic, organizational and ethical issues should inform decision-making about procurement of imaging technology . There is wide variability of the contextual factors across settings (e.g., availability and cost of each modality and availability of the required expertise). Along with other technical considerations, the guide refers to the choice of a chest imaging modality in the remarks that apply to all recommendations (see . Indeed, the GDG gave due consideration to resource use, impact on equity, acceptability and feasibility when drafting the recommendations. This guide is primarily intended for health professionals working in emergency departments, imaging departments, clinical departments, intensive care units and other health care settings involved in the diagnosis of COVID-19 and in the management of COVID-19 patients. The document can also be useful for hospital managers and planners, policy-makers, hospital architects, biomedical engineers, medical physicists, logistics staff, water/sanitation and infection prevention and control officers. Health authorities and radiation regulators can use the guide to develop specific national standards relevant to COVID-19 outbreak preparedness, readiness and response in different contexts. Finally, it can be useful to funders that wish to donate equipment and devices as well as funding priority research. We were able to develop the guideline in about 10 weeks, which fits the 3-month timeframe of 'rapid' guidelines . Two main facilitating factors include the existence of a clear and detailed process in place (as described in the WHO handbook for guideline development) , and the use of a rapid review process . The latter factor is important considering that conducting the systematic review typically consumes a number of months. In addition, we used a staggered approach when developing the guide: e.g., we started training the GDG members even before the findings of the rapid review were available, and we sent out recommendations for peer review (by the external review group) even before all recommendations were developed. Finally, the most critical factor was probably having a dedicated core group that developed and followed a very strict timeline and worked on keeping a steady momentum. The core group members met almost daily (including weekends) and maintained an intense email communication. ## I n p r e s s While the guide was developed within a relatively short timeframe, we do not believe this has affected the quality of the recommendations. Indeed, we followed standard WHO process, including proper development of PICO questions, determination and prioritization of outcomes of interest, conflicts of interest declaration and management, reliance on systematically collected evidence, use of GRADE methodology, and use of Evidence to Decision tables. While the rapid review could have missed relevant studies, it is very unlikely that any impactful studies have been missed. We did have all members of the GDG verify eligible studies, and we continually monitored the literature over the period of the project. The online format of the GDG meetings, due to the travel restrictions during the pandemic, did not impede proper discussions. On the contrary, GDG discussions were lively constructive and allowed all members the opportunity to contribute. Moreover, we conducted a survey of stakeholders to capture their views on factors that were very important to the development of recommendations, namely resource use, impact on equity, acceptability and feasibility. The panel paid attention to the resource implications for low resource settings. As growing body of literature is confirming the multi-systemic nature of COVID-19 (including the nervous, vascular and cardiac systems, kidneys) [28], this raises questions on whether/when/how imaging other than that of the chest (e.g., cardiac ultrasound, brain MRI, vascular imaging, abdominal imaging) may contribute to early diagnosis and/or management of patients with COVID-19. Specifically, pulmonary embolism in patients with COVID-19 is gaining attention with its relatively high prevalence and the ongoing discussion about its embolic versus intravascular thrombotic mechanism . When addressing this question, the GDG members felt that both the published literature and the collective clinical experience were not adequate to justify any recommendation. We are aiming to address it in the next update of the guide. In the future, guidance and policies for procurement of imaging equipment are needed. There is also a need for research on diagnostic accuracy, and desirable and undesirable impact of the different ## I n p r e s s Finally, there is a need for studies addressing contextual factors, including cost, cost effectiveness, impact on equity, acceptability and feasibility of the different imaging modalities. In summary, the guide provides up-to-date guidance on the use of chest imaging in patients with suspected or confirmed COVID-19 for clinicians, and other stakeholders. It also provides research recommendations that can hopefully provide a better evidence base for future updates of the guide. ## I n p r e s s ## 19. Alonso-Coello P, Oxman AD, Moberg J, Brignardello-Petersen R, (1) RT-PCR testing is not available; (2) RT-PCR testing is available, but results are delayed; and (3) initial RT-PCR testing is negative, but with high clinical of suspicion of COVID-19. ## Conditional recommendation based on low certainty evidence Imaging should be used as one element of the diagnostic workup that otherwise includes clinical and laboratory data. Patients likely to benefit are those who: - have presentations that could represent complications of COVID-19, e.g. pneumonia; pulmonary arterial thrombosis or thromboembolism; - need to be admitted irrespective of diagnosis (e.g. disease is severe or likely to progress), to help with disposition or triaging (e.g. to dedicated COVID-19 ward versus non-COVID-19 ward); - need to be transferred to another facility; - live with people at high risk if infected with COVID-19 (e.g. immunocompromised, persons aged over 60 years); - live in small homes, overcrowded households or densely populated settings, where isolation is very difficult to implement; - live in communities with people at high-risk such as retirement homes or dormitories. I n P r e s s R3: For patients with suspected or confirmed COVID-19, not currently hospitalized and with mild symptoms, WHO suggests using chest imaging in addition to clinical and laboratory assessment to decide on hospital admission versus home discharge. ## Conditional recommendation, based on expert opinion Imaging should be used as one element of the patient evaluation that otherwise includes clinical, laboratory and epidemiological data. Patients likely to benefit are those who: - have or are at high risk of disease progression; - represent an increased risk of dissemination within their community due to their occupational, social or other circumstances; - have associated comorbidities (such as diabetes, hypertension, heart disease, obesity) or other chronic diseases which might decompensate and/or are aged over 60 years; - live with individuals at high risk of morbidity and mortality associated with COVID-19 (e.g., elderly, immunocompromised), whether at home or retirement home; - live in small homes, overcrowded households or densely populated settings where isolation is very difficult to implement. - represent an increased risk of dissemination within their community due to their occupational, social or other circumstances. ## Conditional recommendation, based on very low certainty evidence Imaging should be used as one element of the patient evaluation that otherwise includes clinical and laboratory data. Patients likely to benefit are those who: - are at higher risk of disease progression (e.g. with comorbidities) - are not responding to supportive treatment (oxygen supplementation) - present acute clinical deterioration not elucidated I n P r e s s R5: For patients with suspected or confirmed COVID-19, currently hospitalized and with moderate to severe symptoms, WHO suggests using chest imaging in addition to clinical and laboratory assessment to inform the therapeutic management ## Conditional recommendation, based on very low certainty evidence Imaging should be used as one element of patient evaluation that otherwise includes clinical and laboratory data. Patients likely to benefit are those who: - are at high risk of disease progression - are not responding to treatment (oxygen supplementation) - have presentations with clinical suspicion of pulmonary fibrosis, pulmonary artery thrombosis or thromboembolism. R6: For hospitalized patients with COVID-19 whose symptoms are resolved, WHO suggests not using chest imaging in addition to clinical and/or laboratory assessment to inform the decision regarding discharge. ## Conditional recommendation, based on expert opinion When imaging is used, it should be one element of the patient evaluation that otherwise includes clinical and laboratory data. Patients likely to benefit from chest imaging are those who: - have had a severe form of COVID-19 - have pre-existing chronic lung disease I n P r e s s Abbreviations: WHO= World Health Organization, COVID-19= coronavirus disease 2019, RT-PCR= reverse transcriptase polymerase chain reaction I n P r e s s . Factors to consider when choosing the specific imaging modality (applies to all recommendations).  Compared to chest CT, chest radiography appears to have a lower sensitivity and might have higher specificity. Chest radiography is less-resource intensive, is associated with lower radiation doses, is easier to repeat sequentially for monitoring disease progression or disease recovery, and can be performed with portable equipment at the point of care (which minimizes the risk of cross-infection related to patient transport).  Chest CT has the highest sensitivity but relatively lower specificity and can be useful in patients with some pre-existing pulmonary diseases.  Lung ultrasound has very low-certainty evidence supporting its diagnostic accuracy but might be helpful with the appropriate expertise as a supplemental or alternative modality (e.g. in pregnant women, children, patients with mechanical ventilation). Lung ultrasound can be done at the point of care but requires closer physical proximity of the operator to the patient for a longer period and needs specific infection prevention and control precautions.  Consider the differential diagnoses and potential complications for each specific case (e.g. CT angiography for pulmonary arterial thrombosis or thromboembolism, ultrasound for pleural effusions and heart conditions) when choosing imaging modality.  Choice should be made through shared decision-making involving the referring physician, the radiologist and the patient whenever possible. If possible, provide the patient with information regarding the imaging modality and the likelihood of subsequent imaging procedures. Abbreviations: CT= computed tomography I n P r e s s . Implementation considerations that are common across recommendations.  Implement the recommendations based on your equipment availability. Consider the resources needed (budget, health workforce, personal protective equipment, imaging equipment), the need to adapt the clinical workflow and the need to deprioritize other indications for imaging.  When performing chest radiography, consider using portable equipment, and if feasible, a unit dedicated to patients with COVID-19.  When performing chest radiography and chest CT, minimize radiation dose while maintaining diagnostic image quality (e.g. low-dose CT protocols) and use digital imaging rather than film-screen equipment .  Consider the potential harm from exposure to ionizing radiation, in particular for pregnant women and children.  Ensure proper use of personal protective equipment by health care workers and proper disinfection of equipment and devices (see Appendix E6).  Provide appropriate training of radiologists and technologists on infection prevention and control practices and ensure efficient management of typical imaging findings of COVID-19 through accepted local protocols.  Consider the transfer of images for remote reporting (teleradiology) as needed (e.g. settings where radiologists are not available for on-site reporting).  Set policy/pathway for use of imaging related to COVID-19 illustrated with flow charts or diagrams locally developed and accepted. I n P r e s s  Whenever is possible, provide information to patients about safety provisions adopted by the facility for infection prevention and control (see Appendix E6) as well as for radiation protection .  Make provisions to ensure that all patients get the imaging services they need without suffering financial hardship. , as well as the Regional Advisor on Radiological Health in the WHO Regional Office for the Americas. The WHO steering group helped identify the GDG and external review group members. It contributed to the formulation of the key questions and reviewed the recommendations and the final document. ## Abbreviations ## Guideline development group The GDG included experts and relevant stakeholders from multiple disciplines: a guideline methodologist, experts in the field of medical imaging, emergency medicine, intensive care, pulmonology and molecular diagnostics, as well as a representative from a patient advocacy organization. The GDG provided input at all stages of the process and played the main role in development of recommendations. The composition of the GDG ensured geographic representation from five of the six WHO regions, gender balance and absence of conflicts of interest. ## External review group The external review group was composed of experts in the field of medical imaging and pulmonary diseases and representatives of patient advocacy groups and civil society. The experts reviewed the recommendations developed by the GDG and the final document, and commented on the technical accuracy, clarity of language, contextual issues and implications for implementation. The group was asked not to modify the recommendations that were formulated by the GDG. ## Systematic review team The systematic review team was composed of experts in the field of systematic reviews with clinical background in internal medicine and content experts in the field of medical imaging. They conducted rapid reviews of the literature and provided a report summarizing the findings and certainty of evidence for each key question. The systematic review report was shared with members of the GDG. Representatives of the systematic review team attended the GDG meetings to provide an overview of the available evidence and to respond to technical queries from the GDG. ## Core group The development of these recommendations under very compressed timelines during the COVID-19 pandemic represented a challenge in the context of unprecedented demands in terms of global and local public health response. Anticipating this challenge, the WHO Secretariat assembled a core group to assist in project management. This group included two methodologists, the chairperson of the GDG and a radiology consultant who worked in close consultation with the WHO Secretariat and participated in daily planning and coordination meetings held virtually. The core group drafted the key questions using the PICO format, supervised the syntheses and retrieval of evidence, convened and facilitated the GDG meetings, liaised with all established groups, and drafted and finalized the rapid advice guide. In addition, the core group facilitated survey implementation and assessment of current imaging practices in different regions of the world. ## List of contributors ## I n p r e s s ## Appendix e2: management of declaration of interests The disclosure and appropriate management of relevant financial and non-financial conflicts of interest of guideline development group members and other external experts and contributors is a critical part of guideline development at WHO. According to WHO regulations, all experts must declare their interests prior to participation in WHO guideline development processes and meetings. All GDG members were therefore required to complete a standard WHO declaration of interests form before engaging in the guideline development process and before participating in guideline-related processes. All declarations were reviewed before finalizing the experts' invitations to participate based on the criteria for assessing the severity of conflict of interests as outlined in the WHO handbook for guideline development to all participating experts. All findings from the declaration of interests forms received were managed in accordance with the WHO declaration of interests guidelines on a case-by-case basis and communicated to the experts at the start of the first GDG meeting. Annex C shows a summary of the declaration of interests and how conflicts of interest declared by invited experts were managed. ## I n p r e s s ## Appendix e3: pico questions and critical outcomes identified pico questions identified The following seven key PICO questions were identified: 1. In asymptomatic contacts of patients with COVID-19, and in contexts where laboratory testing (reverse transcription-polymerase chain reaction [RT-PCR]) is not available/results are delayed/results are initially negative, should chest imaging (including chest radiography, CT scan, lung ultrasound) vs no chest imaging be used for the diagnostic workup of COVID-19? 2. In symptomatic patients with suspected COVID-19, and in contexts where laboratory testing (RT-PCR) is not available/results are delayed/results are initially negative, should chest imaging (including chest radiography, CT scan, lung ultrasound) vs no chest imaging be used for the diagnostic workup of COVID-19? 3. In patients with suspected or confirmed COVID-19, not currently hospitalized and with mild symptoms, should chest imaging (including chest radiography, CT scan, lung ultrasound) vs no chest imaging be used to support the decision on hospital admission versus home discharge? 4. In patients with suspected or confirmed COVID-19, not currently hospitalized and exhibiting moderate to severe symptoms, should chest imaging (including chest radiography, CT scan, lung ultrasound) vs no chest imaging be used to support decision on regular ward admission versus ICU admission? 5. In patients with suspected or confirmed COVID-19, currently hospitalized and exhibiting moderate or severe symptoms, should chest imaging (including chest radiography, CT scan, lung ultrasound) vs no chest imaging be used to modify the therapeutic management? 6. In patients with suspected or confirmed COVID-19 and clinical deterioration and/or suspicion of pulmonary embolism, should imaging (including CT pulmonary angiography) vs no imaging be used to diagnose pulmonary embolism? 7. In patients with COVID-19 whose symptoms are resolved, should chest imaging (including chest radiography, CT scan, lung ultrasound) be added to vs not added to laboratory criteria to support decisions on hospital discharge vs no discharge? ## Critical outcomes identified The following critical outcomes were identified: - diagnostic accuracy measures (rates of true positive, true negative, false positive, false negative); - clinical outcomes, including the "core outcomes" developed for COVID-19 (mortality, respiratory failure, multi-organ failure, shortness of breath, recovery), adverse effects of imaging (e.g. exposure to radiation), and COVID-19 transmission to health care workers;[1] - health systems outcomes, including service use (length of emergency department stay, length of hospital stay, length of ICU stay), availability of care, access to care and quality of care. ## I n p r e s s # Conclusions ## Recommendation For asymptomatic contacts of patients with COVID19, WHO suggests not using chest imaging for the diagnosis of COVID-19 (conditional recommendation, based on very low certainty evidence) ## Conditions:  Higher risk of disease progression  In need of emergency procedures  implementing public health interventions (e.g., quarantine) I n P r e s s ## Remarks: When choosing the imaging modality, consider the following:  CT scan has the highest sensitivity and is preferred in patients with pre-existing pulmonary disease;  Chest radiography has a lower sensitivity but is associated with lower risk of HCW infection transmission; is less resource intensive; is associated with lower radiation doses than CT scan; and is easier to repeat sequentially for monitoring disease progression;  LUS has limited evidence but is helpful with the appropriate expertise and can be done at the point of care. However, it requires closer physical proximity of the operator to the patient for a longer period of time and requires specific infection prevention and control precautions;  Choice should consider the differential diagnosis in the specific case (e.g., CT angiography for pulmonary embolism, LUS for pleural effusions)  Choice should be through a shared decision making involving the patient, the referrer physician and the radiologist; The voting results are: When PCR testing is not available, conditionally for using CT scan to diagnose COVID 19 · the rate of false-negative will be the lowest in low prevalence settings and in patients with low pretest probability (e.g., clinical presentation not consistent with COVID19) · In patients who need to be admitted irrespective of diagnosis/likelihood of disease progression, to help with disposition (to dedicated COVID floor vs. non COVID floor) Consider different alternatives e.g. chest radiography The voting results are:  Strong recommendation against the intervention: 0  Conditional recommendation against the intervention: 2  Conditional recommendation for either the intervention or the comparison: 0  Conditional recommendation for the intervention: 8  Strong recommendation for the intervention: 6 3-When PCR testing is available, but results are delayed, using vs. not using CT scan to diagnose COVID 19 When PCR testing is available, but results are delayed, conditionally for using CT scan to diagnose COVID 19 · In patients requiring emergency procedures or other urgent interventions (e.g., in patients with stroke, requiring hemodialysis) · In patients who need to be admitted irrespective of diagnosis/likelihood of disease progression, to help with disposition (to dedicated COVID floor vs. non COVID floor) · In patients who need to be transferred to another facility The voting results are:  Strong recommendation against the intervention: 1  Conditional recommendation against the intervention: 3  Conditional recommendation for either the intervention or the comparison: 1  Conditional recommendation for the intervention: 8  Strong recommendation for the intervention: 1 I n P r e s s 4-In patients with negative initial PCR test, but with clinical suspicion of COVID19 (e.g., severe presentation or with co-morbidities), using vs. not using CT scan to diagnose COVID 19 In patients with negative initial PCR test, but with clinical suspicion of COVID19 (e.g., severe presentation or with co-morbidities), conditionally for using CT scan to diagnose COVID 19 The voting results are:  Strong recommendation against the intervention: 0  Conditional recommendation against the intervention: 1  Conditional recommendation for either the intervention or the comparison: 1  Conditional recommendation for the intervention: 8  Strong recommendation for the intervention: 4 ## Conditions (apply to 1 thru 4) · Those who are discharged based on a negative CT scan result, need to consider a small chance of false-negative results and abide by public health measures (e.g., quarantine) until definitive PCR diagnosis is made · Resource use · Feasibility (PPE) · Acceptability (technicians) · Special attention to pregnant women and children · Apply appropriate clinical measures taking into account the possibility of false-negative results. When choosing the imaging modality, consider the following:  CT scan has the highest sensitivity and is preferred in patients with pre-existing pulmonary disease;  Chest radiography has a lower sensitivity but is associated with lower risk of HCW infection transmission; is less resource intensive; is associated with lower radiation doses than CT scan; and is easier to repeat sequentially for monitoring disease progression;  LUS has limited evidence but is helpful with the appropriate expertise and can be done at the point of care. However, it requires closer physical proximity of the operator to the patient for a longer period of time and requires specific infection prevention and control precautions;  Choice should consider the differential diagnosis in the specific case (e.g., CT angiography for pulmonary embolism, LUS for pleural effusions)  Choice should be through a shared decision making involving the patient, the referrer physician and the radiologist; ## Remarks: Patients likely to benefits are those who: I n P r e s s  require emergency procedures or other urgent interventions (e.g., in patients with stroke, patients requiring hemodialysis);  need to be admitted irrespective of diagnosis (e.g., disease is severe or likely to progress), to help with disposition (to dedicated COVID19 floor vs. non COVID19 floor);  need to be transferred to another facility.  when using chest radiography and CT scan, optimize radiation dose, and use digital imaging rather than film (to decrease contamination). **The voting was based on using CT scan vs not using CT scan, however the group decided that this applies to imaging vs no imaging. ## Justification ## Type of recommendation ## Strong recommendation against the intervention ## Conditional recommendation against the intervention Conditional recommendation for either the intervention or the comparison ## Conditional recommendation for the intervention Strong recommendation for the intervention ○ ○ ○ - ○ # Conclusions recommendation For patients with suspected or confirmed COVID-19, not currently hospitalized and with mild symptoms, WHO suggests using chest imaging to support the decision on hospital admission versus home discharge (conditional recommendation, based on very low certainty evidence) ## Remarks: Patients likely to benefits are those who: [formula]  [/formula] # Conclusions recommendation For patients with suspected or confirmed COVID-19, not currently hospitalized and with moderate to severe symptoms, WHO suggests using chest imaging to support the decision on regular ward admission versus intensive care unit admission (conditional recommendation, based on very low certainty evidence) ## Remarks: Patients likely to benefits are those who:  are at high risk of disease progression  are not responding to treatment When choosing the imaging modality, consider the following:  CT scan has the highest sensitivity and is preferred in patients with pre-existing pulmonary disease; I n P r e s s ## Research priorities We identified some research priorities in areas where the certainty of the available evidence is low or very low, or where evidence is lacking. Those relevant to both diagnostic and management recommendations are: - Conduct randomized controlled trials to compare the effects of using the different imaging modalities and using no imaging (in addition to clinical judgement) on clinical and health services outcomes of interest, for the questions addressed in this guidance. # Introduction Modifying working practices and training staff in the proper use of personal protective equipment and in the application of safe clinical imaging techniques, combined with environmental control and equipment disinfection are essential during the COVID-19 pandemic to reduce the risk of infection transmission to patients and staff. This focuses on the imaging modalities referred in the guide recommendations. Building upon WHO guidance on COVID-19 infection prevention and control in health care settings, this addresses good practices for infection prevention and control for front-line staff performing imaging procedures during the COVID-19 pandemic. Additionally, it describes specific infection prevention and control measures necessary while undertaking chest radiography both in the general imaging department and with portable radiography equipment, as well as when undertaking chest CT and lung ultrasound scans. ## General considerations A checklist is provided on infection prevention and control when performing chest imaging in patients with suspected or confirmed COVID-19. Information inis applicable to all imaging modalities addressed. In addition, it is important to remember that those undertaking imaging procedures are at the front line of the healthcare service, so they must follow existing local guidance/protocols. In general, the chest imaging procedures recommended in this guide require following droplet and contact precautions. Airborne precautions are reserved for aerosol-generating procedures (e.g. bronchoscopy, tracheotomy, cardiopulmonary resuscitation, non-invasive ventilation, intubation, nebulization, open suction). Below is a list of additional infection prevention and control considerations and best practices. General environment - Schedule appointments to reduce numbers of patients in the waiting room. Designate a waiting area, which should be set up to adopt international guidelines for social distancing of at least 1 metre minimally or whenever possible adapt to local or national guidelines (e.g. 2 metres is adopted in some settings - Ensure infection prevention and control measures are employed when managing the imaging room. - The imaging room must be subject to regular cleaning and disinfection, consistent with local infection prevention and control guidance and cleaning schedules completed, signed and dated. - Verify that terminal cleaning and disinfection of the imaging room occurred at end of day the previous day. If not done (or not verifiable) ensure that terminal cleaning and disinfection of the imaging room is performed before starting. ## During - Ensure appropriate personal protective equipment worn. - Employ " contact and noncontact radiographer/technologist" scenario of chest radiography, CT and ultrasound. - Ensure single patient attendance to the imaging department wherever possible to enable further imaging, if this is required. - Provide medical mask to the patient (if feasible), as well as comfort and reassurance. - Ensure standard operating procedures for infection prevention and control according to local guidance, contact minimization and barrier precautions in place (e.g. suitable covers whenever possible). - Control access to imaging room or patient area during the portable radiography procedure. - Consider appropriate signage/visual alerts in front of imaging room (e.g. patient inside/arriving, ongoing cleaning/disinfection, time of last cleaning/disinfection). ## Post procedure - Ensure imaging review is made appropriately and apply local protocols to follow up clinical and infection prevention and control actions, if/as required. - If the chest imaging procedure was performed at the imaging department, staff should wear personal protective equipment during patient transfer. - Ensure personal protective equipment is taken off appropriately, if used. - Ensure rapid delivery of the imaging results to guide management. - Ensure appropriate decontamination of medical equipment between patients (applicable to both fixed and portable equipment). - Ensure appropriate environmental cleaning and disinfection (focus on high touch surfaces) between patients. Staff performing this task will be trained on cleaning and disinfection and should wear appropriate PPE. - If bedside imaging was performed using portable equipment, room cleaning and disinfection should occur following the protocols applicable for the specific setting (e.g. emergency room, regular ward, intensive care unit) - When performing CT on patients confirmed with COVID-19, radiographers/radiological technologists must follow the instructions and guidance of the hospital committee responsible for infectious disease control. - However asymptomatic patients pose a latent threat for medical imaging and therapy departments and hence radiographers/radiological technologists in CT are advised to follow the instructions divided in three stages (i.e. preparation, during and post procedure; see table 1). Ultrasound: - Lung ultrasound presents specific challenges. The first is physical proximity to the patient: this is usually within1 m and may be as little as 30-50cm; ultrasound rooms are typically small, ventilation may be restricted and seldom are there windows; examination time may last between 10 and 60 minutes; patients may be asked to inhale/exhale deeply and hold their breath. - If possible, designate a specific ultrasound room and machine and probes for use on patients with COVID-19. - Adjust schedule (appointment times) to avoid crowding in the waiting room and to allow time between appointments for decontamination of the ultrasound system and room. - Best practice is to have patient attend examination alone. - The ultrasound health care workers should follow droplet and contact precautions (airborne precautions required only for aerosol-generating procedures). They should use surgical/medical facemask. For any aerosol-generating procedures, an N95/FFP2/FFP3 medical protective mask or PAPR Powered Air Purifying respirators or respirators that offer a higher level of protection should be used. - The ultrasound health care workers should don personal protective equipment (including long sleeved gowns and gloves) when the patient is suspected or confirmed for COVID-19. - Shorten duration of examination by arranging for the most experienced professional available to perform the examination. Single use ultrasound gel sachets should be considered for patients suspected or having COVID-19. - Reduce the number of probes connected to the ultrasound machine to a minimum and remove all other probes from unit or store in closed cabinet to avoid the necessity of high-level disinfection in the event the patient coughs or sneezes during the procedure. - Separate inpatients on the ward from outpatients. - Cover the equipment such as the ultrasound scanner console to contribute to infection prevention and control and in this way enhance workflow. - Follow manufacturer's recommendation for decontamination of ultrasound system. - Follow local protocols for appropriate decontamination of ultrasound probes between patients. - Cleaning of probes includes three disinfection levels: non-critical, semi-critical and critical. Probes used for lung ultrasound would typically be in the first category, since they are usually in contact with intact skin (i.e. noncritical devices). However, all three levels are described below to cover any other possible scenario that would deserve a higher-level disinfection. - Noncritical devices: ultrasound probes that come in contact with intact skin can be cleaned and disinfected using low-or intermediate-level disinfection. - Semi-critical devices: ultrasound probes that come in contact with non-intact skin, blood, body fluids and/or mucous membranes should be cleaned and disinfected using the high level disinfection method. A single use probe cover is mandatory. - Critical devices: ultrasound probes must undergo sterilization if compatible or, if not available, high-level disinfection as per medical facility guidelines. Use of sterile transducer cover if mandatory. ## - In the context of COVID-19, the normal practices of high-level disinfection are not changed. The only change in the context of COVID-19 is that all external probes must undergo cleaning followed by low-level disinfection to denature any presence of SARS-CoV-2.	None	None	The World Health Organization (WHO) undertook the development of a rapid guide on the use of chest imaging in the diagnosis and management of COVID-19. The rapid guide was developed over two months using standard WHO processes, except for the use of ‘rapid reviews’ and online meetings of the panel. The evidence review was supplemented by a survey of stakeholders regarding their views on the acceptability, feasibility, impact on equity and resource use of the relevant chest imaging modalities (chest radiography, chest CT and lung ultrasound). The guideline development group had broad expertise and country representation. The rapid guide includes three diagnosis recommendations and four management recommendations. The recommendations cover patients with suspected or confirmed COVID-19 with different levels of disease severity, throughout the care pathway from outpatient facility or hospital entry, to home discharge. All recommendations are conditional and are based on low certainty evidence (n=2), very low certainty evidence (n=2), or expert opinion (n=3). The remarks accompanying the recommendations suggest which patients are likely to benefit from chest imaging and what factors should be considered when choosing the specific imaging modality. The guidance also offers considerations about implementation, monitoring and evaluation, and identifies research needs.
7ab0104fd90c9c19af2a88867f2efbfb954ae969	pubmed	Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update of clinical management of cerebral venous sinus thrombosis	Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update of clinical management of cerebral venous sinus thrombosis ## Open access HisTory And CliniCAl MAnifesTATions recommendation 1. Vigilance should be maintained for CVST. The possibility of CVST should be considered in patients presented with headache, papilloedema or increased intracranial pressure with unknown cause. The screening for CVST is reasonable in patients presented with unexplained seizures (including eclampsia), focal brain injury, different levels of unconsciousness, cognitive disorders, psychosis or dural arteriovenous fistula. (Class I, Level of Evidence C). AuxiliAry exAMinATion recommendation 1. Routine blood tests consisting of a complete blood count, chemistry panel, prothrombin time, activated partial thromboplastin time, plasma protein and connective tissue disease or cancer markers are recommended in patients with suspected CVST. (Class I, Level of Evidence C) 2. Screening for potential prothrombotic factors (eg, antithrombin III, protein C or protein S deficiency, factor V Leiden, prothrombin mutation, anticardiolipin antibody, lupus anticoagulant) is recommended in patients with undetermined aetiology, recurrent CVST or a family history of venous thrombosis, to identify the root cause and select appropriate preventive and therapeutic strategies. (Class IIb, Level of Evidence C) 3. An elevated D-dimer level is considered to support the diagnosis of CVST, but a normal D-dimer level should not exclude CVST, especially in patients presented with isolated headache or chronic symptoms. between proximal and distal segment to the stenosis is beyond 8-10 mm Hg. (Class IIb, Level of Evidence C) 3. The long-term antithrombotic treatment after the sinus stenting is not clear. According to clinical practice in arterial stenting, it is reasonable to use dual antiplatelet therapy for the first 3 months followed by single antiplatelet therapy for maintenance. (Class IIb, Level of Evidence C) TreATMenT of CvsT during PregnAnCy recommendation 1. LMWH is recommended in women with CVST during pregnancy. The safety of LMWH is superior to UFH. Subcutaneous injection of LMWH is recommended throughout the pregnancy (0.4 mL, twice a day), followed by LMWH or warfarin with a target INR of 2-3 for at least 6 weeks postpartum. The total duration of treatment is no less than 6 months. (Class I, Level of Evidence C)	None	https://svn.bmj.com/content/svnbmj/5/2/152.full.pdf	Aim Cerebral venous sinus thrombosis (CVST) is a less common cerebrovascular disease that predominantly affects young patients. The incidence of CVST is 2–5/10 000 000/year, accounting for 0.5%–1% of all stroke. To reduce mortality and morbidity associated with CVST, Chinese Stroke Association commissioned the authors to write the current guideline on the management of CVST. Methods PubMed (MEDLINE), CNKI and Wanfang database were searched for studies related to CVST from 1 January 1990 to 31 July 2019. Data were synthesised by evidence tables. Each recommendation was fully discussed by the writing group members and reviewed by Chinese Stroke Association Stroke Fellow Committees. Levels of evidence grading algorithm of Chinese Stroke Association was used to grade each recommendation. Results This guideline mainly focuses on the diagnostic evaluation, therapeutic strategies and secondary prevention of CVST. CT/CTV and MRI/MRV are recommended in the initial imaging evaluation of patients with suspected CVST. Anticoagulation therapy with low-molecular weight heparin should be initiated in patients with CVST immediately. After the acute stage, warfarin is recommended for 3–6 months to prevent the recurrence of CVST and other venous thromboembolic events. Conclusions The guideline summarises the current evidence regarding the management of CVST, and provides references for diagnosis, treatment and secondary prevention of CVST in China.
c7bd24ed0d5c3c4ec683ce852c6299fe0673ef55	pubmed	Guidelines for treatment of renal injury during cancer chemotherapy 2016	Guidelines for treatment of renal injury during cancer chemotherapy 2016 # Introduction Advances in cancer drug therapy have led to improvements in the outcomes of cancer patients, as well as increasing numbers of patients undergoing anticancer chemotherapy and molecularly targeted drug therapy. One adverse event associated with cancer drug therapy is nephrotoxicity, which impedes effective cancer therapy and diminishes the quality of life of cancer patients. Consequently, onconephrology has emerged as a new clinical field concerned with the management of nephrotoxicity in cancer drug therapy, creating expectations for advanced expertise and the accumulation of accurate evidence. However, while patients with renal impairment have heretofore undergone planning regarding administration of cancer drug therapy, procedures for nephropathy prevention, and measures for treatment of drug-induced nephrotoxicity in clinical settings based on tradition, experimental rules, and information from clinical trials, the soundness of the evidence for these practices has been uncertain. Over the past 10 years, estimated glomerular filtration rate (eGFR) has replaced creatinine clearance in the assessment of renal function; in addition, research has revealed the pathologies of and risk factors for chronic kidney disease (CKD) and acute kidney injury (AKI). The objectives of the guidelines presented here are to support improvements in the results of cancer drug therapy and the quality of life of cancer patients through application of these advances in clinical nephrology and the practice of evidence-based treatment. For these guidelines, we have assembled a group of Japanese experts on cancer drug therapy and nephrology to select highly important clinical questions that are frequently encountered in everyday practice. These guidelines ultimately comprise 16 clinical questions in two chapters regarding assessment of renal function and prevention of nephropathy during cancer drug therapy, thereby determining the level of evidence to support clinical assessments and elucidating the nature of current standard treatments. However, in drafting these guidelines, we discovered a number of clinical issues (evidence gaps) regarding cancer drug therapy and renal impairment. For example, 1) there is very little clinical research on cancer drug therapy and nephropathy to begin with; 2) many clinical trials continue to use creatinine clearance to assess renal function; 3) in assessments of renal function in large populations, there is a vast discrepancy between eGFR and measured values of GFR; and 4) it remains unknown whether body surface area corrections of drug doses are appropriate for elderly patients (who have reduced muscle mass) or obese patients. These and other evidence gaps must be resolved for the sake of future research. These guidelines were drafted with reference to the ''Minds Treatment Guideline Creation Companion 2014'' using the Minds Guideline Creation support tool ''GUIDE''. We would like to express our profound gratitude to Doctors Tsuguya Fukui and Takeo Nakayama of Minds for their roles as advisors in the creation of our guidelines. We would also like to take this opportunity to express our appreciation to the many young physicians of the systematic review team for their contributions in drafting structured abstracts. The primary significance of treatment guidelines is their application in daily clinical practice. We would appreciate any criticisms or ideas that would be useful in future revisions of these guidelines. ## On the occasion of publication Cancer has been the leading cause of death among Japanese people for many years; currently, cancer is responsible for approximately 30% of all deaths in Japan. As the Japanese population ages, this figure will continue to increase year after year. Therefore, further development of treatment measures against cancer is undoubtedly one of the most crucial issues for the Japanese population. One such measure is drug therapy, which is widely performed. Many anticancer drugs are strongly associated with effects on various organs; a sufficient understanding of these associations is a prerequisite for effective and successful cancer drug therapy. Unfortunately, there have been no guidelines regarding cancer drug therapy in relation to associations with individual organs. Medical staffs and individuals involved in the treatment of cancer have a great interest for the relevance of the anti-cancer agent and a kidney. However, no previous guidelines exist that systematically described the association between cancer drug therapy and the kidneys. In addition to chronic kidney disease, the concept of acute kidney injury has rapidly become widespread in recent years. As renal function assessment methods and biomarkers continue to develop, evolutions in nephropathy concepts are being observed. Against this backdrop, the Japanese Society of Nephrology, the Japan Society of Clinical Oncology, the Japanese Society of Medical Oncology, and the Japanese Society of Nephrology and Pharmacotherapy have jointly published the ''2016 Guidelines for the Treatment of Nephropathy in Cancer Pharmacotherapy''; the timely and fascinating publication of these guidelines marks a major step in the development of cancer pharmacotherapy. This is truly a document that individuals involved in cancer treatment have long awaited. I sincerely hope that this document will be used appropriately and effectively by all individuals who work on cancer treatment. Lastly, I would like to express my deep gratitude to everyone involved in the drafting of these guidelines. Seiichi Matsuo, MD. PhD. President, Japanese Society of Nephrology (President, Nagoya University) As the Japanese population continues to age, physicians engaged in cancer pharmacotherapy increasingly encounter patients with organ dysfunction due to comorbid diseases; however, there is a lack of information regarding appropriate cancer pharmacotherapy for cancer patients with comorbid nephropathy. Currently, package inserts for the majority of anticancer drugs contain no clear information regarding administration in patients with chronic kidney disease. Although nephropathy is a major adverse event elicited by cancer pharmacotherapy, regimens for the prevention of nephropathy are currently modified based on the experience of individual physicians and the customs of individual facilities. The present guidelines begin with renal function assessment methods necessary for determining doses of anticancer drugs, followed by descriptions of supportive therapy during cancer pharmacotherapy with cisplatin and other drugs for patients with decreased renal function. The guidelines also discuss supportive therapy for maintenance dialysis patients and patients with specific comorbidities. I believe that these guidelines will prove useful in daily clinical practice. As part of its duties as a multidisciplinary academic society, the Japan Society of Clinical Oncology has been engaged in the formulation of guidelines for common supportive therapies for the treatment of cancer of various organs. Our society considers it greatly significant to have had the opportunity to participate in the formulation of these guidelines, which will contribute to improvements in the quality of treatment for patients with renal impairment. Lastly, I would like to express my profound gratitude to Doctor Shigeo Horie, President of the Guideline Preparation Committee, for his tireless leadership in the drafting of these guidelines, as well as the many others who devoted their efforts to drafting the guidelines. Cancer is reported to afflict one in every two Japanese people and kill one in every three. As the Japanese population continues to age, the number of elderly cancer patients is likely to continue to increase. Consequently, an increase is also expected in the number of cancer patients with comorbidities such as nephropathy. In the use of anticancer drugs for cancer patients with nephropathy, consideration must be given to the possibility of the enhancement of adverse events owing to diminished excretion, as well as the possibility that the toxicity of anticancer drugs will exacerbate nephropathy. However, as effective anticancer drugs are not used based solely on comorbid nephropathy, the therapy cannot be considered appropriate. The performance of cancer pharmacotherapy in patients with nephropathy requires knowledge of not only oncology, but also nephrology. I believe that the joint creation of these guidelines by the Japanese Society of Nephrology, kidney specialists with the Japanese Society of Nephrology and Pharmacotherapy, and cancer therapy specialists with the Japan Society of Clinical Oncology is incredibly important and significant for the performance of appropriate pharmacotherapy in cancer patients with nephropathy. These guidelines establish crucial clinical questions and provide clear descriptions about these questions. I anticipate that these guidelines will be utilized effectively by physicians, pharmacists, and nurses throughout Japan, and that they will be useful in the performance of appropriate anticancer drug therapy in cancer patients with nephropathy. ## Yuichiro ohe national cancer center hospital department of thoracic oncology The Japanese Society of Nephrology and Pharmacotherapy strives to foster ''medical professionals who responsibly offer effective, safe, and the most appropriate drug therapy optimized to the individual patient''. Since the society was founded, it has worked toward fulfilling the following four major objectives: 1) to ensure the proper use of drugs and prevention of toxic side effects in patients with decreased renal function, 2) to prevent renal function deterioration and cardiovascular complications through proper medication guidance, 3) to provide appropriate drug therapy to dialysis patients with complications, and 4) to prevent drug-induced renal damage caused by nephrotoxic agents and drugs inducing renal ischemia. The Japanese Society of Nephrology and Pharmacotherapy was granted the opportunity to create the ''2016 Guidelines for the Treatment of Nephropathy in Cancer Pharmacotherapy'' alongside the Japanese Society of Nephrology, the Japan Society of Clinical Oncology, and the Japanese Society of Medical Oncology. The joint creation of these guidelines aligns with our own society's goals, filling me with profound pride. Similar to antibacterial agents and nonsteroidal anti-inflammatory drugs (NSAIDs), anticancer drugs can easily cause drug-induced nephropathy. The renal function of a patient receiving anticancer drugs fluctuates easily due to the effects of various factors such as the patient's condition, activity level, and age. Anticancer drug pharmacokinetics, anticancer drug interactions, and conceptions of patients' renal function are the fortes of our society, which specializes in nephrology and pharmacotherapy. In order to exert our specialized capacity, we recently established a Committee for the Formulation and Drafting of Guidelines. Going forward, with this committee at the center of our efforts, we hope to use our specialized perspective in relation to nephrology and pharmacotherapy to contribute to the drafting and revision of various types of practice and therapeutic guidelines. In conclusion, I earnestly hope that the use of these guidelines will lead to the implementation of safer, more effective cancer drug therapy in all medical care settings through the prevention of anticancer drug-induced irreversible nephropathy, as well as the reduction and prevention of side effects, achieved by the establishment of appropriate dosages for patients with decreased renal function, including elderly patients. # Background Nephropathy is a major potential adverse event in cancer drug therapy. Anticancer chemotherapy, particularly in patients with comorbid chronic kidney disease, requires sufficient examination of the balance of the potential therapeutic benefit with the risk of decreased renal function. However, cancer drug therapy in clinical settings has been performed based solely on physicians' experience and instincts, a situation that calls for evidence-based guidelines. The objective of the present guidelines was to draft clinical questions (CQs) and recommendations for those CQs to be specifically applied in real-world clinical practice. The overwhelming diversity of drugs used to treat cancer involves equally diverse nephropathy pathologies and dose adjustments. In establishing CQs, we have attempted be as comprehensive as possible. These guidelines take into account consistency with not only existing guidelines, but also guidelines on acute kidney injury treatment currently under production (Japanese Society of Nephrology, Japanese Society for Dialysis Therapy, Japan Society for Blood Purification in Critical Care, Japanese Society of Intensive Care Medicine, Japanese Society for Pediatric Nephrology, etc.). In 2016, Japanese Society of Nephrology, Japan Society of Clinical Oncology, Japanese Society of Medical Oncology, and The Japanese Society of Nephrology and Pharmacotherapy established the Committee Of this guideline drafting group, which published Guidelines for treatment of renal injury during cancer chemotherapy 2016 in Jpn J Nephrol. 2016; 58:985-1050. This is the English version of that report. Chairman: Shigeo Horie. ## Guideline objectives, assumed users, and social significance This document includes guidelines regarding nephropathy in patients undergoing cancer drug therapy. These guidelines are intended to serve as a basis for assessing CQs that are likely to be frequently encountered in daily practice; they have been written for physicians, pharmacists, nurses, and all other medical personnel engaged in the treatment of cancer. The objective of the development of these guidelines was to support clinical assessments by obtaining answers as specific as possible regarding questions encountered in real-world practice by cancer specialists in order to convey current standard views and specifics of practice. However, we ultimately treat not cancer, but rather cancer patients; rather than performing individual medical acts uniformly, treatment should sufficiently respect each patient as an individual. It is hereby specified that these guidelines do not contain assessment criteria for medical disputes or medical lawsuits. ## Patients targeted by the guidelines These guidelines are intended for the treatment of all adult cancer patients and not for pediatric cancer patients. The target of these guidelines is nephropathy directly caused by cancer drug therapy; the guidelines do not apply to, for example, nephropathy resulting from other causes in longterm cancer survivors. ## Administrative framework The drafting of these guidelines is characterized primarily by the participation of members from four different academic societies: the Japanese Society of Nephrology, the Japan Society of Clinical Oncology, the Japanese Society of Medical Oncology, and the Japanese Society of Nephrology and Pharmacotherapy. The drafting of these guidelines brought together nearly all of the principal groups currently engaged in cancer treatment and kidney disease in Japan, thereby allowing us to integrate all views currently standard in Japan. Furthermore, these guidelines were drafted in reference to the ''Minds Treatment Guideline Creation Companion 2014'' using the Minds Guideline Creation support tool ''GUIDE''. Therefore, Doctors Tsuguya Fukui and Takeo Nakayama of Minds participated as advisors. We would like to take this opportunity to express out profound gratitude for their unerring advice to the drafting committee and their efforts in keeping our discussions focused. # Drafting method First, the drafting committee formulated and listed 101 CQs, of which they adopted 16. For each CQ, we established keywords for literature searches. After performing a literature search, the systematic review team assessed each piece of literature, the guideline drafting committee made their recommendations and provided explanations for these choices, and the boards of each academic society approved these choices based on public comments in each of their societies. ## Systematic review We requested literature searches from the Japan Medical Library Association, on behalf of the systematic review team, with our searches open to all types of literature abstracted from the keywords. We searched for literature published from 1970 to 2014; the databases searched were PubMed, Ichushi-Web, and the Cochrane Library. Evidence was assessed in accordance with the Minds Treatment Guideline Creation Companion 2014 [fig_ref] Table 1: Assessment and definitions of overall evidence strength in systematic review A [/fig_ref]. The systematic review team performed primary screening and secondary screening, and drafted an assessment sheet. All CQ database search results and literature assessment sheets were posted on each academic society's website. Please feel free to refer to these posts as necessary. ## Drafting of recommendations Recommendation grades were determined based on the overall evidence assessments of the systematic review team with consideration for the trade-offs and balances between benefits and harm/side effects/risks. These recommendation grades were determined communally by the guideline drafting committee via informal consensus; the reasons underlying the committee's assessments were recorded. Recommendation strength was rated on a scale of 1-4 as described below. 1) Strongly recommended 2) Weakly recommended (suggestion) 3) Weakly advised against (suggestion) 4) Strongly advised against ## Outside assessment These guidelines are posted on the websites of the four academic societies that collaborated to author them (the Japanese Society of Nephrology, the Japan Society of Clinical Oncology, the Japanese Society of Medical Oncology, and the Japanese Society of Nephrology and Pharmacotherapy); the guidelines were opened to public comments. All comments and our responses are posted on each society's website. Following publication, these guidelines are scheduled to be assessed by the Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument. 11. Issues in drafting of the guidelines 11.1 Assessment of renal function during cancer drug therapy There is no established method for assessing renal function during cancer drug therapy. Although serum creatinine levels and eGFR, which are used to assess renal function in real-world clinical settings, are generally recognized to be somewhat problematic, there is currently no established method for assessing renal function before and after cancer drug therapy. The same is naturally true for proxy markers. ## Diversity of anticancer drugs The term ''anticancer drug'' covers an extremely large number of drugs. Each drug exerts different effects on renal function; discussing these individual effects is not the purpose of these guidelines. In order to introduce CQs frequently encountered in real-world cancer treatment, we have centered our discussion on widely used drugs. Wider varieties of cancer and drugs will be set aside as topics for future consideration. ## Relationship to medical economics For these guidelines, we did not examine issues in medical economics; therefore, the creation of the guidelines and the determination of recommendation levels were unaffected by concerns related to medical economics. ## Reflection of patients' opinions It has been recommended that patients' opinions be reflected in the creation of these guidelines. However, at the drafting stage, we were unable to construct a framework for incorporating patients' opinions. ## Sources of funding and conflicts of interest All committee members involved in drafting these guidelines have submitted conflict of interest declarations in accordance with the regulations of their respective academic societies; these declarations are managed by each society's secretariat. These guidelines have been drafted based purely on scientific grounds and assessment, as well as public interest. Individual committee members' conflicts The burden of funding the creation of the present guidelines was borne by the Japanese Society of Nephrology and the three related collaborating societies (the Japan Society of Clinical Oncology, the Japanese Society of Medical Oncology, and the Japanese Society of Nephrology and Pharmacotherapy). Funds were used for the drafting committee members' transportation expenses, meeting site expenses, and meal expenses. These funds were not used for remunerations to the guideline drafting committee or the systematic review team. 13. Summary of guidelines # Background and objectives In order to conduct anticancer chemotherapy safely and effectively, it is important to establish appropriate doses to elicit maximum anticancer effects and minimize side effects. When renal function is impaired, renally excreted drugs accumulate in the kidneys, potentially resulting in serious side effects; therefore, anticancer drug doses must be adjusted in accordance with renal function. Estimated GFR is used to assess renal function. Outside of Japan, GFR is measured based on clearance of chromium (Cr) 51-labeled ethylenediaminetetraacetic acid and iodine (I)-125 sodium iothalamate, which are the respective GFR substances EDTA and iothalamate marked with radioisotopes of chromium and iodine, respectively [bib_ref] Measuring GFR: a systematic review, Soveri [/bib_ref] ; in Japan, the gold standard is inulin clearance [bib_ref] Measuring GFR: a systematic review, Soveri [/bib_ref]. However, measurement of GFR requires urine collection following intravenous injection of exogenous clearance substances marked with inulin or radioactive material, thus making testing cumbersome. Therefore, Ccr and GFR are typically estimated based on serum Cr. Although various formulas have been devised for estimating GFR (Note 1) [bib_ref] Prediction of creatinine clearance from serum creatinine, Cockcroft [/bib_ref] [bib_ref] for the Collaborators developing the Japanese equation for estimated GFR. Revised equations..., Matsuo [/bib_ref] [bib_ref] Using standardized serum creatinine values in the modification of diet in renal..., Levey [/bib_ref] [bib_ref] Estimation of glomerular filtration rate in cancer patients, Wright [/bib_ref] [bib_ref] Improvement of the Cockcroft-Gault equation for predicting glomerular filtration in cancer patients, Martin [/bib_ref] [bib_ref] Creatinine clearance: bedside estimate, Jelliffe [/bib_ref] [bib_ref] for the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to..., Levey [/bib_ref] , most of these are intended for patients with chronic kidney disease and healthy individuals; their efficacy for cancer patients has not been sufficiently verified. For patients with renal impairment, dose adjustments are often based on pharmacokinetic data at the time of clinical trials. Many trials of dose adjustment tailored to renal function have used Ccr as calculated from the Cockcroft-Gault equation. In 2010, the United States Food and Drug Administration (FDA) published guidance for pharmacokinetics research in patients with impaired renal function. In addition to the conventional use of Ccr based on the Cockcroft-Gault equation, the guidance document also proposed the use of eGFR based on the Modification of Diet in Renal Disease (MDRD) equation; consequently, for drugs developed in the future, dose adjustments based on eGFR may become the norm. Proposed revised guidelines from the European Medicines Agency (EMA) also describe assessment of renal function using eGFR based on the MDRD equation and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [bib_ref] Guideline on the evaluation of the pharmacokinetics of medicinal products in patients..., European Medicines [/bib_ref]. In Japan, the Guideline for Clinical Evaluation of Oral Hypoglycemic Agents published by the Ministry of Health, Labour and Welfare stipulates that renal function indicators (eGFR, Ccr, etc.) are recommended for assessment of clinical trials . Although this guideline is not related to drug dose adjustments, it shows that eGFR may be used frequently to assess renal function in clinical trials in Japan going forward. The objectives of this draft are to examine existing findings on renal function assessment in the administration of anticancer drugs, and to determine the usefulness and limitations of this assessment in real-world settings. ## Commentary Renal excretion of drugs occurs by glomerular filtration and tubular excretion; however, because there is no simple method for quantitatively assessing the drug excretion function of renal tubules, drug dose adjustments are typically based on GFR. Likewise, in the development of novel agents, doses are often established based on GFR or on Ccr, which reflects GFR. Therefore, GFR has been established as the reference for adjusting doses of anticancer drugs. Measurement of GFR requires measurement of the clearance of a substance that is completely filtered by glomeruli, does not bind to proteins, is not metabolized in the body, and is not secreted or reabsorbed by renal tubules. In Japan, the gold standard is inulin clearance; other countries, however, measure clearance of substances such as 51Cr-EDTA, I-125 sodium iothalamate, or iohexol. Although Ccr is sometimes measured in place of GFR, measurement of Ccr (enzymatic method) yields values 20-30% higher than measurements of GFR based on inulin clearance. This discrepancy arises from the fact that Cr is not only filtered by glomeruli, but also secreted by renal tubules; consequently, GFR & Ccr 9 0.715. The use of these methods in clinical settings is constrained by the need for administration of reagents and urine collection, as well as a certain length of time before results are reported. These constraints have resulted in the development of equations for estimating GFR and Cr based on serum Cr levels. Conventionally, drug doses have generally been adjusted using Ccr as estimated with the Cockcroft-Gault equation. However, because Ccr estimates are higher than GFR values, several different equations have been developed for the accurate estimation of GFR; these equations are now also used to adjust drug doses. Most equations for calculating eGFR and Ccr were developed for use in healthy individuals and CKD patients; few such equations are intended for use in cancer patients. Although the Wright formula [bib_ref] Estimation of glomerular filtration rate in cancer patients, Wright [/bib_ref] , the Martin formula [bib_ref] Improvement of the Cockcroft-Gault equation for predicting glomerular filtration in cancer patients, Martin [/bib_ref] , and the Jelliffe equation [bib_ref] Creatinine clearance: bedside estimate, Jelliffe [/bib_ref] are intended for the estimation of GFR in cancer patients, no method has been developed for estimating GFR specifically in Japanese cancer patients. Therefore, in regard to the CQ of whether eGFR is recommended for assessment of renal function for the adjustment of anticancer drug doses, we conducted literature searches upon establishing the following two questions: ''Is eGFR based on serum Cr values an appropriate substitute for the gold standard of GFR based on clearance of inulin, 51Cr-EDTA, or I-125 sodium iothalamate?'' and ''Is eGFR an appropriate substitute for conventional Ccr calculated with the Cockcroft-Gault equation?'' We found 12 studies that compared actual GFR to eGFR [bib_ref] Carboplatin dosing: gender bias and inaccurate estimates of glomerular filtration rate, Dooley [/bib_ref] [bib_ref] A comparison of bedside renal function estimates and measured glomerular filtration rate..., Poole [/bib_ref] [bib_ref] Evaluation of the Cockroft-Gault, Jelliffe and Wright formulae in estimating renal function..., Marx [/bib_ref] [bib_ref] Evaluation of predictive formulae for glomerular filtration rate for carboplatin dosing in..., De Lemoss [/bib_ref] [bib_ref] Prospective evaluation of pharmacokinetically guided dosing of carboplatin in Japanese patients with..., Shimokata [/bib_ref] [bib_ref] Evaluation of glomerular filtration rate estimation by Cockcroft-Gault, Jelliffe, Wright and Modification..., Ainsworth [/bib_ref] [bib_ref] Monitoring renal function during chemotherapy, Hartlev [/bib_ref] [bib_ref] Overestimation of carboplatin doses is avoided by radionuclide GFR measurement, Craig [/bib_ref] [bib_ref] Dosing of cytotoxic chemotherapy: impact of renal function estimates on dose, Dooley [/bib_ref] [bib_ref] Performance of formulae based estimates of glomerular filtration rate for carboplatin dosing..., Shepherd [/bib_ref] [bib_ref] Renal function evaluation in patients with cancer who were scheduled to receive..., Shibata [/bib_ref] [bib_ref] Estimating GFR in adult patients with hematopoietic cell transplant: comparison of estimating..., Hingorani [/bib_ref] , three studies that compared actual Ccr to eGFR [bib_ref] Impact of different methods of estimating renal function on determining eligibility for..., Goto [/bib_ref] [bib_ref] Is the eGFR formula adequate for evaluating renal function before chemotherapy in..., Uozumi [/bib_ref] [bib_ref] Are the equations for the creatinine-based estimated glomerular filtration rate applicable to..., Inoue [/bib_ref] , and three studies that compared Ccr as calculated with the Cockcroft-Gault equation to formulas for eGFR and other such predictive formulas [bib_ref] Lung cancer and renal insufficiency: prevalence and anticancer drug issues, Launay-Vacher [/bib_ref] [bib_ref] Evaluation of creatinine-based formulas in dosing adjustment of cancer drugs other than..., Jennings [/bib_ref]. Results are inconsistent among studies that have examined the validities of various predictive formulas for cancer patients; this lack of consistency is assumed to potentially lead to the overestimation and underestimation of true GFR within a certain range. Overestimation of GFR can result in excessive doses of anticancer drugs and increased risk of side effects, while underestimation of GFR can lead to insufficient doses of anticancer drugs and a consequent attenuation of anticancer action. Few studies have compared actual GFR to eGFR as calculated with the Japanese Society of Nephrology's equation in Japanese cancer patients; thus, further research is desirable. Research is also necessary to assess the usefulness of equations for estimating GFR based on serum cystatin C rather than serum Cr. Most studies compare eGFR to the gold standard of actual GFR; no studies have examined therapeutic effects and side effects resulting from administration of anticancer drugs based on eGFR. Research is also needed on clinical outcomes comparing the use of eGFR to the use of actual GFR or the use of Ccr as estimated with the Cockcroft-Gault equation. At present, eGFR as calculated with the Japanese Society of Nephrology's equation yields an approximate assessment of renal function; if renal function is normal, anticancer drug dose adjustment can be considered unnecessary. However, in the adjustment of doses based on data from clinical trials, it is safe to use the same renal function assessment methods and predictive equations. No matter which predictive equation is used, for patients with a markedly abnormal condition whose renal function necessitates anticancer drug dose adjustment or who are borderline for such adjustment, rather than using eGFR based on serum Cr value, it is safer to use a combination of other methods such as actual GFR based on urine collection (Note 2) and GFR as estimated based on cystatin C. Although actual GFR based on urine collection and inulin clearance is preferable, when these are difficult to implement, GFR can be approximated by multiplying Ccr (enzymatic method) by 0.715. When performing dose adjustments in accordance with Ccr or GFR, the following point must be noted: when assessing Ccr and GFR, the decision of whether to correct for body surface area is related to the method of measuring serum Cr value using the Cockcroft-Gault equation. Drug doses are either fixed (mg/day) regardless of the patient's condition (body weight and body surface area) or tailored to the patient's condition (body weight and body surface area). In the use of agents for which the dose is fixed regardless of condition, the dose is adjusted in accordance with Ccr or eGFR (mL/min) without correcting for body surface area (Note 3). In regard to this point, the Japanese Society of Nephrology-edited 2012 CKD Practice Guide recommends the following: ''When using renally excreted agents for patients with diminished renal function, renal function should be assessed with eGFR (mL/min) without correcting for body surface area, doses should be reduced, and administration intervals should be prolonged''. The EMA Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with decreased renal function also recommends that GFR be measured and recorded without correcting for body surface area [bib_ref] Guideline on the evaluation of the pharmacokinetics of medicinal products in patients..., European Medicines [/bib_ref]. On the other hand, in the use of agents for which doses are established based on body surface area (mg/m 2 ) and body weight (mg/kg), it is reasonable to use Ccr corrected for body surface area (per 1.73 m 2 ) or eGFR corrected for body surface area (mL/min/1.73 m 2 ). Doing so is reasonable because when using Ccr or GFR per mL/min for correction in the use of agents for which the dose is adjusted in accordance with body surface area, the double-counting of patient condition leads to excessive doses for large-bodied patients and insufficient doses for small-bodied patients. Ccr values as calculated with the Cockcroft-Gault equation are in mL/min without correcting for body surface area, whereas in the MDRD equation and the Japanese Society of Nephrology eGFR equation, Ccr values are corrected per 1.73 m 2 body surface area (mL/min/1.73 m 2 ). Therefore, caution is necessary when applying these equations. In Japan, Cr values are often measured with an enzymatic method; however, it must be noted that the Cockcroft-Gault equation uses Cr values determined with the Jaffé method. In the Jaffé method, Cr values are 0.2 mg/dL higher than Cr values determined with an enzymatic method; therefore, when calculating Cockcroft-Gault Ccr using Cr values determined with an enzymatic method, 0.2 is added to the enzymatic test Cr value. Although some patients who undergo cancer drug therapy for urinary tract tumors possess only one kidney, eGFR reflects the aggregate function of both kidneys; therefore, eGFR can also be used for patients with only a single kidney. * Note 1: Renal function estimation equations 1) Cockcroft-Gault equation Used for patients aged 20-80 years. For women, the above value is multiplied by 0.9. 7) CKD-EPI equation [bib_ref] for the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to..., Levey [/bib_ref] eGFR mL=min=1:73 m 2 À Á ¼ 141 Â serum Cr = j ð Þ a Â 0:993 age j is 0.9 for men and 0.7 for women. a is -1.209 when serum Cr is larger than j; otherwise, a is -0.411 for men and -0.329 for women. For women, the above value is further multiplied by 1.018. For black patients, the above value is further multiplied by 1.159. Note: The unit of serum Cr values is lmol/L in the Wright formula and Martin formula, and mg/dL in all other equations * Note 2: Measurement of actual GFR based on urine collection When renal function must be assessed accurately, measurement of inulin clearance is recommended. There is a standard method and a simple method for doing so. In the standard method, saline solution containing 1% inulin is continuously infused; urine and midpoint blood are collected three times at 30-minute intervals, and the mean of the three clearances is calculated. In the simple method, urine is collected for approximately 1 hour under continuous infusion of inulin, and clearance is determined from blood collected before and after urine collection. The simple inulin clearance method is shown in a [fig_ref] Figure 1: Simple inulin clearance method [/fig_ref]. Measurement of inulin clearance requires approximately 700 mL of additional fluid intake; thus, care must be taken to avoid excessive body fluid volume. * Note 3: GFR not corrected for body surface area Estimated GFR (mL/min/1.73 m 2 ) predicts GFR for a standard body surface area; it does not represent actual GFR in individual patients. In patients whose condition differs greatly from the standard condition for their age and sex, eGFR overestimates or underestimates actual GFR. Therefore, when establishing drug doses, renal function must be assessed using GFR without correcting for body surface area (mL/min). ''Not correcting for body surface area'' means determining the actual GFR of individual patients rather than correcting GFR units per 1.73 m 2 . Values yielded by estimation equations are already corrected per 1.73 m 2 body surface area; therefore, GFR without correcting for body surface area is calculated as follows after determining the individual patient's body surface area: GFR not corrected for body surface area mL=min [formula] ð Þ ¼ eGFR mL=min=1:73 m 2 À Á Ä 1:73 Â patients body surface area m 2 À Á [/formula] The DuBois formula [bib_ref] A formula to estimate the approximate surface area if height and weight..., Dubois [/bib_ref] , shown below, is a typical formula for estimating body surface area. 4) The blood concentrations of inulin in the two blood samples are averaged. Japanese Society of NephrologyBody surface area m 2 À Á ¼ 0:007184 Â body weight kg ð Þ 0:425 Â height cm ð Þ 0:725 CQ2: Is biomarker-based assessment recommended for early diagnosis of anticancer drug-induced AKI? Recommendation grade: Weakly recommended (suggestion) ## Recommendation At present, we cannot strongly recommend biomarkerbased assessment for early diagnosis of anticancer druginduced AKI. Although urine protein, urinary albumin, serum cystatin C, b2 microglobulin, urinary NAG, and urinary L-FABP can be measured as biomarkers of AKI in Japan, we cannot strongly recommend these or any other measurements as biomarkers of AKI. ## Summary In the last several years, several novel biomarkers of AKI have been reported. However, none of these biomarkers have yet demonstrated sufficient reliability, sensitivity, or rapidity in testing and assessment to be used in daily clinical practice. Background and Objectives 1) Diagnostic criteria for AKI In 2004, the Acute Dialysis Quality Initiative proposed the first uniform diagnostic criteria for AKI. These criteria focus on serum Cr and urine collection, which can be easily measured at any facility; the criteria are divided into 5 levels of renal dysfunction described by the acronym RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) [bib_ref] Acute renal failure-definition, outcome measures, animal models, fluid therapy and information technology..., Bellomo [/bib_ref]. Furthermore, in 2007, the Acute Kidney Injury Network (AKIN) proposed its own classification [bib_ref] Acute Kidney Injury Network: report of an initiative to improve outcomes in..., Mehta [/bib_ref]. The AKIN classification defines the diagnostic criteria for AKI as a 1.5-fold increase or an increase of C 0.3 mg/dL in serum Cr within 48 hours, or reduced urinary output (\ 0.5 mL/kg/h) over the span of 6 hours; severity is classified into 3 levels based on the degree of serum Cr increase and urinary output reduction. Severity is also assessed based on serum Cr increase and urinary output reduction within 1 week. ## 2) background and objectives Anticancer drugs frequently result in kidney injury; they are considered to account for 15% of all cases of druginduced kidney injury, the third-leading cause of these injuries, following antibacterial agents and non-steroidal anti-inflammatory drugs. Anticancer drugs are also known to result in AKI; AKI occurred in 36% of a group of 537 patients with acute myeloid leukemia or high-risk myelodysplastic syndrome who underwent induction chemotherapy, while 61.7% of patients who developed ESRD died [bib_ref] Predictors and outcome of acute kidney injury in patients with acute myelogenous..., Lahoti [/bib_ref]. A separate study reported an extremely high mortality rate of 73% among cancer patients with comorbid AKI [bib_ref] Prognosis of critically ill patients with cancer and acute renal dysfunction, Soares [/bib_ref]. Anticancer drug-induced AKI not only increases the risk of CKD and ESRD, but also requires adjustment of anticancer drug doses due to decreased renal function, thus interfering with the impending administration of the next anticancer drug. Due to the wide variety of chemotherapy regimens, AKI presents with a wide variety of clinical symptoms. Examples of anticancer drug-induced AKI are shown in [fig_ref] Table 4: Examples of anticancer drug-induced AKI [/fig_ref] [bib_ref] New drug toxicities in the onconephrology world, Perazella [/bib_ref] [bib_ref] Onco-nephrology: renal toxicities of chemotherapeutic agents, Perazella [/bib_ref]. A classic example of a tubular disorder-inducing drug is platinum-based agents, which primarily result in disorders in the tubulointerstitium. For example, cisplatin is known to cause AKI in approximately one-third of patients [bib_ref] Cisplatin nephrotoxicity, Arany [/bib_ref]. The anti-VEGF antibody bevacizumab is well known to cause vascular disorder and induce TMA. Although the emergence of the RIFLE and AKIN classifications, which are based on serum Cr and urinary output, have resulted in significant advances in the diagnosis of AKI, many issues remain. Serum Cr is affected by several factors such as age, body weight, sex differences, other agents, muscle metabolism, protein intake, and hypervolemia; thus, it is deeply flawed as a biomarker of AKI [bib_ref] A basic science view of acute kidney injury biomarkers, Charlton [/bib_ref] [bib_ref] Biomarkers for the diagnosis and risk stratification of acute kidney injury: a..., Coca [/bib_ref]. In addition, elevated serum Cr does not manifest until 48-72 hours after the initial occurrence of nephrotoxicity, thus hindering prompt AKI diagnosis and therapeutic intervention [bib_ref] Biomarkers for the diagnosis and risk stratification of acute kidney injury: a..., Coca [/bib_ref]. To compensate for the flaws of serum Cr, the usefulness of many novel biomarkers of AKI has been examined. However, the clinical use of novel biomarkers of AKI still faces high hurdles due to the need to establish threshold values in accordance with sex differences, age differences, and primary diseases [bib_ref] Clinical review: Biomarkers of acute kidney injury: where are we now?, Ostermann [/bib_ref]. The objectives of this guideline are to examine the latest findings regarding biomarkers for AKI induced by anticancer drugs, and to determine the usefulness and limitations of these biomarkers in real-world clinical settings. ## Commentary The biomarkers discussed in this draft can be assessed objectively and serve as indicators of pharmacological responses to biological changes, histological changes, and therapeutic interventions [bib_ref] Biomarkers and surrogate markers: an FDA perspective, Katz [/bib_ref]. Biomarkers of anticancer drug-induced AKI must be immune to interference from all types of treatment. Potential roles for biomarkers include: 1) risk assessment, 2) early diagnosis, 3) classification of disease stage, 4) differential diagnosis, 5) indication of therapeutic effects, and 6) determination of prognosis. Anticipation is particularly high for the practical application of biomarkers that enable earlier diagnosis than do serum Cr and eGFR. The present draft divides biomarkers into two categories: those that can be used in clinical practice and are covered by health insurance in Japan, and those that cannot. Also, in 2010, the Predictive Safety Testing Consortium's Nephrotoxicity Working Group submitted results for drug toxicity studies and analyses of biomarker performance to the FDA and the European Medicines Evaluation Agency; these results presented Kidney Injury Molecule-1 (Kim-1), urinary albumin, urine protein, b2 microglobulin, serum cystatin C, clusterin, and trefoil factor 3 (TFF-3) as biomarkers related to renal function safety [bib_ref] Renal biomarker qualification submission: a dialog between the FDA-EMEA and Predictive Safety..., Dieterle [/bib_ref]. Although the objective of this report is limited to safety assessments, we felt it necessary to discuss the usefulness of the above 7 biomarkers as biomarkers of anticancer drug-induced AKI. Urinary albumin levels increase as a result of enhanced glomerular permeability and impaired proximal tubular reabsorption. In fact, short-term and long-term administrations of nephrotoxic anticancer drugs have been reported to increase levels of urinary microalbumin [bib_ref] Hiddemann W. Microalbuminuria during cisplatin therapy: relation with pharmacokinetics and implications for..., Kern [/bib_ref]. However, urinary albumin levels are known to increase not only as a result of AKI, but also due to factors such as fever, exercise, dehydration, diabetes, and hypertension; thus, the specificity of urinary albumin as a biomarker of AKI is considered limited [bib_ref] Next-generation biomarkers for detecting kidney toxicity, Bonventre [/bib_ref]. ## B) urine protein In detection of glomerular disease, urine protein is said to be superior to BUN and serum Cr in terms of diagnostic performance [bib_ref] Urinary clusterin, cystatin C, beta2-microglobulin and total protein as markers to detect..., Dieterle [/bib_ref] ; however, urine protein is reported to have low specificity as a biomarker of AKI [bib_ref] Urinary biomarkers for sensitive and specific detection of acute kidney injury in..., Vaidya [/bib_ref] , and its usefulness has not been established. ## C) serum cystatin c Cystatin is the most important cysteine protease inhibitor in the human body. Cystatin C, a 13-kDa protein secreted by all nucleated cells, is characterized by the fact that it does not bind to plasma proteins. Therefore, cystatin C is freely filtered by the renal glomeruli; after being reabsorbed by the proximal tubules, more than 99% of it is degraded by the endocytic receptor megalin [bib_ref] Megalin-mediated endocytosis of cystatin C in proximal tubule cells, Kaseda [/bib_ref]. Unlike Cr, cystatin C is not secreted by the renal tubules into urine, and its levels are not dependent on sex or muscle mass. In patients with mild to moderate renal impairment, serum cystatin C is well correlated with GFR [bib_ref] Serum cystatin C as an endogenous marker of renal function in patients..., Hojs [/bib_ref] ; thus, cystatin C can be used to detect nephrotoxicity at an early stage with greater sensitivity than serum Cr, thus making serum cystatin C a potentially useful biomarker of AKI. However, serum cystatin C is limited in the following two ways: 1) it is affected by diabetes, high levels of corticosteroids, hyperthyroidism, inflammation, hyperbilirubinemia, and hypertriglyceridemia [bib_ref] Biology of renal function and renal failure'' working group. Cystatin C: current..., Séronie-Vivien [/bib_ref] ; 2) when GFR reaches \ 15 mL/min/ 1.73 m 2 , the increase in serum cystatin C slows and levels off at 5-6 mg/L [bib_ref] Performance of serum cystatin C versus serum creatinine as a marker of..., Horio [/bib_ref]. Benöhr et al. [bib_ref] Cystatin C -a marker for assessment of the glomerular filtration rate in..., Benöhr [/bib_ref] have demonstrated that serum cystatin C levels are significantly elevated on day 5 following cisplatin administration compared to 3 days prior to administration. At present, serum cystatin C has not been established as a useful biomarker of anticancer drug-induced AKI. Although measurement of serum cystatin C is covered by health insurance, measurement of urinary cystatin C is not. [formula] d) b2 microglobulin [/formula] b2 microglobulin is a polypeptide comprising 99 amino acids with a molecular weight of 11,800; it is distributed on the surface of nucleated cells throughout the body as the L chain of the major histocompatibility complex HLA class I antigen. b2 microglobulin passes freely through the glomerular basement membrane and is almost completely reabsorbed by the proximal tubule; in tubular disorders, however, decreased reabsorption leads to increased excretion of b2 microglobulin in urine, thus making b2 microglobulin a potentially useful marker of AKI. In fact, urinary b2 microglobulin has been reported to increase 4-5 days earlier than does serum Cr in tubular disorders [bib_ref] Noninvasive renal diagnostic studies, Tolkoff-Rubin [/bib_ref]. However, in aciduria and at room temperature, b2 microglobulin is extremely unstable, thus limiting its usefulness as a biomarker [bib_ref] beta 2-Microglobulin instability in pathological urine, Davey [/bib_ref]. ## E) nag In the kidneys, NAG is a glycolytic enzyme present in lysosomes and produced in the endoplasmic reticula of proximal tubule cells. Tubular disorders result in increased excretion of NAG in urine, thus making urinary NAG a potentially useful marker of AKI; urinary NAG is reported to demonstrate abnormal values 12 hours to 4 days earlier than does serum Cr [bib_ref] Measurement of tubular enzymuria facilitates early detection of acute renal impairment in..., Westhuyzen [/bib_ref]. Goren et al. [bib_ref] Cumulative renal tubular damage associated with cisplatin nephrotoxicity, Goren [/bib_ref] compared concentrations of NAG before and after cisplatin administration in 12 patients. In their investigation, concentrations of NAG increased following cisplatin administration, reached their peak on day 3, and subsequently decreased. In an examination of NAG and b2 microglobulin in 8 patients before and after cisplatin administration, Ikeda et al. [bib_ref] Urinary excretion of beta 2-microglobulin and N-acetyl-beta-D-glucosaminidase in advanced neuroblastoma patients receiving..., Ikeda [/bib_ref] reported that b2 microglobulin reached peak levels on day 3 and decreased to pretreatment levels in 1 week, although only 1 patient demonstrated increased NAG for 2 weeks. However, urinary NAG activity is inhibited by many nephrotoxic substances, magnesium, and endogenous urea [bib_ref] Inhibition of A and B N-acetyl-beta-D-glucosaminidase urinary isoenzymes by urea, Bondiou [/bib_ref]. Furthermore, urinary NAG levels are increased not only in AKI, but also in rheumatoid arthritis [bib_ref] Urinary N-acetyl-beta-D-glucosaminidase in rheumatoid arthritis, Iqbal [/bib_ref] , impaired glucose tolerance [bib_ref] Increased urinary excretion of N-acetylglucosaminidase in subjects with impaired glucose tolerance, Fujita [/bib_ref] , and hyperthyroidism [bib_ref] Urinary N-acetylbeta-D-glucosaminidase in the patients with hyperthyroidism, Tominaga [/bib_ref] ; thus, the specificity of urinary NAG for AKI is considered low. ## F) urinary l-fabp Liver fatty acid-binding protein is a fatty acid transport protein that is expressed in the proximal tubule and that possesses antioxidant properties [bib_ref] Biomarkers of AKI: a review of mechanistic relevance and potential therapeutic implications, Alge [/bib_ref]. Human L-FABP possesses a hypoxia-inducible factor 1a responsive element; thus, L-FABP expression is induced by hypoxia [bib_ref] Urinary fatty acid-binding protein 1: an early predictive biomarker of kidney injury, Noiri [/bib_ref]. Tubular disorders are known to result in increased excretion of L-FABP into urine; patients who develop AKI following cardiovascular surgery are reported to demonstrated an increase in urinary L-FABP immediately after surgery [bib_ref] for the TRIBE-AKI Consortium. Performance of kidney injury molecule-1 and liver fatty..., Parikh [/bib_ref] , while a high urinary L-FABP value is reported to be an independent predictor of AKI [bib_ref] Evaluation of new acute kidney injury biomarkers in a mixed intensive care..., Doi [/bib_ref]. As a biomarker of AKI, L-FABP compares favorably with Kim-1, NGAL, and NAG [bib_ref] Urinary liver-type fatty acid-binding protein predicts adverse outcomes in acute kidney injury, Ferguson [/bib_ref]. In Japan, assessment of L-FABP for the diagnosis of AKI is covered by health insurance. However, there has been very little investigation of the usefulness of L-FABP as a biomarker of anticancer druginduced AKI in humans; further study is necessary going forward. ## Biomarkers for which measurement is not covered by health insurance a) urinary kim-1 Kidney Injury Molecule-1 is a transmembrane glycoprotein produced in the proximal tubule during kidney injury; for 12 hours following renal ischemia, excretion of the extracellular domain of Kim-1 into urine is increased [bib_ref] Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule..., Han [/bib_ref]. In animal models of cisplatin-induced nephrotoxicity, levels of Kim-1 increased earlier than did levels of serum Cr, indicating that Kim-1 is a useful biomarker of tubular disorders [bib_ref] Kidney injury molecule-1: a tissue and urinary biomarker for nephrotoxicant-induced renal injury, Ichimura [/bib_ref]. In addition, a systematic review reported fluctuation of Kim-1 within 24 hours of kidney injury [bib_ref] The clinical utility of kidney injury molecule 1 in the prediction, diagnosis..., Huang [/bib_ref]. The United States FDA has approved Kim-1 as a marker of AKI. Tekce et al. [bib_ref] Does the kidney injury molecule-1 predict cisplatin-induced kidney injury in early stage?, Tekce [/bib_ref] compared levels of serum Kim-1 and urinary Kim-1 prior to cisplatin administration and at days 1, 3, and 5 after cisplatin administration in 8 patients with AKI and 14 patients without AKI with an eGFR C 90 mL/ min. On day 1, there were no significant differences between the groups in serum Cr, eGFR, or serum Kim-1; however, urinary Kim-1 levels were significantly higher in the AKI group. On day 3, the two groups demonstrated significant differences in serum Cr, eGFR, and urinary Kim-1; however, there were no significant differences in serum Kim-1. Thus, urinary Kim-1 demonstrates potential as an early marker of cisplatin-induced AKI. However, the stability of Kim-1 is markedly reduced in urine; thus, further study of urinary Kim-1 is considered necessary [bib_ref] Effect of pH on the stability of kidney injury molecule 1 (KIM-1)..., Pennemans [/bib_ref]. ## B) ngal Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa glycoprotein secreted primarily by activated neutrophils; under normal circumstances, 100% of NGAL is reabsorbed by the proximal tubule. In tubular disorders, NGAL is expressed in the ascending limb of the loop of Henle and in part of the collecting ducts; due to increased excretion into blood and urine, NGAL demonstrates abnormal values 2-4 hours following AKI. A meta-analysis of more than 2,500 cases found that NGAL is a useful marker not only for the diagnosis of AKI, but also for renal prognosis [bib_ref] Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute..., Haase [/bib_ref]. Peres et al. [bib_ref] Evaluation of the cisplatin nephrotoxicity using the urinary neutrophil gelatinase-associated lipocalin (NGAL)..., Peres [/bib_ref] reported that following the administration of cisplatin, the group of patients with AKI demonstrated higher NGAL levels than the non-AKI group; however, this difference was not significant. Gaspari et al. [bib_ref] Predicting cisplatininduced acute kidney injury by urinary neutrophil gelatinaseassociated lipocalin excretion: a..., Gaspari [/bib_ref] also compared NGAL levels between a group of 12 AKI patients and a group of 12 non-AKI patients at 1 and 4 hours and at 1, 2, 3, 7, and 15 days after cisplatin administration. Although a significant difference between the AKI group and the non-AKI group in serum Cr was first observed on day 3 following cisplatin administration, a significant difference in NGAL was first observed on day 1. Therefore, NGAL may enable detection of cisplatin-induced AKI earlier than does serum Cr. ## C) clusterin Clusterin, a 76-80-kDa glycoprotein, is assumed to exert an anti-apoptotic renoprotective effect in kidney injury. Urinary clusterin is reported to be superior to BUN and serum Cr in the detection of proximal tubular injury [bib_ref] Urinary clusterin, cystatin C, beta2-microglobulin and total protein as markers to detect..., Dieterle [/bib_ref]. However, insufficient research has been done on clusterin in regard to human AKI, and the usefulness of clusterin as a biomarker of anticancer drug-induced AKI is unknown. ## D) urinary tff-3 Urinary excretion of TFF-3 is reduced in AKI. Although urinary TFF-3 has been demonstrated to be a useful marker of AKI in animal models, its usefulness in humans has not been sufficiently examined [bib_ref] Urinary biomarkers trefoil factor 3 and albumin enable early detection of kidney..., Yu [/bib_ref]. ## E) endothelin-1 Endothelin-1 is a 21-amino acid protein that possesses a vasoconstrictor effect; in the kidneys, it is expressed in mesangial cells and collecting ducts. Takeda et al. [bib_ref] Urinary endothelin-1-like immunoreactivity in young male patients with testicular cancer treated by..., Takeda [/bib_ref] measured urinary endothelin-1-like immunoreactivity/Cr before and 1 and 2 weeks after cisplatin treatment; these authors reported that urinary endothelin-1-like immunoreactivity/Cr was significantly increased at 1 and 2 weeks after cisplatin treatment compared to pretreatment levels. Following cisplatin treatment, b2 microglobulin/Cr and endothelin-1-like immunoreactivity/Cr peaked on day 2 and subsequently declined, whereas NAG/Cr peaked on day 6. In addition to the above, other substances have also been examined for their usefulness as biomarkers of AKI, such as interleukin-18, angiotensinogen, tissue inhibitor of metalloproteinase-2, and insulin-like growth factor-binding protein 7 [bib_ref] Biomarkers of AKI: a review of mechanistic relevance and potential therapeutic implications, Alge [/bib_ref]. The usefulness of various biomarkers has been examined in animal models [bib_ref] Age-related differences in kidney injury biomarkers induced by cisplatin, Shin [/bib_ref] ; however, there is a significant dearth of evidence in humans. The following circumstances account for the near-absence of evidence: 1) The lack of uniformity in diagnostic criteria for AKI leads to differences among reports. 2) Although many reports have examined AKI overall, very few reports have focused on anticancer drug-induced AKI. 3) For many biomarkers, evident threshold values have not been established, making assessment in individual studies difficult. 4) Cancer drug therapy often combines multiple drugs. Different drugs induce nephrotoxicity via different mechanisms, while some drugs (cisplatin, etc.) are assumed to act via multiple mechanisms; therefore, assessment with a single biomarker may not be valid (in fact, a study has demonstrated the usefulness of a combination of multiple biomarkers [bib_ref] Urinary biomarkers for sensitive and specific detection of acute kidney injury in..., Vaidya [/bib_ref]. 5) When using serum, the possibility cannot be ruled out that what is being assessed is not AKI, but rather the effects of anticancer drugs throughout the body. Furthermore, in such cases, the effects of other factors, such as age and past history of CKD and other complications, are unknown. Although biomarkers enhance our understanding of drug-induced AKI, much remains unknown regarding their contribution to the diagnosis of AKI. When conducting anticancer chemotherapy, nephrologists must determine when biomarkers are necessary, which biomarkers are useful, how to interpret biomarker data, and how to utilize biomarker data on an individual basis in treatment for each patient. ## Prevention of decreased renal function during cancer drug therapy (1) Overview CQ3: Is reduction of anticancer drug doses recommended for mitigating toxicity in patients with decreased renal function? Recommendation grade: Weakly recommended (suggestion) ## Recommendation When using drugs that lead to an increased risk of adverse drug events in patients with decreased renal function, dose reduction is recommended. However, when the goal is to cure cancer, doses must ultimately be determined with consideration of the balance between risks and benefits. ## Summary When using agents that lead to an increased risk of adverse drug events in patients with decreased renal function, dose reduction is recommended. However, when the objective is to cure cancer, doses must ultimately be determined with consideration of the balance between risks and benefits. # Background and objectives The kidneys are an elimination pathway for many anticancer drugs and their metabolites; therefore, renal impairment can delay the excretion and metabolism of anticancer drugs, potentially resulting in increased toxicity and thus necessitating consideration of dose reduction. For patients with decreased renal function, dose reduction is also sometimes considered for anticancer drugs that are metabolized in the liver. For example, dose reduction is considered necessary when irinotecan is administered to dialysis patients [bib_ref] Increased Plasma Concentrations of Unbound SN-38, the Active Metabolite of Irinotecan, in..., Fujita [/bib_ref] [bib_ref] Delayed elimination of SN-38 in cancer patients with severe renal failure, Fujita [/bib_ref]. For sorafenib, as well, a drug that is primarily metabolized in the liver, some believe that dose reduction should be considered [bib_ref] Clinical results and pharmacokinetics of sorafenib in chronic hemodialysis patients with metastatic..., Kennoki [/bib_ref]. The present draft summarizes evidence related to dose reduction and presents principles for dose reduction for major anticancer drugs. ## Commentary Answering CQ3 requires studies comparing frequencies of adverse drug events between normal doses and reduced doses in patients with decreased renal function; however, the search formula used in the present guidelines yielded no relevant literature. Such studies present ethical issues and are considered difficult to conduct. Much of the available evidence [bib_ref] Phase I studies with carboplatin at the Royal Marsden Hospital, Calvert [/bib_ref] [bib_ref] Prediction of nephrotoxicity induced by cisplatin combination chemotherapy in gastric cancer patients, Moon [/bib_ref] [bib_ref] Influence of baseline renal function and dose reduction of nephrotoxic chemotherapeutic agents..., Maru [/bib_ref] comes from studies that compared the frequencies of adverse drug events in patients with normal renal function and patients with decreased renal function (reduced doses) [bib_ref] Phase I studies with carboplatin at the Royal Marsden Hospital, Calvert [/bib_ref] [bib_ref] Prediction of nephrotoxicity induced by cisplatin combination chemotherapy in gastric cancer patients, Moon [/bib_ref] [bib_ref] Influence of baseline renal function and dose reduction of nephrotoxic chemotherapeutic agents..., Maru [/bib_ref]. However, there are very few such studies; thus, the quality of the evidence is judged to be extremely low (D: Almost no confidence in effect estimates). Consideration of the balance between benefits and risks is particularly important in determining recommendation levels, but due to the paucity of evidence regarding the efficacy of treatment with reduced doses, our recommendation is weak. However, in real-world clinical settings, attempts have been made to reduce doses in accordance with renal function and to control plasma drug concentrations; these attempts have yielded a small number of studies and guidelines that serve as references. One such attempt with carboplatin dosing is the Calvert formula, which calculates doses using target AUC and Ccr as estimated with the Cockcroft-Gault equation based on the results of a phase I clinical trial (see CQ10 for details) [bib_ref] Carboplatin dosage: prospective evaluation of a simple formula based on renal function, Calvert [/bib_ref]. Another study has reported a revised Calvert formula based on data from Japanese patients [bib_ref] Prospective evaluation of pharmacokinetically guided dosing of carboplatin in Japanese patients with..., Shimokata [/bib_ref]. Although there are no comprehensive guidelines regarding dose reduction methods in Japan, the Japanese Society of Nephrology and Pharmacotherapyhas presented opinions on dose reduction methods for several anticancer drugs [fig_ref] Table 5: Dose reduction methods for major anticancer drugs in patients with decreased renal... [/fig_ref] ; in addition, there are various books with information on dose reduction for anticancer drugs. Outside of Japan, the United States FDAand the European Medicines Agencyhave published guidelines calling for the inclusion of methods of administration for patients with decreased renal function in package inserts for all types of drugs; these publicly available package inserts may also serve as a reference for dose reduction. For anticancer drugs, the therapeutic range and the toxic range are extremely close to each other. Therapeutic drug monitoring is considered useful for preventing toxicity in such cases; in fact, therapeutic drug monitoring has been proven effective in randomized clinical trials for some anticancer drugs [bib_ref] Clinical impact of pharmacokinetically-guided dose adaptation of 5-fluorouracil: results from a multicentric..., Fety [/bib_ref] [bib_ref] Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage:..., Gamelin [/bib_ref]. However, at present, attempting to measure blood concentrations of anticancer drugs is not standard practice. A realistic desirable approach for patients with decreased renal function is to begin anticancer drug administration by referring to the above-mentioned dose adjustment guidelines, monitor adverse events more closely than normal, and consider adjusting doses in future treatment. In patients for whom the objective is to cure cancer, doses must ultimately be determined in consideration of the balance between risks and benefits. (2) Platinum-based drugs CQ4: Is risk factor assessment recommended for predicting cisplatin-induced AKI? Recommendation grade: Weakly recommended (suggestion) ## Recommendation Reported predictors of cisplatin-induced AKI include hypoalbuminemia; smoking; female sex; age (1.03-fold increase in risk per year of age); concomitant use of other anticancer drugs; comorbid cardiovascular disease or diabetes; advanced cancer; and total cisplatin dose. In order to prevent cisplatin-induced AKI, risk factors should be assessed prior to drug administration. ## Summary Reported predictors of cisplatin-induced AKI include hypoalbuminemia; smoking; female sex; age (1.03-fold CarboplatinMethotrexateCapecitabineTegafur/gimeracil /oteracil potassium [bib_ref] Phase II tailored S-1 regimen study of first-line chemotherapy in elderly patients..., Shiroyama [/bib_ref] Contraindicated For patients with serious renal impairment, administration is contraindicated due to concern for pronounced side effects such as myelosuppression, due to marked delay in renal excretion of gimeracil, catabolic enzyme inhibitor of 5-FU, leading to an increase its blood concentration. Single dose of 300-400 mg/m2; cease for at least 4 weeks. This constitutes 1 course. # Background and objectives Cisplatin, a key drug in treatment for many types of cancer, is one of the most commonly used anticancer drugs. However, cisplatin is known to produce side effects such as myelosuppression, intestinal toxicity, and neurotoxicity; another crucial side effect, nephrotoxicity, is a potential subsequent cisplatin dose-limiting factor. One-third of patients receiving cisplatin are presumed to have comorbid AKI [bib_ref] Cisplatin nephrotoxicity, Arany [/bib_ref] , which often results in the limitation of subsequent doses of cisplatin. Furthermore, AKI sometimes develops into chronic tubulointerstitial fibrosis and irreversible chronic tubulopathy, which may further progress to CKD [bib_ref] Cisplatin nephrotoxicity: mechanisms and renoprotective strategies, Pabla [/bib_ref] [bib_ref] Nephrotoxicity from chemotherapeutic agents: clinical manifestations, pathobiology, and prevention/therapy, Perazella [/bib_ref]. The present draft examines risk factors that may serve as predictors of cisplatin-induced AKI. ## Commentary Cisplatin-induced renal injury is considered to manifest primarily as proximal tubular injury, particularly in the S3 segment [bib_ref] Mechanism of cis-platinum nephrotoxicity: II. Morphologic observations, Dobyan [/bib_ref]. Cisplatin is absorbed from the basolateral surface into cells and injures mitochondrial DNA, thereby activating apoptosis. Intracellular accumulation of cisplatin results in inflammation, oxidative stress, and ischemic injury [bib_ref] Cisplatin nephrotoxicity: mechanisms and renoprotective strategies, Pabla [/bib_ref]. Hypomagnesemia is also considered to cause renal injury. Magnesium is thought to be involved in active transport mechanisms in the renal tubules. Sobrero et al. have supposed that hypomagnesemia leads to an increased concentration of cisplatin in renal tubular cells, thereby causing proximal tubular injury [bib_ref] Current strategies to reduce cisplatin toxicity, Sobrero [/bib_ref]. In an investigation by de Jongh et al. [bib_ref] Weekly high-dose cisplatin is a feasible treatment option: analysis on prognostic factors..., De Jongh [/bib_ref] of weekly-dose cisplatin for 400 patients with locally advanced or metastatic cancer, 36% of patients received cisplatin alone, 49% received cisplatin ? etoposide, and 15% received cisplatin ? paclitaxel. A total of 116 patients (29%) demonstrated a reduction in Ccr of C 25%, while 29 patients (7%) were unable to continue cisplatin due to nephrotoxicity. Independent predictors of post-cisplatin nephrotoxicity as determined by multivariate analysis were paclitaxel coadministration (odds ratio [OR] 4.0, p = 0.001), hypoalbuminemia (OR 3.5, p = 0.006), smoking (OR 2.5, p = 0.002), female sex, and old age. According to age group, the risk of nephrotoxicity was 26% among patients aged \ 48 years, and increased with age to 35% for patients aged 48-62 years and 41% for patients aged [ 62 years; the risk of nephrotoxicity increased 1.03-fold per year (OR 1.03, p = 0.007). Regarding gender, the risk of nephrotoxicity was twice as high for women as for men (OR 2.0, p = 0.025). Another study reported that cisplatin excretion capacity is lower in women than in men [bib_ref] Body-surface area-based dosing does not increase accuracy of predicting cisplatin exposure, De Jongh [/bib_ref] ; however, the cause of this difference is unknown. The involvement of smoking in nephrotoxicity has been surmised to be the effect of oxidant stress [bib_ref] Oxidant stress in the vasculature, Maytin [/bib_ref] ; however, one possibility that cannot be ruled out is that smoking causes cardiovascular disease, which secondarily leads to post-cisplatin nephrotoxicity. Also, in hypoalbuminemia, an increased concentration of unbound cisplatin is considered to enhance nephrotoxicity [bib_ref] Weekly high-dose cisplatin is a feasible treatment option: analysis on prognostic factors..., De Jongh [/bib_ref]. The cited study, which defines nephrotoxicity as a reduction in Ccr of C 25%, is not strictly an assessment of predictors of AKI. In an investigation of 425 patients treated with cisplatin (total dose 220 mg/m 2 [median]), Stewart et al. [bib_ref] Association of cisplatin nephrotoxicity with patient characteristics and cisplatin administration methods, Stewart [/bib_ref] reported that in multivariate analysis, the factors that predicted maximum increases in serum Cr up to 4 weeks after cisplatin treatment were serum albumin, serum potassium, body surface area, and number of administrations. However, this study contains flaws: renal function was assessed with serum Cr alone, and the authors' method of assessing maximum increases in serum Cr up to 4 weeks after cisplatin treatment is neither a well-established method nor period for assessment. Furthermore, anticancer drugs were used in combination with many other drugs; thus, the degree to which cisplatin contributes to changes in renal function is unknown. In an examination of 1,721 patients treated with cisplatin, Mizuno et al. [bib_ref] The risk factors of severe acute kidney injury induced by cisplatin, Mizuno [/bib_ref] found, in multivariate analysis, that cancer stage 4 diagnosis (OR 1.8, p = 0.011) and total cisplatin dose were risk factors for moderate AKI (1.5-1.9fold increase in serum Cr within 7 days of cisplatin treatment), while comorbid cardiovascular disease, comorbid diabetes mellitus, and cancer stage 4 diagnosis were risk factors for severe AKI (C 2.0-fold increase in serum Cr within 7 days of cisplatin treatment [bib_ref] Pharmacokinetic and toxicity evaluation of fiveday continuous infusion versus intermittent bolus cis-diamminedichloroplatinum(II)..., Forastiere [/bib_ref]. The subjects were patients with head and neck cancer; 6 patients received cisplatin 30 mg/m 2 via continuous infusion (24 hours) for 5 days, while another 5 patients received cisplatin 30 mg/m 2 via intermittent intravenous bolus (20 minutes) for 5 days; the two groups were compared in terms of total platinum concentration, free platinum concentration, and adverse events. Although the continuous infusion group demonstrated an extremely low maximum unbound platinum concentration compared to the intermittent bolus group, the exposure to unbound platinum (AUC) was 1.5-2 times higher in the continuous infusion group. An assessment of subclinical nephrotoxicity based on measurement of urinary excretion of the renal enzymes NAG and alanine found no differences between the two groups in nephrotoxicity, or in hearing loss or nausea/vomiting. In contrast, myelosuppression and hypomagnesemia were observed frequently in the continuous infusion group, suggesting that total platinum exposure contributes to nephrotoxicity more than does peak concentration. Because adverse events in continuous administration were clinically acceptable, the authors recommended larger-scale trials with continuous infusion of cisplatin. However, because this study compared two forms of divided doses against each other, the merits of divided doses remain unknown. Ikeda et al. investigated the optimal administration method for combined 5-FU ? cisplatin therapy in patients with gastric cancer and esophageal cancer [bib_ref] Pharmacokinetics of cisplatin in combined cisplatin and 5-fluorouracil therapy: a comparative study..., Ikeda [/bib_ref]. The study compared pharmacokinetic differences (AUC and C max ) in 12 courses of therapy for 9 subjects. Comparisons were made among three groups: 4 courses of cisplatin 80 mg/m 2 (2 hours), 4 courses of 20 mg/m 2 (2 hours) for 5 days, and 4 courses of 100 mg/m 2 (120 hours). In all three groups, 5-FU was continuously infused at a dose of 800 mg/m 2 (24 hours) for 5 days. The authors concluded that continuous infusion is the pharmacokinetically optimal administration method; however, this method has not been recognized to be superior in terms of adverse events. Takahashi et al. also compared pharmacokinetics and nephrotoxicity according to different cisplatin administration methods (5 divided doses, 24 hours continuous infusion, 12 hours continuous infusion, 6 hours continuous infusion); they found no differences in clinical adverse events. The above-cited three studies found no difference in nephrotoxicity based on the cisplatin administration method; thus, there is no basis for the active recommendation of divided doses. Therefore, due to the current absence of appropriately designed studies, there is no basis for actively recommending divided doses of cisplatin for the prevention of nephrotoxicity. On the other hand, the National Comprehensive Cancer Network's 2014 bladder cancer guidelines state that divided doses (35 mg/m 2 on days 1 and 2 or days 1 and 8) may be considered for patients with borderline renal function or minimal dysfunction. However, no references are cited for these proposed divided doses. In addition, the therapeutic effect of divided doses is unclear. Nonetheless, some believe that continuous administration of cisplatin is safe for preventing and alleviating nephrotoxicity. Erdlenbruch et al. compared pharmacokinetics and nephrotoxicity between two groups: a group of 4 pediatric osteosarcoma patients who received continuous infusion of 120 mg/m 2 cisplatin over 72 hours, and a group of 6 pediatric medulloblastoma patients who received 1-hour bolus infusions of 40 mg/m 2 cisplatin per day for 3 consecutive days [bib_ref] Cisplatin nephrotoxicity in children after continuous 72-h and 3x1-h infusions, Erdlenbruch [/bib_ref]. The divided dose group demonstrated a peak concentration of free platinum 19 times that of the continuous infusion group, as well as a lower minimum GFR and a higher rate of persistent nephrotoxicity within 1 year after the completion of cisplatin therapy. The authors concluded that continuous administration of cisplatin is less nephrotoxic than divided doses. ## Summary The nephrotoxicity of cisplatin was established at the preclinical level (animal trials); therefore, cisplatin dosage regimens were formulated from the outset using hydration and other forms of supportive therapy. Consequently, despite the absence of high-quality evidence from sources such as randomized clinical trials, hydration is strongly recommended during cisplatin administration. # Background and objectives Platinum-based agents are renally excreted anticancer agents used to treat various forms of cancer; these agents are well known to be nephrotoxic. Cisplatin is particularly nephrotoxic and has thus been examined frequently. The primary measures for preventing cisplatin nephrotoxicity are hydration and administration of diuretics. The issues of fluid replacement volume and the use versus non-use of diuretics are covered in another CQ and are thus not discussed here. ## Commentary Answering the present CQ fundamentally requires a randomized clinical trial examining the use versus non-use of hydration during cisplatin therapy in human subjects; however, our search formula did not retrieve any such trials. Most of the existing relevant literature consists of reviews that discuss nephrotoxicity. As a basis for recommending fluid replacement, one typical review [bib_ref] Cisplatin nephrotoxicity: a summary of preventative interventions, Finley [/bib_ref] cites an animal trial [bib_ref] Improvement of cis-dichlorodiammineplatinum (NSC 119875): therapeutic index in an animal model, Cvitkovic [/bib_ref] that divided dogs into a control group, a prehydration group, and a mannitol infusion group; nephrotoxicity was alleviated in the latter two groups. Many other reviews have also recommended forced diuresis with hydration and diuretics. Cisplatin was developed in the 1970s; as a result of the different development methodologies of today, as well as the fact that cisplatin was known early in its development to be nephrotoxic, the absence of validation studies in human subjects is considered inevitable. Consequently, the quality of the evidence is assessed as extremely poor (D: Almost no confidence in effect estimates). In the evidence for various existing cancer drug therapies, implementation plans prescribe normal hydration when using cisplatin. For other platinum-based agents (carboplatin, etc.), hydration is not typically prescribed. The Japanese package insert for cisplatin states in the dosage section that hydration is to be performed before, during, and after administration; however, the package insert for carboplatin does not contain such instructions. In the United States as well, the package insert for cisplatin calls for hydration, whereas the package insert for carboplatin does not (rather, it specifies that, unlike with cisplatin, massive hydration and forced diuresis are normally not to be performed). In consideration of the above information, and of the balance between benefits and risks, hydration during cisplatin administration is strongly recommended. Hydration is not recommended during administration of other platinum-based agents such as carboplatin. In the past, hydration during cisplatin administration commonly consisted of approximately 2 L saline solution or half-normal saline solution prior to cisplatin and C 1 L saline solution or half-normal saline solution after cisplatin. In regard to ''short hydration'', which reduces this hydration volume and uses oral rehydration, please see CQ7. CQ7: Is short hydration recommended during cisplatin administration? Recommendation grade: Weakly recommended (suggestion) ## Recommendation When administering cisplatin on an outpatient basis, short hydration is recommended with consideration of renal function, performance status (PS), and age. However, performing short hydration safely requires sufficient oral rehydration and establishment of sufficient urinary output. Short hydration is intended for patients who, from day 0 to day 3 of chemotherapy, can consume a normal amount of food and undergo an additional 1,000 mL of hydration per day. When oral rehydration is insufficient, it is necessary to modify the environment to enable rapid hydration via intravenous infusion. ## Summary When administering cisplatin, short hydration is recommended with consideration of renal function, PS, and age. Performing short hydration safely requires sufficient oral rehydration; short hydration is intended for patients who, from day 0 to day 3 of chemotherapy, can consume a normal amount of food and undergo an additional 1,000 mL of hydration per day. When oral rehydration is insufficient, the environment must be modified to enable rapid hydration via intravenous infusion. In addition, short hydration requires establishment of sufficient urinary output via diuretics (mannitol or furosemide), supplementation of magnesium and potassium, and confirmation of serum electrolyte levels. # Background and objectives Before and after administration of cisplatin, hydration must be performed in order to prevent nephrotoxicity. In Japan, standard practice is to replace 1,000-2,000 mL fluid over the course of C 4 hours before and after cisplatin and to administer cisplatin diluted with C 500-1,000 mL infusion solution over the course of C 2 hours. However, this hydration is performed over a long period of time and requires hospitalization. A number of studies have examined methods of hydration for preventing cisplatin-induced nephrotoxicity. Here, we have examined the safety of short hydration via 2,000-2,500 mL fluid replacement over the course of approximately 4 hours. ## Commentary In 2007, Tiseo et al. [bib_ref] Short hydration regimen and nephrotoxicity of intermediate to high-dose cisplatin-based chemotherapy for..., Tiseo [/bib_ref] reported the results of a retrospective two-center observational study regarding the safety of high-dose cisplatin (C 75 mg/m 2 ) administered with short hydration. Following administration of approximately 2,000 mL saline solution and furosemide over the course of 4 hours on the day of cisplatin administration, nephrotoxicity resulted in withdrawal of chemotherapy in 5 of 107 subjects (4.6%); among these 5 subjects, 2 demonstrated Grade 2 nephrotoxicity according to National Cancer Institute Common Toxicity Criteria. In Japan, Horinouchi et al. [bib_ref] Short hydration in chemotherapy containing cisplatin (C75 mg/m2) for patients with lung..., Horinouchi [/bib_ref] and Hotta et al.have conducted small-scale prospective trials with patients who received 75 mg/m 2 and 60 mg/m 2 cisplatin, respectively. With short hydration incorporating potassium, magnesium, and mannitol, elevations in serum Cr of Grade 2 or higher (based on the reference range upper limit in the Common Terminology Criteria for Adverse Events ver. 4.0) occurred in 2.2% (1/44) and 0% (0/46) of subjects, respectively. In all other literature we assessed [bib_ref] The feasibility of CDDP administration for gastric cancer outpatients undergoing S-1/cisplatin combination..., Kishimoto [/bib_ref] [bib_ref] Cisplatin administration for outpatients with short hydration of less than four hours, Hata [/bib_ref] [bib_ref] Use of high-dose cisplatin with aprepitant in an outpatient setting, Furukawa [/bib_ref] [bib_ref] Disorders of serum electrolytes and renal function in patients treated with cis-platinum..., Giaccone [/bib_ref] [bib_ref] Routine administration of a single dose of cisplatin C75 mg/m2 after short..., Lavolé [/bib_ref] [bib_ref] Toxicity of cis-diamminedichloroplatinum II given in a two-hour outpatient regimen of diuresis..., Vogl [/bib_ref] [bib_ref] Safe and effective two-hour outpatient regimen of hydration and diuresis for the..., Vogl [/bib_ref] , compared to conventional hydration, short hydration was found not to increase the incidence of nephrotoxicity and was concluded to be safe; the results of these studies were judged to be consistent. The short hydration method assessed in the present CQ is as follows: a total of approximately 1,600-2,500 mL fluid is replaced over the course of approximately 4 hours; potassium and magnesium are supplemented; and urinary output is established via diuretics (furosemide and mannitol). In contrast, the United States National Comprehensive Cancer Network presents a chemotherapy order template of a total of 1,000-3,000 mL hydration before and after cisplatin administration at a rate of 250-500 mL/h for many carcinomas. In Japan, the Japan Lung Cancer Society and the Japanese Society of Medical Oncology have created a guide that mentions short hydration, stating that short hydration can be performed safely if the target patients are limited to those who meet certain criteria. These target patients fulfill conditions such as the following: age\75 years, serum Cr value below the center's reference value, Ccr C 60 mL/min, PS of 0-1 on the Eastern Cooperative Oncology Group scale, no pleural effusion or ascites, cardiac function capable of withstanding approximately 500 mL/h hydration (left ventricular ejection fraction C 60% on echocardiography, etc.), completion of appropriate antiemetic therapy, and ability to receive approximately 1,000 mL/day oral hydration from day 0 to day 3 of cisplatin administration. Therefore, consciousness of disease and assurance of adherence are important when selecting patients. In addition, in the event of serious side effects or insufficient water intake, fluid replacement should be performed at a center that can adapt rapidly to such circumstances. All of the target studies were observational studies; therefore, the quality of the overall evidence was initially graded as C (weak). There were judged no serious problems with risk of bias, indirectness, inconsistency, imprecision, or publication bias, all of which downgrade the quality of evidence. In addition, intervention effects, dose-response gradient, and confounders, all of which improve the quality of evidence, were judged not to apply; therefore, the overall quality of evidence was ultimately graded as C (weak). ## Cq8: are diuretics recommended for preventing cisplatin-induced nephrotoxicity? Recommendation grade: Weakly recommended (suggestion) ## Recommendation We cannot definitively recommend diuretics for preventing cisplatin-induced nephrotoxicity. Such a preventive effect has not been proven in small-scale randomized clinical trials; therefore, there is no basis for recommending diuretics to achieve this effect. Nevertheless, diuretics are used to prevent nephrotoxicity during cisplatin treatment, which has been widely performed since the 1970s. The efficacy and safety of diuretics for preventing nephrotoxicity have been confirmed in large-scale clinical trials of cisplatin and other therapies. Therefore, there is also no basis for rejecting the use of diuretics to prevent cisplatin-induced nephrotoxicity. ## Summary We cannot definitively recommend diuretics for preventing cisplatin-induced nephrotoxicity. Such a preventive effect has not been proven in small-scale randomized clinical trials; therefore, there is no basis for recommending diuretics to achieve this effect. Nevertheless, diuretics are used to prevent nephrotoxicity during cisplatin treatment, which has been widely performed since the 1970s. The efficacy and safety of diuretics for preventing nephrotoxicity have been confirmed in large-scale clinical trials of cisplatin and other therapies. Therefore, there is also no basis for rejecting the use of diuretics to prevent cisplatininduced nephrotoxicity. # Background and objectives High-dose cisplatin administration was first reported to be possible with the combined use of hydration and diuretics in the 1970s. Since then, the osmotic diuretic mannitol and the loop diuretic furosemide have been used to prevent nephrotoxicity in the administration of cisplatin. Here, we examine whether these diuretics are effective for preventing cisplatin-induced nephrotoxicity. ## Commentary A phase I clinical trial for cisplatin has demonstrated that nephrotoxicity is a dose-limiting factor [bib_ref] Diaminodichloroplatinum: a phase I study showing responses in testicular and other tumors, Higby [/bib_ref]. Hydration and diuretics have been used in attempts to rapidly excrete toxic platinum metabolites and reduce their duration of contact with the renal tubule in order to alleviate nephrotoxicity. However, pharmacokinetic analysis has shown that diuretics do not affect the half-life of free platinum following cisplatin administration and are considered to reduce the urinary excretion rate and increase serum platinum concentration [bib_ref] Evaluation of the effect of furosemide on ultrafilterable platinum kinetics in patients..., Dumas [/bib_ref] [bib_ref] Pharmacokinetics of non-protein-bound platinum species following administration of cis-dichlorodiammineplatinum (II), Belt [/bib_ref]. Even if diuretics are effective in preventing nephrotoxicity, the mechanism of this effect is not sufficiently understood. Hayes et al. were the first to report that fluid replacement and mannitol alleviate cisplatin-induced nephrotoxicity. High-dose cisplatin (120 mg/m 2 ) was administered to 60 patients with the combined use of hydration and mannitol. The 52 patients who were analyzed demonstrated only temporary increases in serum Cr; no serious nephrotoxicity was observed. Serum Cr increased by \ 2 mg/dL in almost all patients; although 10 patients demonstrated greater increases, 9 of those patients demonstrated reduced renal function at baseline and were at high risk for nephrotoxicity [bib_ref] High dose cis-platinum diammine dichloride: amelioration of renal toxicity by mannitol diuresis, Hayes [/bib_ref]. Following this report, diuretics have been used in the majority of subsequent clinical trials for therapies that include cisplatin. Ostrow et al. conducted the first trial comparing mannitol and furosemide. Twenty-two patients with advanced cancer resistant to existing therapies received 100 mg/m 2 cisplatin. The subjects were assigned to one of two groups; one group received 37.5 g mannitol by 6-hour infusion, while the other group received 40 mg furosemide by intravenous injection 60 minutes prior to treatment. All subjects underwent hydration with 1 L normal saline following cisplatin administration. Nephrotoxicity (defined as Ccr B 50 mL/min or serum Cr[2 mg/dL) occurred in 28% of the 22 courses in the mannitol group and 19% of the 25 courses in the furosemide group. Mean Ccr values in the mannitol group and the furosemide group were 34 mL/min and 26 mL/min, respectively. Although the mannitol group demonstrated a tendency toward more severe nephrotoxicity, the difference was not statistically significant. Therefore, the interpretation is that neither diuretic was demonstrated to be superior [bib_ref] High-dose cisplatin therapy using mannitol versus furosemide diuresis: comparative pharmacokinetics and toxicity, Ostrow [/bib_ref]. In a prospective randomized phase II trial, Al-Sarraf et al. compared the incidence of post-cisplatin nephrotoxicity between hydration alone and hydration ? mannitol. Nephrotoxicity occurred following initial cisplatin administration in 30% of patients who received hydration only and in 15% of patients who received hydration ? mannitol. The overall incidence of nephrotoxicity in the hydration only group and the hydration ? mannitol group was 39% and 32%, respectively. Thus, mannitol demonstrated a prevention effect against cisplatin-induced nephrotoxicity in the initial administration of cisplatin; however, this effect was not evident in subsequent administrations [bib_ref] Cisplatin hydration with and without mannitol diuresis in refractory disseminated malignant melanoma:..., Al-Sarraf [/bib_ref]. Santoso et al. conducted a randomized comparative trial to compare the cisplatin-induced nephrotoxicity prevention effects of hydration (500 mL normal saline), hydration ? furosemide (40 mg), and hydration ? mannitol (50 g). Forty-nine patients with gynecologic cancers underwent therapy with 75 mg/m 2 cisplatin ? paclitaxel or 5-FU and were randomly assigned to one of the three above-described combination therapies. A total of 15 women were assigned to the hydration only group, while 17 were assigned to the hydration ? furosemide group and 17 were assigned to the hydration ? mannitol group. The three groups demonstrated nearly equal Ccr at baseline. However, following cisplatin therapy, Ccr (± standard deviation) in the hydration only group, the hydration ? furosemide group, and the hydration ? mannitol group was 80.4 (±33.5), 81.4 (±23.3), and 60.6 (±26.8) mL/min, respectively; thus, the hydration ? mannitol group demonstrated a result significantly inferior to that of the other two groups [bib_ref] Saline, mannitol, and furosemide hydration in acute cisplatin nephrotoxicity: a randomized trial, Santoso [/bib_ref]. Several issues have been highlighted in relation to this trial: the trial was discontinued due to poor outcomes in the hydration ? mannitol group, the sample size was small, the dose of mannitol was larger than in previous trials, and urine collection for Ccr lacked rigor, among other issues. Thus, despite being a randomized comparative trial, its quality is lacking. Therefore, although diuretics have been widely used since the 1970s to prevent nephrotoxicity induced by platinum-based agents, no randomized comparative studies have clearly demonstrated that diuretics are effective to that end, and there is no sufficient basis to recommend diuretics for that purpose. The European Society of Clinical Pharmacy Special Interest Group on Cancer Care states in their recommendations on the prevention of cisplatin nephrotoxicity that there is no reason to recommend the use of diuretics [bib_ref] for the European Society of Clinical Pharmacy Special Interest Group on Cancer..., Launay-Vacher [/bib_ref]. However, diuretics have been widely used in the administration of cisplatin for many years, and this approach has been used to create evidence for various therapies; thus, the safety of diuretics in cisplatin administration is well established. In short hydration as well, which has been attempted in recent years, the use of diuretics is presumed, and they have been reported to be safe. Therefore, without proof that diuretics pose evident risks, there is little basis to advise against the use of these agents. ## Cq9: is magnesium recommended for preventing cisplatin-induced nephrotoxicity? Recommendation grade: Weakly recommended (suggestion) ## Recommendation Administration of magnesium, which can be expected to prevent hypomagnesemia, has been indicated to affect renal function favorably; therefore, administration of magnesium is recommended for preventing nephrotoxicity. ## Summary Prophylactic administration of magnesium can be expected to prevent hypomagnesemia and alleviate nephrotoxicity following the administration of cisplatin. # Background and objectives Due to enhanced excretion primarily from the kidneys as well as intestinal toxicity, cisplatin administration frequently results in hypomagnesemia, which has been reported to potentially cause nephrotoxicity. Therefore, prophylactic administration of magnesium is anticipated to alleviate nephrotoxicity. ## Commentary In our searches for studies comparing nephrotoxicity in the use versus non-use of magnesium in patients receiving high-dose cisplatin, we found two randomized comparative trials and one retrospective analysis [bib_ref] Kaye SB Effects of magnesium supplementation in testicular cancer patients receiving cis-platin:..., Willox [/bib_ref] [bib_ref] Renal protection with magnesium subcarbonate and magnesium sulphate in patients with epithelial..., Bodnar [/bib_ref] [bib_ref] Protective effect of magnesium preloading on cisplatin-induced nephrotoxicity: a retrospective study, Yoshida [/bib_ref]. Willox et al. randomly assigned 17 cancer patients (16 patients with testicular cancer and 1 patient with an ovarian dysgerminoma) scheduled to receive cisplatin into a magnesium treatment group and a non-magnesium treatment group; the non-magnesium group subsequently demonstrated significant tubular damage (high NAG value) [bib_ref] Kaye SB Effects of magnesium supplementation in testicular cancer patients receiving cis-platin:..., Willox [/bib_ref]. Bodnar et al. conducted a double-blind, randomized comparison of magnesium administration and non-administration (placebo) in ovarian cancer patients scheduled to receive cisplatin; the magnesium group subsequently demonstrated significantly favorable GFR compared to the placebo group [bib_ref] Renal protection with magnesium subcarbonate and magnesium sulphate in patients with epithelial..., Bodnar [/bib_ref]. Although both of the above studies indicate that prophylactic administration of magnesium affects renal function favorably, the sample sizes were small, and the endpoints and statistical hypotheses were unclear. Therefore, although magnesium can be anticipated to prevent nephrotoxicity, this preventive effect has not been definitively verified. However, prophylactic administration of magnesium is inferred to prevent hypomagnesemia and consequently alleviate adverse reactions such as nephrotoxicity, while adverse reactions induced by prophylactic administration of magnesium are minor; considering these points, prophylactic administration of magnesium is currently recommended. ## Cq10: is carboplatin dose setting based on renal function recommended? Recommendation grade: Strongly recommended ## Recommendation In adult cancer patients receiving carboplatin, there is insufficient evidence to prove that the method of setting doses based on renal function following the establishment of a target AUC increases therapeutic effects and reduces side effects compared to the general method of determining doses based on body surface area. However, the setting of doses based on renal function is both reasonable and widespread in daily clinical practice. ## Summary In adult cancer patients receiving carboplatin, there is insufficient evidence to prove that the method of setting doses based on renal function following the establishment of a target AUC increases therapeutic effects and reduces side effects compared to the general method of determining doses based on body surface area. However, the setting of doses based on renal function is both reasonable and widespread in daily clinical practice. Therefore, we graded our recommendation as ''strong''. # Background and objectives The platinum-based agent carboplatin is almost completely excreted from the kidneys following administration; therefore, its pharmacokinetics can be predicted based on GFR. Furthermore, AUC, an indicator of drug exposure volume in the body, is closely correlated with hematotoxicity and antitumor effect. Consequently, it is now widespread practice to set carboplatin doses based on GFR after establishing a target AUC. In many cases, GFR is substituted by Ccr. The present draft examines the validity of the routine clinical practice of setting carboplatin doses based on renal function. ## Commentary Carboplatin is a platinum-based agent with a broad antitumor spectrum that primarily includes gynecologic cancer and lung cancer. Because carboplatin is almost completely excreted from the kidneys following administration, its pharmacokinetics can be predicted based on GFR [bib_ref] Phase I studies with carboplatin at the Royal Marsden Hospital, Calvert [/bib_ref]. Furthermore, AUC, an indicator of drug exposure volume in the body, is strongly correlated with thrombocytopenia and other forms of hematotoxicity, which limit carboplatin doses; AUC is also strongly correlated with antitumor effect. Therefore, individual differences in the side effects and therapeutic effects of carboplatin can be explained by individual differences in AUC arising from pretreatment GFR [bib_ref] Pharmacokinetics of cis-diammine-1,1-cyclobutane dicarboxylate platinum (II) in patients with normal and impaired..., Harland [/bib_ref]. Setting carboplatin doses based on GFR after establishing a target AUC minimizes individual differences in AUC, which can consequently be expected to reduce the risks of serious hematotoxicity and undertreatment. Based on this idea, Calvert et al. created a formula for setting carboplatin doses based on GFR; this formula, called the Calvert formula, remains widely used in daily clinical practice today [bib_ref] Carboplatin dosage: prospective evaluation of a simple formula based on renal function, Calvert [/bib_ref]. [formula] Calvert formula : dose mg ½ ¼ target AUC mg=mL Â min ½ Â GFR mL=min ½ þ25 ð Þ [/formula] To calculate doses, the previously established target AUC and the patient's GFR are entered into the Calvert formula. Based on clinical trials, AUC is set at 5-7; however, analysis of a model for ovarian cancer patients demonstrates that while the antitumor effect of carboplatin nearly plateaus at an AUC of 5-7, thrombocytopenia and other forms of hematotoxicity are enhanced as AUC increases [bib_ref] Relationships between carboplatin exposure and tumor response and toxicity in patients with..., Jodrell [/bib_ref]. Similar formulas for calculating carboplatin doses based on renal function have been created by Egorin et al. [bib_ref] Pharmacokinetics and dosage reduction of cis-diammine (1,1-cyclobutanedicarboxylato) platinum in patients with impaired..., Egorin [/bib_ref] [bib_ref] Prospective validation of a pharmacologically based dosing scheme for the cis-diamminedichloroplatinum (II)..., Egorin [/bib_ref] and Chatelut et al. [bib_ref] Prediction of carboplatin clearance from standard morphological and biological patient characteristics, Chatelut [/bib_ref] ; however, the Calvert formula remains the most widely used due to its simplicity. In any case, setting dosages based on renal function is reasonable. However, no clinical trial has prospectively examined the setting of doses based on renal function from the perspective of increasing therapeutic effects and reducing side effects in comparison to typical methods based on body surface area; thus, the evidence for setting doses base on renal function is insufficient. In the process of creating the Calvert formula, the investigators employed actual GFR based on clearance of EDTA labeled with 51 Cr, a radioisotope of chromium. In Japan, the gold standard for GFR is inulin clearance; although measurement of inulin clearance is covered by health insurance, the procedure is cumbersome, and thus, Ccr is often used instead in daily clinical practice. However, not only does serum Cr undergo glomerular filtration, approximately 20-30% of it is secreted from the renal tubules; consequently, Ccr yields higher values than does GFR, a point which requires caution. The serum Cr values used to calculate Ccr are measured with the Jaffé method and an enzymatic method. The Jaffé method is affected by non-specific substances in serum; therefore, the measured value of serum Cr is approximately 0.2 mg/dL higher than the true serum Cr value. However, in calculations of Ccr, this measurement error is cancelled out by the difference with GFR resulting from tubular secretion; therefore, in effect, Ccr calculated with serum Cr as determined by the Jaffé method approximates GFR. With an enzymatic method, on the other hand, serum Cr measurements are precise, and Ccr values are higher than GFR values. Consequently, the Calvert formula, which uses Ccr as a substitute for GFR, engenders a risk of excessive carboplatin dosing. Since the mid-1990s, most medical centers in Japan have used the enzymatic method, whereas the United States and Europe have used the Jaffé method until recently. Caution is necessary when interpreting clinical trials of carboplatin conducted outside Japan. One proposed measure is to add 0.2 to enzymatic method-based serum Cr values when calculating Ccr [bib_ref] Adjustment of creatinine clearance improves accuracy of Calvert's formula for carboplatin dosing, Ando [/bib_ref] [bib_ref] Multi-institutional validation study of carboplatin dosing formula using adjusted serum creatinine level, Ando [/bib_ref]. When GFR is used, it is calculated with the Japanese Society of Nephrology's GFR estimation formula (eGFR) without correcting for body surface area (see CQ1). However, many Japanese clinical trials currently use Ccr calculated from enzymatic method-based serum Cr values in place of GFR. When evidence from these trials is used in clinical practice, regardless of the presence of evident bias between the actual AUC and the target AUC, what is effectively being used is GFR estimated with the same methods as in the relevant trials. However, considering the objective of individualized patient doses based on renal function, renal function should be accurately assessed from the clinical trial stage in order to prevent bias between actual AUC and target AUC. In the United States, since 2010, serum Cr has been measured by isotope dilution mass spectrometry, which are as accurate as the enzymatic method. Accordingly, establishing an upper limit for the GFR used in the Calvert formula (125 mL/min) is recommended to avoid the excessive carboplatin dosing that would result from overestimation of renal function. In gynecology, for extremely low serum Cr, a lower limit (0.7 mg/dL) is sometimes established. With these methods, it must be noted that actual AUC is larger than target AUC in the majority of Clin Exp Nephrol (2018) patients, while actual AUC is smaller than target AUC in some patients with favorable renal function. The ''GFR?25'' component of the Calvert formula corresponds to total carboplatin clearance; ''GFR'' corresponds to renal clearance, while the constant ''25'' corresponds to non-renal clearance. Non-renal clearance depends primarily on an individual's physical size. The Calvert formula was created in the United Kingdom; when using the Calvert formula for Japanese individuals, who are physically smaller on average than Caucasians, the proportion of non-renal clearance increases relative to GFR, particularly in patients with severely decreased renal function, thereby potentially leading to excessive carboplatin dosing [bib_ref] Prospective evaluation of pharmacokinetically guided dosing of carboplatin in Japanese patients with..., Shimokata [/bib_ref]. Measurement of Ccr requires urine collection (typically for 24 hours); thus, estimates calculated based on serum Cr values are sometimes used as a substitute for GFR. Formulas for estimating Ccr include the Cockcroft-Gault equation and the Jelliffe equation. Formulas for estimating GFR in the United States and Europe include the MDRD equation, the CKD-EPI equation, and the Wright formula; for Japanese patients, the previously described GFR estimation formula (eGFR) is used (see CQ1). When using these formulas, the patient's background (e.g., racial differences and pathologies) and the serum Cr measurement method must be noted. Furthermore, these formulas presume that serum Cr is stable; when renal function fluctuates markedly (such as in the acute phase of renal failure) or when muscle mass is greatly reduced (such as in sarcopenia or undernutrition), renal function will be overestimated. (3) Other agents CQ11: Is urine alkalinization recommended for preventing nephrotoxicity in high-dose methotrexate therapy with leucovorin rescue? Recommendation grade: Strongly recommended Recommendation Urine alkalinization is recommended for preventing nephrotoxicity in methotrexate with leucovorin rescue. ## Summary In methotrexate with leucovorin rescue, in addition to urine alkalinization and diuresis via sufficient hydration, monitoring of blood methotrexate levels is recommended. In addition, increased doses and prolonged administration of leucovorin in accordance with serum methotrexate levels are recommended. # Background and objectives Methotrexate with leucovorin rescue was developed in the 1970s; supportive therapies such as urine alkalinization and diuresis via sufficient hydration were generally established by the 1990s. The present draft re-examines this method based on recent findings. ## Commentary More than 90% of methotrexate is excreted from the kidneys. In animal experiments, methotrexate nephrotoxicity has been shown to arise from the accumulation of methotrexate or its metabolite 7-OH-MTX in the renal tubules. The solubility of methotrexate and its metabolites depends on urinary pH; this solubility is considered to increase five-to eight-fold with an increase in pH from 6.0 to 7.0 [bib_ref] Understanding and managing methotrexate nephrotoxicity, Widemann [/bib_ref]. Methotrexate with leucovorin rescue was developed in the 1970s with the following theoretical basis: when high-dose (generally C 500-1000 mg/m 2 ) methotrexate is administered, the methotrexate is passively incorporated into cancer cells; after a certain amount of time has elapsed, leucovorin is administered as a methotrexate antidote and is passively incorporated by healthy cells capable of doing so, thereby rescuing those cells. Methotrexate with leucovorin rescue has been demonstrated as effective against osteosarcoma, acute leukemia, and malignant lymphoma; however, in the 1970s, the frequency of drug-related deaths was at a high rate of approximately 6% [bib_ref] Incidence of drug-related deaths secondary to high-dose methotrexate and citrovorum factor administration, Hoff [/bib_ref]. The pathological explanation for these drug-related deaths emphasized the following: methotrexate nephrotoxicity results in delayed excretion of methotrexate itself, thereby aggravating myelosuppression and other serious adverse events [bib_ref] Incidence of drug-related deaths secondary to high-dose methotrexate and citrovorum factor administration, Hoff [/bib_ref]. Subsequently, in addition to diuresis with urine alkalinization [bib_ref] Hyper-alkalinization without hyper-hydration for the prevention of high-dose methotrexate acute nephrotoxicity in..., Mir [/bib_ref] and sufficient hydration [bib_ref] Effect of hydration on plasma-methotrexate levels, Romolo [/bib_ref] , monitoring of blood methotrexate levels has become widespread, as have increased doses and prolonged administration of leucovorin based on serum methotrexate levels [bib_ref] Use of plasma pharmacokinetics to predict and prevent methotrexate toxicity, Stoller [/bib_ref]. In accordance with these technical improvements, deaths related to methotrexate with leucovorin rescue have decreased; data for 3,887 cases of osteosarcoma aggregated in 2004 showed a rate of deaths related to methotrexate with leucovorin rescue of 0.08% [bib_ref] High-dose methotrexate-induced nephrotoxicity in patients with osteosarcoma, Widemann [/bib_ref]. Based on the above, although there is no evidence from randomized comparative trials, the establishment of urinary output through urine alkalinization and sufficient hydration are recommended to prevent nephrotoxicity in methotrexate with leucovorin rescue. However, in the above-cited 2004 data, nephrotoxicity Grade C 2 (WHO criteria, serum Cr levels 1.5-3.0 9 upper limit of normal) was observed in 68 patients (1.8%); the methotrexate with leucovorin rescue-related mortality rate among these patients was 4.4%, thus remaining high [bib_ref] High-dose methotrexate-induced nephrotoxicity in patients with osteosarcoma, Widemann [/bib_ref]. Increased doses of leucovorin are reported to be effective for delayed excretion of methotrexate resulting from nephrotoxicity [bib_ref] High-dose leucovorin as sole therapy for methotrexate toxicity, Flombaum [/bib_ref]. The efficacy of recombinant enzymes for directly degrading methotrexate in plasma has recently been reported in a prospective trial [bib_ref] Carboxypeptidase G2 rescue in patients with methotrexate intoxication and renal failure, Buchen [/bib_ref] and a retrospective analysis [bib_ref] leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors..., Widemann [/bib_ref] ; these recombinant enzymes have been approved in the United States, but not in Japan. Methotrexate is a small molecule with a molecular weight of only 454.44 and thus can be removed by hemodialysis. On the other hand, approximately 50% of methotrexate binds to proteins, and its volume of distribution is tens of liters; in 4 hours, hemodialysis removes only 10.8% of methotrexate (according to drug information). However, the use of high-flux membranes in hemodialysis has been reported in case studies to remove methotrexate more efficiently [bib_ref] Effective clearance of methotrexate using high-flux hemodialysis membranes, Wall [/bib_ref] [bib_ref] Effective removal of methotrexate by high-flux hemodialysis, Saland [/bib_ref] , thus making this technique worthy of consideration as a therapeutic approach. On the other hand, in combination chemotherapy that includes standard-dose methotrexate, i.e., cyclophosphamide, methotrexate, and 5-FU (CMF) for breast cancer and methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) for urothelial carcinoma, there is no definitive evidence showing that leucovorin and urine alkalinization are useful for preventing nephrotoxicity. In addition, the combined use of non-steroidal anti-inflammatory drugs in combination chemotherapy that includes standard-dose methotrexate is reported to exacerbate adverse events; therefore, methotrexate should not be used in combination with non-steroidal anti-inflammatory drugs [bib_ref] Understanding and managing methotrexate nephrotoxicity, Widemann [/bib_ref]. ## Cq12: is withdrawal or reduction of angiogenesis inhibitors recommended when proteinuria is observed? Recommendation grade: Strongly recommended Recommendation When proteinuria is observed during administration of angiogenesis inhibitors, withdrawal or reduction of these drugs is recommended upon consideration of the grade of proteinuria and of the risks/benefits of continued drug therapy. ## Summary Administration of angiogenesis inhibitors requires regular measurement of blood pressure, urinalysis for early detection of hypertension and proteinuria, and proactive administration of antihypertensive agents for sufficient control of blood pressure. If proteinuria manifests, temporary withdrawal of angiogenesis inhibitors or continued treatment with reduced doses are reasonable options; however, in the case of grade 1 proteinuria, for patients with advanced cancer, another option is to continue treatment upon consideration of the risks and benefits. When proteinuria is grade 2 or higher, angiogenesis inhibitors are temporarily withdrawn or reduced, and the patient is treated by a nephrologist as necessary. # Background and objectives Angiogenesis inhibitors, which are clinically applied in the treatment of various carcinomas, inhibit tumor angiogenesis primarily by suppressing the VEGF pathway. The actions and adverse events of angiogenesis inhibitors differ from those of cytotoxic anticancer drugs. Proteinuria, like hypertension, is an adverse event that occurs during treatment with angiogenesis inhibitors [bib_ref] VEGF signaling inhibition-induced proteinuria: Mechanisms, significance and management, Izzedine [/bib_ref]. Proteinuria and microalbuminuria have been demonstrated to be independent risk factors for renal disease and cardiovascular disease [bib_ref] Proteinuria and hypertension with tyrosine kinase inhibitors, Kandula [/bib_ref] ; thus, when proteinuria manifests during administration of angiogenesis inhibitors, appropriate management is necessary. There are many different types of angiogenesis inhibitors, each of which is indicated for a different carcinoma and has a different treatment regimen. Angiogenesis inhibitors are administered upon initiation of drug therapy for carcinomas that in most cases occur in a solitary kidney, such as advanced renal cell carcinoma. Furthermore, angiogenesis inhibitors are sometimes administered alone and also sometimes used as part of multidrug therapy. With this diverse background, the incidence of proteinuria during administration of angiogenesis inhibitors has been determined to differ for each individual agent [bib_ref] VEGF signaling inhibition-induced proteinuria: Mechanisms, significance and management, Izzedine [/bib_ref]. According to Japanese special drug use surveillance, during the administration of bevacizumab in 2,696 cases of advanced colorectal cancer, proteinuria occurred in 4.60% of cases; proteinuria was serious in 0.11% of these cases. The incidence of proteinuria during the administration of sunitinib in 2,141 cases of advanced renal cell carcinoma and gastrointestinal stromal tumors was 1.59%, versus an incidence of 1.20% in advanced renal cell carcinoma and 2.98% in gastrointestinal stromal tumors. During the administration of sorafenib in 3,335 cases of advanced renal cell carcinoma, the incidence of proteinuria was 0.71%, with no cases of serious proteinuria reported. In a phase II clinical study of 64 Japanese patients with cytokine-refractory metastatic renal cell carcinoma, proteinuria occurred in 58% of patients, 9% of whom developed serious proteinuria of grade 3 or higher [bib_ref] for the Japan Axitinib Phase II Study Group. Key predictive factors of..., Tomita [/bib_ref]. ## Commentary Angiogenesis inhibitors, i.e., VEGF pathway inhibitors, result in proteinuria during treatment; although the precise mechanism of onset of this adverse effect has not been determined, the presumed mechanism is a breakdown of glomerular structure and filtration function originating from the inhibition of VEGF production by podocytes [bib_ref] Antiangiogenic agents for the treatment of nonsmall cell lung cancer: characterizing the..., Wu [/bib_ref]. Angiotensin-converting enzyme inhibitors and ARBs dilate efferent arterioles, reduce intraglomerular pressure, and reduce proteinuria; therefore, administration of angiogenesis inhibitors must involve regular measurement of blood pressure, urinalysis for early detection of proteinuria, and proactive administration of antihypertensive agents for sufficient control of blood pressure [bib_ref] VEGF signaling inhibition-induced proteinuria: Mechanisms, significance and management, Izzedine [/bib_ref]. While the incidence of proteinuria is different for each individual angiogenesis inhibitor, the risk of proteinuria is considered to be dose-dependent [bib_ref] Bevacizumab increases risk for severe proteinuria in cancer patients, Wu [/bib_ref] [bib_ref] Proteinuria with first-line therapy of metastatic renal cell cancer, Land [/bib_ref]. Thus, when proteinuria manifests, reduction or temporary withdrawal of angiogenesis inhibitors are practical options. In fact, in a clinical trial that investigated the therapeutic effects of various molecularly targeted agents, many patients who demonstrated grade 2 or higher proteinuria during treatment were able to resume treatment following dose reduction or withdrawal [bib_ref] Phase II trial of bevacizumab and everolimus in patients with advanced renal..., Hainsworth [/bib_ref]. When advanced cancer patients with limited outcomes develop grade 1 proteinuria during treatment with angiogenesis inhibitors, withdrawal or reduction is not always necessary; rather, the decision must be based on an examination of the benefits/risks of continued drug therapy and on the individual patient's wishes. However, cases of nephrotic syndrome have been confirmed during treatment with various types of angiogenesis inhibitors [bib_ref] Nephrotic syndrome caused by the angiogenesis inhibitor sorafenib, Overkleeft [/bib_ref] [bib_ref] VEGF inhibition and renal thrombotic microangiopathy, Eremina [/bib_ref] [bib_ref] Inhibition of tyrosine kinases by sunitinib associated with focal segmental glomerulosclerosis lesion..., Costero [/bib_ref]. In cases in which proteinuria worsens despite temporary withdrawal or reduction of angiogenesis inhibitors, referral to a nephrologist should be considered [bib_ref] VEGF signaling inhibition-induced proteinuria: Mechanisms, significance and management, Izzedine [/bib_ref]. CQ13: Is reduction of bisphosphonates and anti-RANKL antibodies recommended for patients with decreased renal function? Recommendation grade: Strongly recommended Recommendation Reduction of bisphosphonates is recommended for patients with decreased renal function. However, reduction of anti-RANKL antibodies is not recommended for patients with decreased renal function. ## Summary Reduction of bisphosphonates is recommended for patients with decreased renal function. However, reduction of anti-RANKL antibodies is not recommended for patients with decreased renal function. # Background and objectives Injectable bisphosphonates have been established as useful for improving malignancy-induced hypercalcemia and inhibiting skeletal-related events associated with bone lesions resulting from multiple myeloma or bone metastases from solid tumors (defined as pathologic fracture, radiotherapy for bone lesions, surgery for bone lesions, spinal cord compression, and hypercalcemia). The primary bisphosphonates used in treatment for malignancies in Japan are zoledronic acid and pamidronate. Pamidronate is approved for malignancy-induced hypercalcemia and osteolytic bone metastases from breast cancer, whereas zoledronic acid is approved for malignancy-induced hypercalcemia and bone lesions resulting from multiple myeloma or bone metastases from solid tumors. In Europe, intravenous ibandronate is approved for the inhibition of bone metastasis-related events. One known adverse event associated with bisphosphonates is nephrotoxicity; the present draft examines the necessity of dose reduction in accordance with renal function. ## Commentary High-dose (90-360 mg/month) pamidronate has been reported to induce glomerulosclerosis and acute tubular necrosis, as well as to accelerate acute renal failure and nephrotic syndrome [bib_ref] Collapsing focal segmental glomerulosclerosis following treatment with highdose pamidronate, Markowitz [/bib_ref]. A subsequent examination of dosage and administration time found that nephrotoxicity was mild when pamidronate 90 mg was administered over the course of C 3 hours, while a phase III trial found no significant pamidronate-induced nephrotoxicity compared to placebo. Based on these results, the American Society of Clinical Oncology (ASCO) guidelines were revised to specify that when pamidronate 90 mg is administered over the course of C 2 hours, reduction of the pamidronate dose is unnecessary even when Ccr is 30-60 mL/min; the guidelines also specify that when Ccr is \ 30 mL/min, further prolongation of pamidronate administration time (4-6 hours) or pamidronate dose reduction is recommended [bib_ref] update on the role of bisphosphonates and bone health issues in women..., Hillner [/bib_ref] [bib_ref] American Society of Clinical Oncology 2007 clinical practice guideline update on the..., Kyle [/bib_ref]. Several phase III trials of zoledronic acid for breast cancer with osteolytic lesions, multiple myeloma, lung cancer, and other solid tumors began with a protocol of 4 mg or 8 mg administered over the course of 5 minutes; however, the group that received 8 mg over 5 minutes demonstrated a high incidence of nephrotoxicity, thereby necessitating a two-stage protocol amendment. First, the administration duration was extended from 5 minutes to 15 minutes; second, the 8 mg dose was reduced to 4 mg. These amendments reduced the incidence of nephrotoxicity induced by zoledronic acid to a rate equal to that induced by placebo or by pamidronate (the control group) [bib_ref] Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients..., Rosen [/bib_ref] [bib_ref] Zoledronic acid is superior to pamidronate for the treatment of bone metastases..., Rosen [/bib_ref] [bib_ref] Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in..., Rosen [/bib_ref] [bib_ref] Zoledronic acid versus placebo in the treatment of skeletal metastases in patients..., Rosen [/bib_ref] [bib_ref] Long-term efficacy and safety of zoledronic acid in the treatment of skeletal..., Rosen [/bib_ref]. In 2005, Novartis Pharmaceuticals filed a package insert revision with the FDA stating that for patients with decreased renal function (Ccr 30-60 mL/min), the dosage of zoledronic acid was to be reduced to achieve the same AUC as that for patients with a Ccr of 75 mL/min (specifically, doses of 3.5 mg, 3.3 mg, and 3.0 mg for patients with a Ccr of 50-60 mL/min, 40-49 mL/min, and 30-39 mL/min, respectively). The revised ASCO guidelines specify the following: the recommended dose and duration for zoledronic acid is 4 mg over C 15 minutes; when Ccr is 30-60 mL/min, the dose should be reduced in accordance with the recommendation in the package insert; and when Ccr is \ 30 mL/min, zoledronic acid should not be administered. In a retrospective analysis of 220 patients, Shah et al. reported that when zoledronic acid doses were adjusted as recommended in the package insert, patients with decreased renal function demonstrated the same incidence of acute renal failure (as an adverse event associated with zoledronic acid) as patients with normal renal function [bib_ref] Risk of renal failure in cancer patients with bone metastasis treated with..., Shah [/bib_ref]. Ibandronate, for which an intravenous formulation is approved in Europe, is used to inhibit associated skeletal-related events associated with bone metastasis (in Japan, ibandronate is approved only in oral form for osteoporosis). Ibandronate is considered to be associated with the lowest incidence of nephrotoxicity of all intravenous bisphosphonates [bib_ref] Renal safety of ibandronate 6 mg infused over 15 min versus 60..., Pivot [/bib_ref] However, the package insert recommends that when Ccr is [ 50 mL/min, infusion time should be extended from 15 minutes to 1 hour; and when Ccr is \ 30 mL/min, the dose should be reduced from 6 mg to 2 mg. Anti-RANKL antibodies were developed to treat bone metastasis; in a phase III trial, anti-RANKL antibodies were significantly superior to zoledronic acid in inhibiting skeletal-related events. Renal impairment did not occur; thus, dose adjustments in accordance with renal function are considered unnecessary [bib_ref] Randomized, doubleblind study of denosumab versus zoledronic acid in the treatment of..., Henry [/bib_ref]. However, patients with Ccr \ 30 mL/min and ESRD patients requiring dialysis were excluded from the trial; therefore, it is necessary to consider the potential onset of serious hypocalcemia and to assess the suitability of anti-RANKL antibodies carefully for patients with severe renal impairment. (4) Maintenance dialysis patients CQ14: Is dialysis therapy recommended for drug removal following cisplatin administration in maintenance dialysis patients? Recommendation grade: Weakly advised against (suggestion) ## Recommendation The majority of cisplatin binds to tissue and proteins and remains in the body even if dialysis is performed, with the resultant potential for a post-dialysis rebound. Therefore, dialysis therapy for drug removal is not recommended following cisplatin administration for maintenance dialysis patients, regardless of timing. ## Summary The majority of cisplatin binds to tissue and proteins and remains in the body even if dialysis is performed, with the resultant potential for a post-dialysis rebound. Therefore, dialysis therapy for drug removal is not recommended following cisplatin administration for maintenance dialysis patients, regardless of timing. However, this is only an expert opinion based on case reports; further clinical study is necessary to close the evidence-to-practice gap. # Background and objectives Due to concerns regarding accumulated toxicity following cisplatin administration, ESRD patients sometimes undergo dialysis for drug removal. In the present draft, we assess the efficacy of dialysis therapy for drug removal following cisplatin administration. ## Commentary Cisplatin rapidly binds to plasma proteins upon entering the blood, thereby undergoing conversion from unbound cisplatin (free Pt) to protein-bound cisplatin (&total Pt). One side effect of cisplatin is nephrotoxicity; dialysis patients, whose renal function has already been eliminated, may instead face problems such as myelotoxicity and peripheral neuropathy. Aside from case reports, there are very few systematic studies of the pharmacokinetics of cisplatin in dialysis patients. In their investigation of the pharmacokinetics of cisplatin in five patients who developed gastric cancer during maintenance dialysis, Miyakawa et al. reported the following results. When cisplatin was administered concurrently with the initiation of dialysis, the concentration of free Pt in blood rapidly decreased and was below measurable levels following dialyzer use; the concentration of total Pt fluctuated relatively sharply in the early stage and subsequently decreased gradually. When dialysis was initiated 1 hour after cisplatin administration, changes in concentrations of free Pt and total Pt in blood were considered to be the same as when cisplatin and dialysis were initiated simultaneously. However, the study does not specify which patients began cisplatin and dialysis immediately and which patients began dialysis 1 hour after administration of cisplatin. In the same year as the above study, Miyakawa et al. reported on the pharmacokinetics of cisplatin in 2 gastric cancer patients undergoing maintenance dialysis; however, it is unclear whether these 2 patients were also included in the other study. In all case reports, aside from a report by Inozume et al. stating that, ''In order to maximize the effect of the key drug cisplatin, we elected to perform dialysis the day after cisplatin'', dialysis was initiated 30 minutes to 1 hour following the administration of cisplatin. Without allowing a certain interval following cisplatin administration, free Pt will be eliminated from the blood by dialysis before it can bind to plasma proteins, thus greatly reducing the antitumor effect. Patients with normal renal function who receive cisplatin demonstrate a biphasic pattern in which the blood concentration of cisplatin increases sharply in the early stage (a-phase), then gradually decreases (b-phase). This pattern is also observed in patients with chronic renal failure; the a-phase is considered to be result of the entry of cisplatin into tissue. The b-phase is the result of excretion of cisplatin from the kidneys; in patients with renal failure, this reduction in the blood concentration of cisplatin is either diminished or completely absent. This biphasic pattern is also observed in reports in which dialysis is initiated 30 minutes to 1 hour following cisplatin administration. Cisplatin administered in vivo binds to proteins in plasma and tissue in a short time, after which it is not dialyzed; therefore, in 3.5 to 4 hours of dialysis, only approximately 10% of cisplatin is removed [bib_ref] Kinetics of cisplatin in an anuric patient undergoing hemofiltration dialysis, Gouyette [/bib_ref] [bib_ref] Combination therapy with methotrexate, vinblastine, adriamycin, and cis-platinum for ureteral cancer with..., Yokogi [/bib_ref]. Most cisplatin removed from the body is free Pt; the majority of cisplatin binds to tissue and proteins, thus remaining in the body even when dialysis is performed. A post-dialysis rebound results in a renewed increase in free Pt in blood [bib_ref] Successful treatment with 5-Fluorouracil and cis-dichlorodiammineplatinum combined with 60Gy of radiation in..., Arai [/bib_ref]. In addition, as the volume of accumulated cisplatin increases, the rate of cisplatin removed by dialysis further decreases [bib_ref] Pharmacokinetics of cisplatin and fluorouracil in hemodialysis patients, Goto [/bib_ref]. The above-cited studies demonstrate that although most free Pt can be removed by dialysis, the majority of cisplatin binds to tissue and proteins and thus remains in the body even when dialysis is performed, thereby potentially resulting in a post-dialysis rebound and a consequent renewed increase in cisplatin concentration. Therefore, the answer to the present CQ can be considered to be, ''Even when dialysis is performed following cisplatin administration, not only is the cisplatin removal rate roughly a mere 10%, a rebound phenomenon occurs; therefore, regardless of timing (whether immediately after cisplatin or 30 minutes to 1 hour after cisplatin), dialysis is not recommended for the removal of cisplatin''. However, this is an only an expert opinion based on case reports; further clinical study is necessary to close the evidence-to-practice gap. When cisplatin is administered to dialysis patients, a 50-75% dose reduction is recommended [bib_ref] Proposal for dosage adjustment and timing of chemotherapy in hemodialyzed patients, Janus [/bib_ref] [bib_ref] International Society of Geriatric Oncology (SIOG) recommendations for the adjustment of dosing..., Lichtman [/bib_ref]. When dialysis is performed following cisplatin administration, caution is necessary regarding cisplatin accumulation. ## Summary The suitability of rasburicase for preventing tumor lysis syndrome (TLS) has been described according to risk in the Japanese Society of Medical Oncology's Tumor Lysis Syndrome Practice Guidance; rasburicase has also been reported to reduce the need for hemodialysis. Rasburicase reduces uric acid levels, prevents nephropathy, and is effective in preventing TLS. # Background and objectives Rasburicase is a recombinant version of urate oxidase that rapidly metabolizes uric acid to allantoin. Compared to uric acid, allantoin is much more soluble in urine; this metabolism thus rapidly reduces uric acid levels in blood. Administration of rasburicase requires caution regarding the following three points: 1) rasburicase is an enzyme preparation and may thus trigger hypersensitivity reactions; 2) antibody formation has been reported, thereby rendering repeated administration is not recommended; 3) rasburicase is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency. The present draft examines whether rasburicase is recommended for the prevention of TLS. ## Commentary The suitability of rasburicase for preventing TLS has been described according to risk in the Japanese Society of Medical Oncology's Tumor Lysis Syndrome Practice Guidance; for high-risk and moderate-risk patients, in cases in which uric acid levels continually increase despite the use of allopurinol and febuxostat, or in cases in which hyperuricemia is observed at diagnosis, rasburicase should be administered or at least considered. The TLS preventive effect of rasburicase has been demonstrated in a phase III study that randomly assigned subjects at high risk for TLS to rasburicase only (0.20 mg/kg/day, days 1-5), rasburicase plus allopurinol (rasburicase 0.20 mg/kg/day, days 1-3; allopurinol 300 mg/day days 3-5), or allopurinol only (300 mg/day, days [bib_ref] Measuring GFR: a systematic review, Soveri [/bib_ref] [bib_ref] Prediction of creatinine clearance from serum creatinine, Cockcroft [/bib_ref] [bib_ref] for the Collaborators developing the Japanese equation for estimated GFR. Revised equations..., Matsuo [/bib_ref] [bib_ref] Using standardized serum creatinine values in the modification of diet in renal..., Levey [/bib_ref] [bib_ref] Estimation of glomerular filtration rate in cancer patients, Wright [/bib_ref]. In comparison to the allopurinol only group, the rasburicase only group demonstrated a significantly lower incidence of laboratory TLS 1 [bib_ref] Control of plasma uric acid in adults at risk for tumor Lysis..., Cortes [/bib_ref]. In a number of other studies conducted in children, rasburicase significantly reduced uric acid levels compared to allopurinol [bib_ref] A randomized comparison between rasburicase and allopurinol in children with lymphoma or..., Goldman [/bib_ref] [bib_ref] Urate oxidase for the prevention and treatment of tumour lysis syndrome in..., Cheuk [/bib_ref]. Regarding the nephropathy preventive effect of rasburicase, a systematic review of multiple clinical trials conducted in leukemia and lymphoma patients found that hemodialysis was performed for 0-2.8% of patients who used rasburicase, versus 15.9-25.0% of patients who did not use rasburicase; thus, the use of rasburicase tended to reduce the need for hemodialysis [bib_ref] Efficacy and safety of rasburicase, a recombinant urate oxidase (Elitek), in the..., Jeha [/bib_ref]. Rasburicase has also been shown to reduce uric acid levels in patients at high risk for TLS in a number of randomized comparative trials [bib_ref] A randomized trial of a single-dose rasburicase versus five-daily doses in patients..., Vadhan-Raj [/bib_ref] [bib_ref] A study of rasburicase for the management of hyperuricemia in pediatric patients..., Kikuchi [/bib_ref]. The above-cited studies demonstrate that rasburicase reduces uric acid levels, prevents nephropathy, and is effective for preventing TLS. CQ16: Is plasmapheresis recommended for anticancer drug-induced thrombotic microangiopathy? Recommendation grade: Weakly advised against (suggestion) ## Recommendation Due to the absence of definitive evidence, plasmapheresis is currently not recommended for anticancer drug-induced thrombotic microangiopathy (TMA). Although plasmapheresis has been observed to inhibit the progression of TMA-induced renal impairment in a handful of isolated cases, the efficacy of plasmapheresis for this purpose has not been properly assessed and therefore is currently not recommended. ## Summary Plasmapheresis is currently not recommended for anticancer drug-induced TMA due to the dearth of reliable evidence on its efficacy for this purpose. Although there are several case series and cross-sectional studies regarding mitomycin C, these studies have been no assessments of therapy with plasmapheresis alone. Because, plasmapheresis is often performed following hemodialysis or is combined with drug therapy based on anti-platelet drugs and steroids. On the other hand, regarding TMA-induced renal impairment, several reports have only stated that plasmapheresis inhibited further worsening of renal function. In addition, plasmapheresis is often combined with hemodialysis. Thus, the usefulness of plasmapheresis against drug-induced TMA has not truly been assessed. # Background and objectives Thrombotic microangiopathy is a disorder that presents with thrombocytopenia, microangiopathic hemolytic anemia, and organ dysfunction. Classical TMAs include thrombotic thrombocytopenic purpura (TTP) and Shiga toxin-induced hemolytic-uremic syndrome (HUS), in both of which activity of a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) is reduced. However, there is a great deal that remains unknown regarding the pathology of TMA, while the pathology of TMA is diverse; therefore, in 2013, all TMAs other than TTP and HUS were defined as atypical hemolytic-uremic syndrome (aHUS), for which diagnostic criteria were created. While TTP can present with both congenital and acquired ADAMTS13 deficiency, most cases involve acquired deficiency, in which anti-ADAMTS13 autoantibodies are involved. Therefore, plasmapheresis is the firstline treatment for acquired TTP. The objectives of plasma-pheresis are ADAMTS13 replenishment; removal of anti-ADAMTS13 antibodies; and removal of unusually large von Willebrand factor multimers (UL-vWFM), which are multimers composed of a hemostatic factor called von Willebrand factor. For HUS, plasmapheresis has not been established as effective and is used primarily as supportive therapy. Plasmapheresis is also used for aHUS induced by complement system abnormalities; however, due to the diverse etiology of aHUS, the efficacy of plasmapheresis for this purpose has not been established. Drug-induced TMA includes TTP caused by production of immunological autoantibodies against ADAMTS13 associated with ticlopidine and other antiplatelet drugs; for this form of TTP, plasmapheresis is effective. On the other hand, calcineurin inhibitors such as cyclosporine and tacrolimus are not associated with ADAMTS13 deficiency; these drugs considered to cause aHUS, which primarily induces vascular endothelial injury without decreasing ADAMTS13 activity, for which plasmapheresis is often ineffective. Many cases of drug-induced TMA are considered to present with a pathology resembling that of aHUS; however, the detail mechanism of drug-induced TMA remains poorly understood. Anticancer drugs that induce TMA include mitomycin C, cisplatin, bleomycin, gemcitabine, pentostatin, and sunitinib. Although plasmapheresis is combined with antiplatelet drugs and steroids to treat TMA, there is no established treatment. The present draft examines the efficacy of plasmapheresis for anticancer drug-induced TMA. ## Commentary In regard to the efficacy of plasmapheresis for mitomycin C-induced TMA, a case series of 4 patients [bib_ref] Plasmapheresis and antiplatelet agents in the treatment of the hemolytic uremic syndrome..., Chow [/bib_ref] reported the results of antiplatelet drugs ? plasmapheresis (3-4 L) administered 5-7 times over 1-2 weeks. Two patients demonstrated rapid improvement in platelet count, red blood cell count, and other hematologic parameters, as well as a tendency toward recovery of renal function within 6 weeks. Another patient continued to demonstrate decreased renal function following plasmapheresis; however, over the following C 4 months, renal function gradually improved. The last patient, despite demonstrating an increase in platelet count following plasmapheresis, did not show improvement in renal function and subsequently died. No relationship was demonstrated in these patients between overall mitomycin C dose and TMA onset; thus, no definitive conclusion was reached about the usefulness of plasmapheresis. In some cases, plasmapheresis is combined with antiplatelet drugs (e.g., dipyridamole and sulfinpyrazone) or hemodialysis (conditions unknown); therefore, the effects of plasmapheresis monotherapy are difficult to assess. In regard to cancer-associated HUS, a cross-sectional study of patients in a national registry with hematocrit B 25%, platelet count \ 10 9 10 4 lL, and serum Cr C 1.6 mg/dL (accounting for 99% of patients receiving mitomycin C and 68% of patients receiving 5-FU) [bib_ref] Cancer-associated hemolytic-uremic syndrome: analysis of 85 cases from a national registry, Lesesne [/bib_ref] found that of the 37 patients who underwent plasmapheresis, 11 patients (30%) responded to treatment, while 26 patients (70%) either did not respond to treatment or worsened. In a case series of 12 patients who developed TMA following mitomycin C-containing chemotherapy regimens [bib_ref] Carcinoma-associated hemolytic-uremic syndrome: a complication of mitomycin C chemotherapy, Cantrell [/bib_ref] , all patients demonstrated renal failure at the time of diagnosis; although 2 of these patients demonstrated low serum Cr values of 1.8 mg/dL and 2.7 mg/dL, the remaining 10 patients demonstrated serum Cr values of 3.4-9.6 mg/dL. Six of these patients underwent 2 L plasmapheresis 3 times over the course of 1-2 weeks while also receiving antiplatelet drugs or steroids. However, only 1 of these patients responded to plasmapheresis; this patient was also receiving steroids, azathioprine, and dipyridamole. In a cross-sectional study of breast cancer patients, plasmapheresis was performed 2-49 times (median 46 times) to treat TMA which had developed following high-dose chemotherapy with cyclophosphamide, cisplatin, and carmustine ? autologous bone marrow stem cell transplantation [bib_ref] Thrombotic microangiopathy as a complication of high-dose chemotherapy for breast cancer, Fisher [/bib_ref]. High-dose chemotherapy was performed for 581 patients, 15 of whom (2.6%) developed TMA; 4 of these patients survived. Of the 15 patients who developed TMA, 12 underwent steroid therapy ? plasmapheresis. Survival following TMA diagnosis was 2-76 days (median 41 days); 3 of the 4 survivors had undergone plasmapheresis a mean 50 times. In a case series of 9 patients who developed TMA among a total of 2,586 patients receiving gemcitabine [bib_ref] Gemcitabine-associated thrombotic microangiopathy, Humphreys [/bib_ref] , the median time to development of TMA in the 9 patients was 8 months (3-18 months) following a total gemcitabine dose of 19.2 g/m 2 (9-56 g/m 2 ). Six of the patients survived, while 3 died. Of these 9 patients, 5 underwent plasmapheresis. Among these 5 patients, 2 died, while the other 3 developed chronic renal failure; of these latter 3 patients, 2 required dialysis. Of the 3 patients whose renal function recovered, none underwent plasmapheresis; however, the report does not explain the details of this recovery. [fig] Yuko: Kitagawa, M.D., Ph.D., F.A.C.S. Chairman of Board of Directors, Japan Society of Clinical Oncology Professor and Chairman, Department of Surgery, Keio University School of Medicine [/fig] [fig] Figure 1: Simple inulin clearance method. 1) Complete urine collection 45 minutes after initiating inulin administration. Blood collection during urination. 2) Urine sampling upon urge to urinate at approximately 60 minutes of urine collection. Blood collection during urine sampling. 3) Accurate recording of urine collection time. [/fig] [table] Table 1: Assessment and definitions of overall evidence strength in systematic review A (Strong): Strong confidence in effect estimates B (Moderate): Moderate confidence in effect estimates C (Weak): Limited confidence in effect estimates D (Very Weak): Almost no confidence in effect estimates of interests associated with business-academia collaborations are managed properly in compliance with the Policy of Conflict of Interest in Clinical Research adopted by academic societies related to internal medicine. [/table] [table] Table 4: Examples of anticancer drug-induced AKI (includes only anticancer drugs covered by insurance in Japan) Kidney Int. 2015;87:909-17, Clin J A Soc Nephrol. 2012;7:1713-21.Ó [2012] Modified from the American Society of Nephrology [/table] [table] Table 5: Dose reduction methods for major anticancer drugs in patients with decreased renal function CAPD: continuous ambulatory peritoneal dialysis, CG: Cockcroft-Gault [/table] [bib_ref] Tumour lysis syndrome: new therapeutic strategies and classification, Cairo [/bib_ref]	None	https://link.springer.com/content/pdf/10.1007%2Fs10157-017-1448-z.pdf	None
49025c0b5da183b812a4d6cd72f37aeeaf98f230	pubmed	The Saudi Clinical Practice Guideline for the treatment of venous thromboembolism	The Saudi Clinical Practice Guideline for the treatment of venous thromboembolism ## Question 1: should home treatment versus hospital treatment be used for patients with acute dvt of the leg? The summary of evidence on this question was based on a systematic review by Othieno et al.The updated literature search identified one new study conducted in KSA by Algahtani et al.This new study was included in the updated meta-analysis. The summary of findings is provided in.Benefits and harms of the option. The meta-analysis of 7 trials )total of 1769 participants( found moderate quality evidence that home treatment of DVT reduces recurrent VTE )risk ratio Values and preferences. The SEP judged that the values and preferences may vary. Some patients and carers would prefer for the patient to be admitted. Some others would prefer to be discharged if they know they could easily access a physician. Resource use. Health economic evaluations in settings different from that of KSA conclude that home treatment is cost-saving of approximately US$500-US$2500 per patient.Other considerations. The SEP judged home treatment of DVT to be acceptable to physicians and the Saudi MoH. However, they were concerned with the lack of ultrasound service after 4:30 P.M. and on weekends in emergency rooms. Implementation considerations. The SEP thought that there is a need to have ultrasound services to diagnose DVT available 24 hours per day 7 days per week, and to have 24-hour clinic coverage for these patients )for example, thrombosis services -Interpretation of strong and conditional )weak( recommendations. ## Implications ## Strong recommendation conditional (weak) recommendation for patients Most individuals in this situation would want the recommended course of action and only a small proportion would not. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences. Most individuals in this situation would want the suggested course of action, but many would not. ## For clinicians Most individuals should receive the intervention. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator. Recognize that different choices will be appropriate for individual patients and that you must help each patient arrive at a management decision consistent with his or her values and preferences. Decision aids may be useful helping individuals making decisions consistent with their values and preferences. ## For policy makers The recommendation can be adapted as policy in most situations Policy making will require substantial debate and involvement of various stakeholders. CI -confidence interval, LMWH -low molecular weight heparin, PE -pulmonary embolism, RCT -randomized controlled trial, RR -risk ratio, UFH -unfractionated heparin, The basis for the assumed risk )for example, the median control group risk across studies( is provided in footnotes. The corresponding risk )and its 95% CI( is based on the assumed risk in the comparison group and the relative effect of the intervention )and its 95% CI(. RCTs included recruited patients "whose home circumstances were adequate", † RCTs included patients with leg DVT. They excluded those with PE and pregnant women, ‡ Four RCTs had partial hospital treatment for some participants in the home group: Levine et alCI -confidence interval, ITT -intention to treat, RRrisk ratio, The basis for the assumed risk )for example, the median control group risk across studies( is provided in footnotes. The corresponding risk )and its 95% CI( is based on the assumed risk in the comparison group and the relative effect of the intervention )and its 95% CI(, The 2 trials included patients at low risk: low risk on clinical prediction rule ) Monitoring and evaluation. The SEP proposed monitoring the percentage of patients treated at home versus hospital and studying the impact of implementing this recommendation on outcomes and costs. The recomendation for question one is presented in. ## Question 2: should early discharge versus standard discharge be used for patients with acute pe? The summary of evidence is based on a systematic review Otero et al,and a more recent trial by Aujesky et al.The updated literature search identified one new systematic review by Piran et al,which did not identify any trial not already considered. The summary of findings is provided in.Benefits and harms of the option. The meta-analysis of 2 trials )total of 471 participants( found moderate quality evidence of possible increase in VTE )RR 1.23; 95% CI: 0.25-6.03( and major bleeding )RR 2.74; 95% CI: 0.45-16.71However, any absolute increase in these outcomes would be of small size given the low baseline risks )2 more VTE per 1000 and 8 more major bleeding per 1000 over a 3 months period(. Observational data confirm low risk of recurrent VTE in patients with low risk acute PE.Values and preferences. The SEP judged that values and preferences may vary. Some patients and carers would prefer for the patient to be admitted. Some others would prefer to be discharged if they know they could easily access a physician. Resource use. We did not identify any studies directly related to PE, so the SEP relied on indirect evidence related to DVT. As stated earlier, health economic evaluations in both KSAand non-KSA settingsconclude that home treatment of DVT is cost-saving. Other considerations. The SEP advocated assessing PE severity using a validated tool such as the Pulmonary Embolism Severity Index.The SEP also judged that the acceptability of early discharge might vary by physician. Some of them might be apprehensive to releasing patients early given the gravity of the condition. Implementation considerations. Early discharge is potentially feasible but requires 24-hour clinic coverage for the patients )for example, thrombosis services(. Monitoring and evaluation. The SEP proposed auditing the percentage of patients discharged early versus late and studying the impact of implementing this recommendation on outcomes and costs. The recommendation for question 2 is presented in. Discussion. The purpose of this clinical practice guideline is to provide guidance on selected clinical questions related to the management of acute DVT and PE, and the best and safe management settings. This guideline is a part of a larger initiative of the Saudi MoH aiming at providing evidence-based guidance for clinicians and reducing variability in clinical practice in This guideline was the first from KSA and the region on this topic. As it took into consideration the local context, it has higher chance of acceptance by HCP working in the area, which may improve health care quality and promote efficient use of the available resources. The recommendations in this guideline shared similarities with other recommendations. For example, the 9th Edition of Antithrombotic Therapy by the American College of Chest Physicians recommended initial treatment at home over treatment in hospital for patients with acute DVT of the leg, and who had adequate home circumstances )namely, strong recommendationThe European Society of Cardiology guideline stated that early discharge and continuation of treatment at home should be considered for patients with acute low risk PE if proper outpatient care and anticoagulant treatment can be provided.The 9th Edition of Antithrombotic Therapy suggested early discharge over standard discharge in patients with low risk PE and whose home circumstances are adequate )namely, conditional recommendationIt should be noted that this guideline did not address all the questions related to VTE treatment. For instance, the use of direct oral anticoagulants for the initial management of VTE is not addressed. Based on recent randomized controlled trials, the 2014 European Society of Cardiology guideline on acute PE treatment recommended the new direct oral anticoagulants as alternatives to the combination of parenteral anticoagulation with a vitamin K antagonist.In addition, the SEP suggested local research on the values and preferences of the Saudi population regarding VTE in general, its treatment with the various modalities and the potential side effects from such treatments. The SEP advocated the performance of studies that compare the impact of early versus late hospital discharge on various outcomes, such as recurrent VTE, post-thrombotic syndrome, bleeding and mortality, and the effectiveness of newer oral anticoagulants versus the different heparins. In conclusion, this Saudi clinical practice is on outpatient versus inpatient VTE management. The SEP suggests home treatment over hospital treatment for patients with simple acute DVT, and suggests early discharge over late discharge for patients with low risk acute PE.	None	https://www.smj.org.sa/index.php/smj/article/download/smj.2015.8.12024/7529	Venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE) is commonly encountered in daily clinical practice. After diagnosis, its management frequently carries significant challenges to the clinical practitioner. Treatment of VTE with the inappropriate modality and/or in the inappropriate setting may lead to serious complications and have life-threatening consequences. As a result of an initiative of the Ministry of Health of the Kingdom of Saudi Arabia, an expert panel led by the Saudi Association for Venous Thrombo-Embolism (a subsidiary of the Saudi Thoracic Society) and the Saudi Scientific Hematology Society with the methodological support of the McMaster University Guideline working group, this clinical practice guideline was produced to assist health care providers in VTE management. Two questions were identified and were related to the inpatient versus outpatient treatment of acute DVT, and the early versus standard discharge from hospital for patients with acute PE. The corresponding recommendations were made following the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach.
86e7a5783863d6570b099fe577a93614278c5b5f	pubmed	Evolving consensus on managing vitreo-retina and uvea practice in post-COVID-19 pandemic era	Evolving consensus on managing vitreo-retina and uvea practice in post-COVID-19 pandemic era The COVID-19 pandemic has brought new challenges to the health care community. Many of the super-speciality practices are planning to re-open after the lockdown is lifted. However there is lot of apprehension in everyone's mind about conforming practices that would safeguard the patients, ophthalmologists, healthcare workers as well as taking adequate care of the equipment to minimize the damage. The aim of this article is to develop preferred practice patterns, by developing a consensus amongst the lead experts, that would help the institutes as well as individual vitreo-retina and uveitis experts to restart their practices with confidence. As the situation remains volatile, we would like to mention that these suggestions are evolving and likely to change as our understanding and experience gets better. Further, the suggestions are for routine patients as COVID-19 positive patients may be managed in designated hospitals as per local protocols. Also these suggestions have to be implemented keeping in compliance with local rules and regulations. The global Corona virus disease 2019 (COVID-pandemic has brought in several unprecedented challenges that the world has no experience in dealing with. The All India Ophthalmological Society (AIOS) -Indian Journal of Ophthalmology (IJO) recently published a consensus statement on preferred practices during the COVID-19 pandemic and suggested that these general practices be followed during the post-lockdown period as well.However, as the super specialty clinics are gearing up to resume their practices, there are lot of queries being generated that need to be addressed both by evidence and consensus. The pandemic has highlighted geopolitical differences in management and screening protocols. Thus, although there are guidelines being issued by several international ophthalmic societies, it may not be possible to apply them uniformly to a country like India with social and economic constraints.Moreover, the practice patterns may be influenced by factors like the size of facility, number of patients being handled, strength of the staff and facilities available besides their capability and preparedness to handle COVID-19 positive patients. The present preferred practice patterns have been formulated by a leading group of experts constituted from the representatives of Vitreoretinal Society of India (VRSI), Uveitis Society of India (USI), iROP and from major institutes and the IJO leadership. These practice patterns are being formulated to help restart vitreo-retinal services amongst tertiary institutions, corporate and group practices as well as individual eye clinics. The suggestions are for routine patients as COVID-19 positive patients may be managed in designated hospitals as per local protocols. # Methods This consensus was developed in continuation to the previous publication by Sengupta et al.The experts included the representatives of VRSI, USI, iROP as well as the retina chiefs from major centres in India. The base document was prepared by the allocation of sections to different experts. The paper was then compiled and reviewed by the entire committee. In case there was any difference of opinion, a mutual consensus was reached by discussion amongst all the experts. The final version of the document was approved by all the authors. ## Practice guidelines for vitreo-retina services i. tele-counseling for triage and appointments The group encourages the use of tele-consults to maintain communication with patients and provide staggered appointments to avoid crowding in the clinic. With regard to new patients, this can also be used to fill up patient details, prior to patient's arrivals in the clinic. Each clinic can design a flow chart to suit their practice to direct patient flow. A sample flow chart is shown in. Encourage tele-consultation to prioritize patients as well as reduce walk-ins. Any patient directly asking for a retinal consultation may need to be questioned further to ascertain the urgency of the condition. A trained assistant/fellow can be given the responsibility of talking to the patient to see if they need to be seen urgently. The following list is to help prioritization for those with large number of patients to avoid the overcrowding. The clinics with lesser number of patients, however, can see patients who have been listed under semi-urgent or delayed appointments: A. Urgent: The following complaints would need to attended on urgent basis at the earliest: i. Sudden or rapid loss of vision ii. Acute onset Flashes, floaters, iii. Painful loss of vision, iv. Recent onset metamorphopsia/reading difficulty. v. Conditions needing urgent surgerye.g., open globe injuries, rhegmatogenous retinal detachment (RRD), recent onset macular tractional retinal detachment (TRD) or combined RD, endophthalmitis, recent onset submacular haemorrhage, nucleus drop or retained cortical matter with secondary glaucoma as per guidelines of AIOS-IJO.vi. New cases of retinoblastoma, ocular tumours or Retinopathy of Prematurity (ROP) vii. Conditions where early surgery should be considered including bilateral vitreous haemorrhage, vitreous haemorrhage in one-eyed patient etc. Or any other condition where treating physician feels the urgency to see the patient. B. Semi-urgent Appointments The next priority would be the patients with following complaints: i. Patients with diabetes mellitus with complains of slow onset of vision loss. ii. Any patient who has been treated with injections recently elsewhere/operated elsewhere seeking consultation. iii. Any retina case referred by another colleague can be considered as semi urgent and given an appointment. iv. Patients receiving injections for neovascular age related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). v. Patients receiving injections for non AMD choroidal neovascular membrane (CNV) vi. Retinal Vein Occlusion (RVO) and Diabetic Macular Edema (DME) patients needing frequent injections, and mono-ocular patients. vii. Patients operated within the last 3 months and who have silicone oil will need to be reviewed soon. viii. Patients on anti-glaucoma medications also need to be seen early. C. Delayed Appointments: The following patients can be given appointments later, depending upon the slots available and given tele-consult in the meantime: i. All patients who have been receiving regular injections but are stable ii. Routine follow up for wet AMD, DME and RVO iii. Patient who is stable and has not needed injection in the last visit iv. Regular patients with Non proliferative diabetic retinopathy (NPDR) and Proliferative Diabetic Retinopathy (PDR stable) post Laser/surgery v. Stable post RD surgery. Patients who have maintained stable vision with infrequent injections are candidates for telephonic consultation. COVID-19 testing is not mandated for OPD examination, Lasers or Intravitreal injections. ## Ii. techniques of retinal examination A. Home versus clinic dilation Dilation at the hospital may increase the possibility of spread of infection during a pandemic due to: 1. Inadvertent spread by the assistant tasked to instil the eye drops if the dropper or the assistant's fingers come in contact with an infected person 2. Patients are usually clustered at the dilation area of the hospital which increases their time in hospital and risk of exposure. This risk can be mitigated by home dilation. Revisit Patients: Home dilation is thus advisable for review patients where information regarding prior history of allergy to dilating drops and history of systemic hypertension can be obtained from their case records. An electronic prescription detailing the above may be given. The patient and family can preferably be counselled about the proper technique through appropriate visual aids such as a video or a graphic. New Patients: In new patients and in those where home dilation is not possible, dilation at the hospital is necessary, we recommend following precautions: 1. The assistant should be wearing gloves and a face shield and disinfect her/his hand appropriately after each patient 2. Non-touch technique of applying the dilating drops -requesting the patient to retract the lower eye lid and extending the neck, instead of the assistant retracting the lid or touching the head of the patient []. In those unable to self-retract the lid, a disposable cotton tipped applicator may be used to retract the lid, taking care not to touch the end that has come in contact with the patient]. The cotton tipped applicator is then disposed appropriately 3. Dilation should be performed in an airy, open area, the patients being seated with distancing norms being followed.We can also consider dilating the patient in the clinic area itself to avoid unnecessary movement of the patient. B. Slit-lamp examination All precautions regarding the breath shield disinfection of slit lamp and lenses to be followed as per AIOS-IJO recommendations.Indirect ophthalmoscopy may be preferred. In case of slit lamp biomicroscopy, the lenses used for retinal examination can be covered with cling film that can be cleaned easily without damaging the lens surface. ## Iv. retinal lasers A. Indications and priority While the indications for laser treatment would remain same, we may have to prioritise them in practices that are overloaded and wish to reduce the number of patients on any given day. We should prioritise them, as captured intoo, in the following way:Early lasers to be done on priority basis 1. Active Proliferative Diabetic Retinopathy (PDR) 2. ROP laser 3. Retinal tears or breaks (e.g., Horse shoe tears) 4. Laser barrage wherever required e.g., macula on RD, sub clinical RD 5. Extra foveal CNVM. Lasers that can be delayed to next available appointments 1. Diabetic macular edema 2. Macular edema of other causes. In patients with DME, Anti vascular endothelial growth factor (VEGF) injections may be preferred over laser photocoagulation and photo dynamic therapy (PDT) laser as well, wherever indicated. B. Laser delivery modes There are two modes of laser delivery: a) Contact delivery system-slit lamp delivery systems-single spot or multispot laser and b) Non-contact laser delivery -Indirect laser delivery system (ILO). The following consensus could be reached amongst experts on the preferred mode of delivery: 1. Prefer non-contact laser delivery system over slit lamp for non-macular lasers 2. If non-contact indirect laser delivery system is not available, then multispot laser is preferred over single spot laser in order to make the process faster with lesser number of sittings 3. Avoid sharing of drops such as Paracaine 1% eye drops and prefer to instil a drop of betadine in the cul-de-sac of the patient after the removal of the contact lens 4. The laser contact lenses or 20 dioptre lens to be washed with soap and water after every use or dip in sodium hypochlorite (0.5%) solution. ## V. intravitreal injections (ivi) The guidelines for Intravitreal injections during these unprecedented COVID-19 times are only suggested where high volume practices have to use preferences. These can be modified based on the patient load in each health care facility and the presumed transmissibility of the virus in the region. The prioritization of these, as encapsulated in, can be done as follows:A. Emergent Need for IVI (inject within 1 week) In addition to the standard practices being followed in the post-COVID-19 era, few additional considerations are: 1. All our protocols for Intravitreal injections should be in sync with the measures being taken by the authorities and the consensus statement on preferred practices during COVID-19 pandemic by AIOS2. The injections should be given with patient wearing a mask, draped and the person injecting should wear gown, N95, face shield (Personal protective equipment -PPE) or as per their institute's protocol 3. Between the injections 10-15 minutes time can be given during which scrubbing can happen 4. The injections must not be loaded and kept on the trolley in advance for all the Intravitreal injections scheduled that day 5. During the pre-COVID-19 times, numerous institutions have created separate areas (following all norms) for Intravitreal injections in the OPD to prevent disruption of OT workflow. If this is not possible, intravitreal injections should be given in the operation theatre 6. Longer acting drugs maybe preferred to reduce hospital visits. ## Follow-up after intravitreal injections The main aim of follow-up is to ensure that the patient does not develop any post injection intraocular inflammation. Ideally, the patient may be called for review in 24-72 hours. However, in these COVID-19 times, patient can be asked to give a call next day. In case the patient is comfortable, he/she can be called after 4-8 weeks depending on the drug used and the disease process. Patient should also have the freedom to connect with the health care facility in case of any problem in-between. ## Vi. cleaning and maintenance of equipment and lenses: special considerations Contact Lenses for Laser and Examination: As mentioned previously, these should be avoided. If one needs to use them, the contact surface of the lens washed with detergent and running water for 20 seconds prior to applying it on the cornea, repeating the washing after the examination. The lens can be disinfected by immersing the contact surface in 0.5% sodium hypochlorite for 10 minutes after washing. Laser lenses can be covered with cling film that can be removed at the end of procedure []. Lens for Indirect Ophthalmoscopy and slit lamp biomicroscopy: The condensing lens is washed with soap and water or wiped with 95-99.9% isopropyl alcohol between patients. Please refer to manufacturer's instructions for sterilization regarding the time of contact and also some may prohibit the use of alcohol. To minimize the risk of damaging the condensing lens, Shanmugam et al. have modified the lens Slit Lamps, Lasers, OCT and OCTA: Protecting the lens of these equipment from droplet contamination can be done by wrapping a cling film over the lens. The surface of the film is cleaned with an alcohol based disinfectant or is changed after every patient or the lens of the machine may be cleaned by the technique recommended by the manufacturer. Laser front lens too can be covered with cling film that allows reasonable quality of placement of laser burns []. Fundus Cameras: Cling film causes compromise in image quality and thus fundus cameras can be left uncovered while the rest of the device is covered with cling wrap to allow for more frequent cleaning. The cleaning of the forehead band, chin rest, lens, the handles and the table which comes in contact with the patient has to be done with alcohol wipes routinely in between cases. Touch Screen Devices: All touch screen devices also function well with a cling wrap B scan probe: Since it is a contact procedure, please clean the probe with alcohol wipes between scans. A cap and mask should be worn by the patient while the procedure is being done with minimal or no patient contact. Electrophysiology: Cleaning of equipment between patients, use of disposable electrodes and non-contact lens type. ## Vii. paediatric retina: special considerations Virtually all pediatric examinations and procedures are potential aerosol generating procedures (AGPs), therefore the utmost care should be taken while managing these children. Few extra precautions include:1. Only one person may be allowed to accompany the child for consultation 2. Since all children may not hold a mask on the face, social distancing becomes even more important 3. It is recommended to close the playing area for children in the OPD All the soft toys must be removed from the office as they can serve as potential fomitesUnlike SOPs for other retinal conditions, Retinopathy of Prematurity (ROP) screening and treatment has some critical differences with respect to delay resulting in permanent blindness and medico-legal considerations for failing to execute the well-defined protocols. To address the issue of ROP management, the Indian Retinopathy of Prematurity (iROP) Society, has formulated guidelines in March 2020,with the caveat that it is dynamic and requires to be customized for regional settings and in concurrence with evolving guidelines for COVID-19 management issued by the Government of India and other professional bodies. With the aim of reducing the number of screening visits and restricting them to have the highest yield of detection of vision threatening ROP, the following modification to the screening schedule are suggested and summarized in. Additionally, the following points may be kept in mind while dealing with these preterm babies: 1. Mothers with infants must maintain social distance while waiting for dilatation 2. The mother places the infant on a sanitized surface or table and moves more than 6 feet before the team approaches and handles the baby. The procedure is repeated for the next baby. 3. During counseling, social distancing norms must be maintained 4. Indirect ophthalmoscopy with 20 or 28 D lens or wide-field ROP cameras can be used and sanitized between babies as per the standard guidelines 5. Infant speculum and depressor if used must be single use or sanitized/autoclaved between babies 6. Tele-medicine must be encouraged. ## Rop treatment modifications The modifications to ROP treatment (outside early treatment for ROP (ETROP)) during this period are detailed in. Wherever possible, PPE prescribed by the ICMR must be used. ## Ix. intraocular tumours and ocular metastasis 1. Prior assessment of fundus photographs and imaging studies in cases of suspected malignancy or an establish case of treated intraocular tumour can be assessed over a video consultation for an initial assessment, and thereby help in reducing the consultation time when the patient is physically present in the clinic ## Pa t i e n t s w i t h m e t a s t a s i s t o t h e e ye m a y b e immunocompromised. These cases should be evaluated on an individual basis while assessing their visual potential for considering ocular treatment 3. Cases of intraocular lymphoma may continue to receive systemic chemotherapy and be brought in the clinic for periodic intraocular injections. Alternately, this can be arranged with the local retina specialist. Also, for such patients, converting the treatment to external beam radiation therapy (EBRT) may be considered. However, new patients suspected of vitreoretinal lymphoma must be promptly seen 4. EUA for newly suspected retinoblastoma and enucleation for retinoblastoma shall be performed within a week 5. EUA for children with active retinoblastoma undergoing treatment must follow continued care every 3-4 weeks. Systemic chemotherapy and focal consolidation/local ocular treatment can continue 6. EUA for children at high risk for retinoblastoma due to family history or known RB1 mutation or with stable Can delay the next screening by an additional 1 week from the current guidelines disease, who received treatment within the past 6 months can be performed within 1-2 months 7. Intraocular injection of chemotherapy agents for high-grade neoplasia (e.g., Rituximab/Methotrexate for Intraocular lymphoma) can be performed within 1-2 months 8. Systemic chemotherapy for adult patients with ocular metastasis may continue with the consultation of medical Oncologist. ## X. vitreo retinal (vr) surgery in post covid era It is emphasized that best practice protocols in VR surgery will be influenced by the practice situation of each facility and surgeon. These suggestions are advisory in nature and aim to provide means to achieve safe care in the best manner possible. 1. Preoperative COVID-19 Testing: Due to the difficulties around obtaining COVID-19 tests, the yield time and the presence of asymptomatic carriers, it is unlikely that every infected patient will be detected preoperatively. Hence, each surgeon and hospital administrator would be well advised to assume that every surgical patient is a potential COVID-19 spreader and the following practice patterns devolve from this premise. - Emergency surgeries may be undertaken without mandating a COVID-19 test universally. A very strong suspicion, however, based on history or symptoms may prompt an urgent referral to a COVID-19 designated center - Definitively proven COVID-19 (Reverse transcription polymerase chain reaction (RT PCR)) positive patients should not be taken for ophthalmic surgery in non-designated COVID-19 centers - Asymptomatic patients, RT PCR negative patients and those who have not had the test done -all these patients are to be considered as potentially COVID-19 positive and all due precautions should be taken during surgery - Centres may consider mandating COVID-19 tests preoperatively in patients who have been in quarantine or have had people in their premises who have been in quarantine in the past one month. 2. Prioritization of Surgeries: The urgency of surgery should be an ophthalmologists' discretion taking into consideration the patient's clinical situation and the prevalent COVID-19 zone status and circumstances at that given time in their locale. Needless to say, emergency cases would take precedence and have to be prioritized for surgery at the earliest. The priority list for VR surgeries is detailed in, adapted from the recent AIOS -IJO publication. ## Operation theater engineering Since VR surgeries are prolonged, extra caution maybe required as the time of exposure to the surgeon and team is prolonged. a. OT designation and flow: In Multispecialty hospitals, the designated surgical OT will be earmarked by the Hospital administration. In ophthalmic hospitals and clinics, the facility should designate a donning and doffing area for each OT. The doffing area should adjoin the OT but not be a considerable distance to avoid walking outside the OT in potentially contaminated garments. The donning of protective gear could be done in the usual washing area but will need adequate space. In case of surgeries under GA, the surgeon should not enter the OT until the patient is fully stabilized on the anesthesia circuit and the surgical team is adequately protected.b. OT Air conditioning: i. It is not a practical solution to switch off air conditioning in our environment. The consensus of this committee is that air conditioning should be operational during surgery with increased rate of air exchanges and increased ratio of fresh air mixing in the Air Handling Units (AHUs). Negative Pressure OTs are not considered mandatory and Positive Pressure OTs may continue to be used if it is not technically possible to convert to a negative pressure facility ii. If positive pressure air-conditioning is continued, care should be taken to switch off the air-conditioning momentarily at times of patient entry and exitiii. Negative pressure OTs can be created within existing facilities by use of damper, altering fan speeds and various other engineering modifications. It is understood that this will be an adhoc modification that can only be tested up to the extent of a smoke test to confirm the presence of negative pressure in the OT. If an exhaust system is added, the exhausted air should be expelled after passing through a high-efficiency particulate air (HEPA) filter.4. Patient-related Protocols: a. Patients being operated should wear a surgical mask if being operated under local anesthesia. If the patient is uncomfortable, any device to keep the drapes away from the nose can be used. Under General anesthesia, the respiratory tract is isolated by the anesthesia circuit. b. It is all the more critical, in this COVID-19 period, to mandate that 5% Povidone iodine be instilled in the conjunctival sac 5-10 minutes before the surgery and also used for prepping. Povidone iodine is virucidal and disinfects the ocular surface and conjunctival cul-de-sac in 15 seconds.5. Personal protective equipment: a. The donning sequence differs significantly from that used for usual PPE wear in medical wards and clinics. The change in sequence is necessitated by the need to wear the N95 mask, boot covers and goggles before hand washing, so as to maintain sterility b. It is evident that coveralls are significantly difficult to wear in a sterile manner, therefore it is suggested that Gowns be worn for surgery, along with N95 masks, goggles and a hood and boot covers. Face shield are not easily compatible with surgery through a microscope; therefore, goggles are preferred and must be worn before the hood so that the hood fits nicely around the goggles and does not fall over the eyes. If the hood is worn first, it tends to ride over the eyes and the goggles then do not push it back. If any of the components of the PPE mentioned above are unavailable, a coverall can be used, and a sterile gown worn over it c. The doffing sequence is almost identical to standard protocols, but goggles can be reused after decontamination and N95 masks if reused on the same day must not be touched or reworn between cases. If an N95 with a respiratory valve is worn, it may be covered with a surgical mask which may also decrease the contamination on its surface d. We are aware that some institutions may modify the PPE made available to the surgical team depending upon the perceived risk but urge that this be done with due deliberation after considering the consequences of inadequate protection. ## Sterilization protocols and re-use practices: There is no need to alter conventional preset institutional protocols regarding sterilization of the instruments that ideally should comply with the manufacturer's recommendations. - It is preferable not to re-sterilize or reuse residual silicone oil and perfluorocarbon liquids - It is advisable to use a fresh bottle of Ringer Lactate or balanced salt solution (BSS)/BSS Plus for each case Sterile surgical consumables (trocar-cannulas, cutters, tubings, cassettes, endoilluminator, endolaser probes etc.) to be used in each case undergoing retinal surgery and all precautions to prevent cross-infection amongst consecutive surgical patients need to be stringently followed - It has been suggested that using Ultraviolet (UV) light for 15 minutes after cleaning the OT, between cases, may have a beneficial effect. 7. Surgical technique modifications: a. Draping: It is important to ensure that the draping is done properly. The edge of the drape should be adequately and properly stuck around the eye to create watertight sealing. This will minimize chances of aerosol dispersion from nose and mouth b. Post draping, the betadine maybe instilled into the conjunctival sac by using the syringe without cannula to minimize aerosol generation c. Valved vs. Non-valved cannulas: It is preferable to use valved cannulas as much of the fluid spills and bubbling during fluid air exchange may be avoided. Non-valved cannula system can cause spillage of fluid or air over the surgeon and assistant(s) especially with IOP controlled machines or a high bottle height. At present there is no substantial evidence to suggest presence or absence of virus in intraocular fluids. Hence, it is advised to avoid or minimize contact with intraocular fluid as far as possible and valved cannulas are recommended. - If a valved cannula system is not available, reduce the bottle height or intraocular pressure during instrument exchange to minimize sclerotomy leakage. - Preferable to use viscoelastics over irrigation of eye to keep cornea wet. - Non-contact viewing systems to be preferred over the contact systems. d. Diathermy: A known source of aerosolization, any step needing diathermy should be considered carefully and a suction tubing used to evacuate the smoke from the surgical fielde. Scleral Buckle vs. Vitrectomy: Scleral buckling involves more tissue contact and diathermy and would therefore be considered theoretically more of an aerosol generating procedure than vitrectomy which takes place in a closed chamber. At present there is no substantial evidence of COVID-19 transmission through blood or body fluids. The choice of procedure should be dictated primarily by the eye condition including patient age and lens status. Importance to be given to time and minimal intervention when choices are even During a pars plana vitrectomy, the steps that merit care are prevention of fluid spill, prevention of high pressure bubbling at the ports or the flute needle during Fluid air exchange. This can be avoided by using active rather than passive aspiration. Minimize instrument exchanges as much as possible f. Experienced surgeons should do the surgeries whenever possible. Over time, as protocols are crystallized, trainee surgeons would be expected to also operate. 8. Resource management a. Due to the long hiatus and changed protocols, it is no longer advisable to operate more than one case at a time in one operation theatre b. Surgical camps should be deferred, and surgical times are likely to be prolonged due to the necessity to clean and decontaminate the OT after each surgery c. Also, expendables are likely to expire due to reduced caseloads and fresh supplies may not fructify due to broken supply chains. Therefore, inventory management at such a time assumes importance d. Extra items may be kept in in closed cupboards in the operation theatre to avoid a circulating nurse going back and forth to the instrument room. However, this will need to be balanced with keeping excess items in the OT which will result in all these extras being considered exposed ## Xi. financial impact of new sops There is a genuine fear of an increased expenditure that would need to be incurred for the new set of SOPs. Also the patient inflow may decrease due to fear of traveling or visiting the hospital, reduced financial resources in the post-COVID-19 economy and decreased health care capacity. This can be overcome by increasing the number of working hours to compensate for reduced number of patients seen per hour as per physician's discretion, use of electronic medical records with automation wherever possible, online prepayment portal and pre-registration through online portals or WhatsApp. The additional cost including sanitization, cleaning, providing 3-ply mask to patient and PPE as per guidelines to ophthalmologists has been calculated to be about Rs 88/patient. This includes the cost of sanitizer: Rs. 16/-(for patient and attendant) +Rs. 16/-for cleaning instruments +Rs. 16/-for cleaning floors and fomites +Rs. 40/-cleaning person salary. The cost of face shields (varies from Rs 75/-to 200/-), and goggles (100/-to 300/-) is a one time. The estimate of the added cost can be demystified and remove the fear in peoples' minds. Thus, the potential extra cost per patient is an estimated Rs. 88/-that can be added to the consultation fee with added precautions. This is then likely to be completely revenue neutral. These estimates are being provided as a useful yardstick and may be variable. ## Xii. telemedicine and artificial intelligence (ai) for retinal disorder screening: expanding role in post covid-19 era Telemedicine and artificial intelligence (AR) are two of the promising aspects of retina practice evolving in the recent years which can provide safer alternatives over conventional examination in various case scenarios in the post COVID-19 era.The utility of telemedicine has been well established for screening of DR, AMD and ROP.A wide variety of non-mydriatic fundus cameras have been in use with varying efficacy as far as image quality and field is concerned.In the current scenario, hospitals can promote more of screening through telemedicine in order to avoid congestion and unnecessary hospital visits at tertiary eye care centers. Depending on the available resources, hospitals can install suitable fundus cameras and arrange for online consultation with retina specialists. Non-mydriatic ultra-wide field cameras like Optos or Clarus can help detect a wide variety of retinal pathologies, apart from DR, ARMD and ROP, although cost can be a factor for their installation by general ophthalmologists.Tertiary eye care centers which lack ROP screening through telemedicine can establish the same based on highly successful existing models.A lot has been done in the recent past to explore the utility of AI in enhancing the efficacy of telemedicine. Conventional machine learning has facilitated recognition of abnormalities like macular edema, exudates, cotton-wool, microaneurysms, neovascularization on optic disk, drusens and geographic atrophy.Deep learning algorithms have brought higher sensitivity and specificity in diagnosing retinal pathologies with higher accuracy. However, most of them need validation in larger patient cohorts.Chatbot, which uses a field of AI called natural language processing, can be yet another way of bringing AI to our aid in the current scenario to avoid the burden of routine questions from patients' phone calls, and also to ease the task of triaging patients who need urgent visit at a retina clinic.It has the potential to resolve minor issues and complaints of many retina patients, who then need not make a hospital visit, once their queries are resolved on Chatbot. It can be developed by the individual hospitals with appropriate technical support on various available platforms and can cover a wide range of topics, right from the various ocular complaints suffered by the patient to the possible diagnosis and its seriousness. It also provides the necessary patient details as the patients answer to the questionnaires and the patients can be directed to online consultation or appointment, if the need be so, based on their response to the questionnaires. Consultation through video-conferencing can also be a useful way to re-assure post-operative patients and routine patients of retina clinic with minor issues.Recently, the government has given the guidelines for telemedicine making it all the more legal and also encouraging its use especially in this crisis period.XIII. Managing uveitis in post-COVID-19 era General ophthalmologists as well as uveitis specialists are now faced with the dilemma about the usage of steroid and immunosuppressive agents. There are no published guidelines so far regarding this. The following consensus is being accepted by the International uveitis study group (IUSG), International Ocular Inflammation Society (IOIS) and Foster Ocular Inflammation Society (FOIS) have jointly released an evolving consensus experience with uveitis at the time of COVID-19 infection (latest version April 3 rd 2020).Few specific points about Uveitis management: A. Anterior uveitis: Topical steroids may be started or continued at the discretion of the treating doctor B. Intermediate uveitis/posterior uveitis/panuveitis 1. Guidelines for a new patient of uveitis: - To prefer local therapy in the form of posterior sub-tenon triamcinolone or intravitreal dexamethasone implant over systemic corticosteroids - Intravenous methyl prednisolone is best avoided and one should prefer local therapy (periocular or intravitreal steroids) alone or in combination with lower doses of systemic steroids - Avoid starting high dose oral corticosteroids or immunosuppressants in high risk patients defined as the following: age ≥70 years, severe chronic lung disease (e.g., asthma, bronchiectasis, cystic fibrosis, chronic obstructive pulmonary disease (COPD), etc.), severe heart disease, CD4 count <200, history of diabetes/hypertension/ smoking/cardiovascular event - Any one-eyed patient or one with a vision threatening condition requiring the initiation of corticosteroids or immunosuppressants maybe started on the treatment at the discretion of the treating doctor and after evaluation by a physician - Strict vigilance has to kept on the blood counts of the patient with a special precaution to maintain white blood count is kept above >4000 per microliter. 2. The COVID-19 pandemic is not a contraindication for the initiation of immunosuppressants. Patients need to be explained regarding the additional risk of secondary infections at the time of start of the therapy including the following precautions: - Hand and personal hygiene. - Avoiding crowds and working from home - To have the face mask on at all times - If they are sick with fever, malaise then should contact the infection control specialist and if advised then to consider stopping the therapy. 3. Guidelines for uveitis patients on maintenance therapy a. On Corticosteroids - Patient is stable then one may consider a gradual taper and stopping of the drug or maintain at a low dose <10 mg/day. However if there is a high risk of recurrence at it might be vision threatening then one may continue at the same dosage (as per the discretion of the treating doctor) - Strict monitoring of blood sugar and blood pressure is recommended - In case of any illness or symptoms suspicious of COVID-19 then to be referred to an infection control clinic - In a case of recurrence, then to prefer local therapy (sub-tenon or intravitreal) over systemic corticosteroids. b. On Immunosuppressants i. Patient with systemic immunosuppression without sign of COVID-19 infection or negative with COVID-19 test: - If the patient has been stable for the last two visits and one was considering the stoppage of the drugs then it may be done at the discretion of the treating doctor however they do not need to be discontinued due to COVID-19 pandemic - In addition, they should strictly follow the precautions like a) staying at home as much as possible b) practice social distancing approximately 6 feet from other individuals c) wearing a mask d) washing hands frequently with soap or alcohol based sanitizer. If such patients feel sick they should contact their doctor immediately - Patients on immunosuppressants are already primed to monitor their blood counts regularly, however we may need to reiterate the importance of the same again - Strict vigilance has to kept on the blood counts of the patient with a special precaution to maintain white blood count is kept above >4000 per microliter and tele consultation maybe useful for the same - A patient on immunosuppressant if develops symptoms suspicious of COVID-19 infection, then needs to be referred to infection control specialist and if they feel necessary to stop the ongoing medication, it may be done at their discretion. ii. Patient with systemic immunosuppression in either confirmed COVID-19 infection or clinical signs' of COVID-19 infection - These patients should not be denied of treatment. If the patient is asymptomatic, they may continue with immunosuppressive agents along with monitoring of blood counts under the close monitoring of infectious disease expert - Symptomatic patients should temporarily stop immunosuppressive agents or biologics. Patients taking anti Tumor necrosis factor (TNF) agents like infliximab or adalimumab should omit their next dose until they fully recovered. In such cases local treatment options like intravitreal injection should be considered - I t i s t o b e r e m e m b e r e d t h a t p a t i e n t s w i t h immunosuppressive agents will have altered blood parameters like decrease of lymphocyte count, decrease albumin, decrease haemoglobin, increase C-reactive protein, increased erythrocyte sedimentation rate (ESR), increased lactate dehydrogenase (LDH) and increase D-dimer. Patients on tocilizumab may be continued on the same as it reduces the cytokine storm. Standard precautions should be followed in uveitis patients like other ophthalmic patients in this COVID-19 pandemic. ## Xiv: training of the residents, fellows and students during the covid-19 pandemic As training the residents and post-graduates is one of the integral component of medicine, special attention needs to be given to the potential deficit in conventional training opportunities for the students during this COVID-19 era. New norms need to be established to train the residents and fellows. Innovative methods focussed training through webinars, online didactics, case presentations, review of electronic medical records may be considered as means of imparting teaching and engaging students. # Conclusion To conclude, our practices are going to be different in the post-COVID-19 era and we have to make modifications in every way that suits our practice, taking the government regulations and local rules under consideration. It is important to keep training the staff on a regular basis, so that we are able to manage these patients in a safe environment and prevent ocular morbidity as much as possible.	None	None	The COVID-19 pandemic has brought new challenges to the health care community. Many of the super-speciality practices are planning to re-open after the lockdown is lifted. However there is lot of apprehension in everyone's mind about conforming practices that would safeguard the patients, ophthalmologists, healthcare workers as well as taking adequate care of the equipment to minimize the damage. The aim of this article is to develop preferred practice patterns, by developing a consensus amongst the lead experts, that would help the institutes as well as individual vitreo-retina and uveitis experts to restart their practices with confidence. As the situation remains volatile, we would like to mention that these suggestions are evolving and likely to change as our understanding and experience gets better. Further, the suggestions are for routine patients as COVID-19 positive patients may be managed in designated hospitals as per local protocols. Also these suggestions have to be implemented keeping in compliance with local rules and regulations.
e1df484f8b7c64a853be3704a65b31d2b3415d9b	pubmed	Radiotherapy in head and neck cancer management: United Kingdom National Multidisciplinary Guidelines	Radiotherapy in head and neck cancer management: 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. Radiotherapy is one of the key treatment modalities used in head and neck cancer management. This paper summarises the current role and some of the recent advances in radiotherapy in head and neck cancer management. Radiotherapy (RT) and surgery are the two most frequently used therapeutic modalities in head and neck cancer. For early-stage tumours in many sites, surgical excision or RT have similar cure rates but have a different side-effect profile. Radiotherapy traditionally offered higher rates of organ preservation and for some cancers where function is important, it is the treatment of choice. For example, RT allows preservation of natural speech and swallowing in carcinomas of the larynx and tongue base. [bib_ref] A systematic review of current and emerging approaches in the field of..., Denaro [/bib_ref] At other sites (e.g. carcinoma of the oral cavity), surgical excision alone may be curative and be associated with a very satisfactory functional outcome. The choice of treatment modality therefore depends on individual factors including patient preference. For an advanced squamous cell carcinoma of the head and neck, single modality treatment (either surgery or RT alone) is associated with poor outcomes. For these tumours, the combined use of surgery and post-operative RT or use of combined chemotherapy and radiation schedules frequently offer the highest chance of achieving cure. In recent years, RT has benefited from advances in cancer imaging, treatment planning computer software and developments in radiation delivery technology. It is now one of the most technology-driven branches of medicine. Typically head and neck cancer patients will have radiation therapy which is based on the state-of-the-art imaging technology including computed tomography, magnetic resonance imaging, positron emission tomography or other imaging techniques. Optimisation of treatment planning is performed on high-speed computer software, which intelligently selects the most appropriate beam directions and shapes. Treatment is delivered by computer-driven linear accelerators with sub-millimetre accuracy allowing radiation to be focused on the tumour bearing tissues and minimising radiation to normal tissue structures. Intensity-modulated radiotherapy (IMRT) is now an established form of radiation therapy which allows better control of radiation dose delivery in the head and neck. In a randomised trial performed in the UK, IMRT has been shown to reduce radiation-induced xerostomia (the main long-term side effect of the standard RT) from 75 to 39 per cent ( p = 0.004) at 12 months following treatment. [bib_ref] Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT):..., Nutting [/bib_ref] A similar result has been demonstrated for patients with nasopharyngeal cancer. [bib_ref] Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage..., Kam [/bib_ref] Intensity-modulated radiotherapy in now used to treat 70-80 per cent of patients with advanced head and neck cancer, where sparing of salivary glands is required. Improvements in local tumour control have been demonstrated with accelerated (delivery of radiation over a shorter time period) or hyperfractionated (delivery of a higher dose of radiation by two to three lowdose fractions per day) RT. These treatments have not shown consistent improvements in overall survival, and for that reason have not been adopted widely outside of North America. [bib_ref] A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare..., Fu [/bib_ref] Particle therapy such as with protons or stereotactic RT may allow additional advantages to patients with tumours close to particularly radiosensitive organs such as the brain, spinal cord or in children's cancers. Presently, proton therapy is not available in the UK, but the NHS Proton Clinical Reference Panel can approve treatment abroad for adult head and neck cancer patients with base of skull chordoma or chrodrosarcoma, as well as a variety of paediatric cancers. UK proton facilities at The Christie Hospital in Manchester and University College Hospital in London will be treating patients within the next few years and additional indications for head and neck cancer patients may become apparent based on future research. In a large meta-analysis of 93 trials and over 17 000 patients, concomitant chemotherapy (given during RT) was shown to improve locoregional control rates and was associated with a 6.5 per cent increase in survival ( p < 0.0001). [bib_ref] Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on..., Pignon [/bib_ref] [bib_ref] Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis..., Blanchard [/bib_ref] The benefits were largely confined to chemotherapy given during RT rather than the adjuvant or neo-adjuvant setting. In addition, combining chemotherapy with radiation improves the rates of organ conservation. Cisplatin chemotherapy schedules are the most effective. Similarly the concurrent administration of cetuximab, an anti-epidermal growth factor receptor antibody, with RT, was shown to increase overall survival and locoregional control in this setting. [bib_ref] Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck, Bonner [/bib_ref] [bib_ref] Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival..., Bonner [/bib_ref] This was the first demonstration of activity of a biologically targeted therapy in cancer treatment. In the post-operative setting, two randomised controlled trials have demonstrated the use of concomitant cisplatin during radiation to increase tumour control and overall survival in high-risk patients with positive resection margins or extracapsular lymph node spread. [bib_ref] Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and..., Bernier [/bib_ref] [bib_ref] Long-term follow-up of the RTOG 9501/ intergroup phase III trial: postoperative concurrent..., Cooper [/bib_ref] While concomitant chemotherapy has a proven role in improving outcomes for head and neck cancer, the role of neo-adjuvant chemotherapy remains controversial. Two large studies suggested that the use of docetaxel, cisplatin and 5-fluorouracil prior to definitive RT improved survival. [bib_ref] Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer, Posner [/bib_ref] [bib_ref] Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer, Vermorken [/bib_ref] The use of non-standard RT and/or chemoradiation schedules in these trials has led to uncertainty as to the benefits of this approach when a standard chemoradiation is prescribed. Induction chemotherapy is now becoming less frequently used, and its benefit is probably limited to patients who are at high risk of systemic metastatic spread. There is increasing evidence that human papilloma virus-related oropharyngeal cancer has an excellent outcome with chemoradiotherapy and that less intensive RT schedules may be more appropriate, which is currently being investigated. ## Key points - Radiotherapy is a key modality in the treatment of head and neck cancer - Conformal radiotherapy planning and chemoradiation techniques should be available in all treatment centres - Intensity-modulated radiotherapy has been shown to reduce long-term xerostomia and should be offered to all appropriate patients. © 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/S0022215116000463	None	https://www.cambridge.org/core/services/aop-cambridge-core/content/view/16792B8CD3D3A69FB563C6C81E9750A8/S0022215116000463a.pdf/div-class-title-radiotherapy-in-head-and-neck-cancer-management-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. Radiotherapy is one of the key treatment modalities used in head and neck cancer management. This paper summarises the current role and some of the recent advances in radiotherapy in head and neck cancer management.
0e15e4bd9e07983e6e0d847abc2e745a49c9d8f7	pubmed	Guidelines on Standard and Therapeutic Diets for Adults in Hospitals by the French Association of Nutritionist Dieticians (AFDN) and the French Speaking Society of Clinical Nutrition and Metabolism (SFNCM)	Guidelines on Standard and Therapeutic Diets for Adults in Hospitals by the French Association of Nutritionist Dieticians (AFDN) and the French Speaking Society of Clinical Nutrition and Metabolism (SFNCM) Citation: Vaillant, M.-F.; Alligier, M.; Baclet, N.; Capelle, J.; Dousseaux, M.-P.; Eyraud, E.; Fayemendy, P.; Flori, N.; Guex, E.; Hennequin, V.; et al. Guidelines on Standard and # Introduction ## Hospital food provision: interest and societal challenges While medical knowledge, therapeutic molecules and treatment avenues have evolved, disease-related diets have more to do with (a long-standing tradition of prescription, longstanding prescribing habits). The questioning of these practices must be part of a rational approach based on evidence-based medicine and, failing the latter, on expert opinions. ## Constraints related to meals Food provision in the hospital setting encompasses multiple dimensions: biological, economic and health security, but also socio-cultural, symbolic and ecological. Faced with such challenges, food provision for the patient is a complex act insofar as it is at the very end of the nutritional chain where catering staff, caregivers and hospital management intervene directly or indirectly on the meals that are distributed to the patients. Food catering services have evolved over the course of many decades, notably taking into account both the economic and organizational aspects (invention of the cook-and-chill method, meal recovery carts, food waste, etc.). Meal quality mobilizes the various catering and nutritional teams, as well as hospital management. New food trends are also influencing the desires of consumers who demand the latter after their hospitalization. Nevertheless, the hospital meal remains negatively connoted by professionals, as well as by patients, as highlighted by results of satisfaction surveys (i.e., the e-Satis survey proposed by the French Health Authority (HAS, Haute Autorité de Santé)). ## Nourishing the ill patients The above ensemble of facts determines and influences hospital meals, in which nutritional diets occupy a predominant place. Thus, diet prescriptions as well as proposals (types of dishes, preparation methods, possible restrictions such as salt, fat and carbohydrates in the recipe, etc.) can lead to a risk of non-consumption contributing to the spiral of undernutrition. ## Objectives of the present guidelines The objective of this work is to propose recommendations regarding food and nutritional management and prescriptions based on scientific evidence, or failing the latter, on expert consensus. The main objectives of these recommendations are: ## - To ensure the nutritional needs of the patients and adapt to their pathophysiological condition as well as to the needs associated with hospitalization (acute care, follow-up and rehabilitation care, long-term stay). ## - To show consideration for the patient by conferring food provision its full meaning: both nutrition-wise as well as personal-wise (taking into account choices, mealtimes, etc.). ## - To rationalize and harmonize practices related to nutritional diet prescriptions. ## - To lighten the constraints that could induce restrictions on meal provision (choice of food for the preparation of dishes, implications on meal costs, consequences on the palatability and consumption of meals/dishes by patients). These recommendations are intended for the personnel involved at every level of the food chain, including people involved in patient care: catering industry overseers (catering engineer or kitchen manager), catering assistants, care workers; nursing staff supervisors: managers, senior health managers and care coordinators; dieticians, nurses, caregivers, hospital services agents, physicians, upper management overseers such as hospital heads, purchasing or economic services directors/logistics directors, and institutional stakeholders. # Materials and methods ## Description of the method The present guidelines were developed using the following methodology: - A preliminary survey was carried out by the French speaking Society of Clinical Nutrition and Metabolism (SFNCM, Société Francophone de Nutrition Clinique et Métabolisme) in 2017, with the goal of establishing an inventory of food practices and diets in French healthcare establishments. This survey revealed a wide heterogeneity in the various nutritional regimens offered, whereby the same diet name could correspond to different contents in terms of authorized or prohibited foods as well as threshold levels in the case of restrictions. This discordance, induced by historical practices or prescribing habits, has direct consequences on the food intake of patients and their nutritional status. - This inventory led to the creation of a working group comprised equally of members of the French Association of Nutritionist Dieticians (AFDN, Association Française des Diététiciens Nutritionnistes) and the SFNCM. Proposals for recommendations were put forward based on the results of the survey and data from the literature. - These proposals were submitted to a group of 50 national experts (25 dieticians and 25 physicians). The experts were drawn from all regions of the country and chosen for their expertise in the various specialties pertaining to nutrition (gastroenterology, nephrology, obesity, etc.). The experts were consulted on the basis of the DELPHI method, as proposed by the French Health Authority (HAS). ## Procedural design of the delphi method The DELPHI method was used to obtain formal consensus on the recommendations. This steering group (14 clinical dieticians, 5 physician nutritionists, 1 methodology assistant) henceforth: ## 1. Analyzed, synthesized and debated the literature on hospital food provision and nutritional diets. ## 2. Produced 22 initial proposals stemming from the baseline survey of 2017. 3. Submitted the 22 version 1 recommendations online for a 1st assessment rating (score ranging from 0 to 9) by the 50 experts. ## 4. Analyzed the responses from this first round: the comments were used to upgrade the proposals and ultimately led to proposing a 23rd recommendation to complete version 1. ## 5. Submitted the 23rd recommendation as well as the version 2 recommendations (with accompanying arguments) for a second assessment rating of the version 1 proposals which had an initial rating below 7. 6. Analyzed the responses of the 2nd round. All of the recommendations were deemed appropriate (median ≥ 7) with strong agreement for 18 of the latter (scores between 7 and 9), and relative agreement (scores between 5 and 9) for the remaining 5. The experts who gave a score less than 7 on these 5 recommendations with relative agreement were contacted individually for a 3rd rating and comments. 7. Following the 3rd round, the 23 recommendations were all accepted with strong agreement. All proposals were the subject of a drafting of a supporting rationale based on a comprehensive analysis of the literature and submitted to the experts during the 2nd round. Certain recommendations are based on a consensus of experts in instances where literature data are non-existent or insufficient. ## The 23 recommendations on standard and therapeutic diets ## Lexical scope of the recommendations Given the disparity of terminologies used in health establishments, it appeared essential for the steering group to redefine and harmonize the various terminologies. Whether in acute care or rehabilitation, whether in health establishments or in-city facilities, each stakeholder involved in the care of the patient must convey the same level of care management information, both in terms of quality (indication of the prescription, foods or nutrients involved) and quantity, etc. In addition, for the purpose of eliminating directly identifying designations, at times including the patient's diagnosis via the meal sheet, the decisions were to: - Prefer the term "standard" to "normal" with regard to standard food offered in health establishments. ## - Only retain therapeutic diets-i.e., that imply restrictions or modifications on foodsthat fall under prescribed medical settings. All of these proposed changes are intended to provide a vocabulary more suited to the evolution of care management and knowledge. In the recommendations relative to the gastrointestinal field and fiber control component, vocabulary development choices related to current knowledge on the topic are notably specified. ## Structuring of the recommendations The recommendations aim to: ## - Define food provision (quantitative and qualitative) in hospital establishments, both in terms of adaptation to the patient's needs as well as to promote food intake (recommendations 1, 2, 3, 4). ## - Highlight the indications/importance of nutritional prescription and its re-assessment (recommendations 5, 6, 7). - Specify the food provision modalities that must sometimes be implemented in order to adapt the diet to the patient's capabilities and appetite (recommendations 8, 9). - Streamline and limit the restrictions in therapeutic diets which exclude certain nutrients, in order to only retain the indications based on scientific evidence and to define these indications with regard to the benefit/risk balance of undernutrition (recommendations 10 to 22). ## - Highlight the importance of the place of specifically adapted diets for undernourished patients and those at risk of undernutrition (recommendation 23). Scope of the recommendations: These recommendations are only intended for adult populations, pediatrics being a very specific field which requires completely distinct recommendations. # Results ## Recommendations on food provision Recommendation 1: It is recommended that food provision offer several choices to the patient. ## Comment: Qualitative and quantitative food provision should be considered an essential component of the treatment of hospitalized patients. Two recent cross-sectional Nutrition Day ® surveys conducted in nearly 20,000 patients in European and Australian hospitals demonstrated the reality of nutritional risk and highlighted that nearly one in two patients consumed less than half of the meals served. in 2011 furthermore described an association between protein-energy deficits, lower evening meal quality and specific diet prescriptions, suggesting the importance of the quality of food provision. Inadequate food provision, without the possibility of choosing menus, more easily exposes the patient to his/her dislikes, or to a meal that does not integrate his/her culinary preferences, lifestyle, beliefs, culture, or philosophy of life. The objective of food provision of a health establishment (HE) is to ensure the nutritional needs of each patient. This goal can only be achieved if the patient's tastes, dislikes, requests and clinical condition are taken into account. Thus, the hospital should offer users a tangible possibility of personal choice, by making available a list of foods that is as broad as possible, taking into account the variable constraints according to the HE. This choice of menus must allow the fulfilling of all nutritional diets (standard or therapeutic), in accordance with the recommendations, and taking into account allergies, dislikes and/or patient preferences. Few studies have examined the impact of choice of menu preferences. In a 2013 study by Jarrin et al., choosing the meal in an internal medicine department did not affect the satisfaction felt by patients and did not increase their food intake. However, this singlecenter observational study was carried out in a single short-stay department, on a small number of patients with acute disease, and hence not a reflection of all hospitalized patients. According to other authors, provision of food comprising preferred menu choices with the possibility of indicating food dislikes would limit patient dissatisfaction, a frequent source of lower consumption and risk of undernutrition. Accordingly, for Stanga et al., patient satisfaction was improved by the choice of menu preferences. According to , the proposing of multiple-choice menus, ordered at bedside, within the limits of available choices in the HE, improved patient satisfaction regarding their meal. Other authors, however, suggest that menu choices left to the patient alone are not necessarily beneficial if, for example, the most undernourished individuals choose a low-energy menu, normally adapted to a healthy person: menu choices, and particularly in instances of implementation of a therapeutic diet, should probably be supervised and guided according to the patient's clinical condition. Finally, the possibility of preferred menu choices appears to be an effective means to significantly reduce food waste. ## Recommendation 2: It is recommended that the standard diet meet the guidelines for prevention and health promotion. Comment: Food provision in health establishments (HE) must enable fulfilling the needs for maintaining a proper nutritional and hydration state while respecting a balanced diet as much as possible. There are no data to date comparing the average nutritional needs of hospitalized individuals with those of the general population. It is likely that a standard diet, based on recommendations for the prevention and promotion of health in the general population, does not meet the needs of many hospitalized patients, e.g., undernourished patients or those at risk of undernutrition, and patients with metabolic syndrome or overload. Therefore, an initial nutritional assessment and subsequent adaptation of the standard diet into a therapeutic diet tailored to the patient's clinical condition is imperative. Nevertheless, a standard diet corresponds to the basic food provision often proposed by default to the greatest number of hospitalized individuals. In addition, several reports condemn the excessive use of therapeutic diets, in particular restrictive diets, emphasizing the need for a more frequent use of a healthy, balanced and appropriate standard diet. In order to propose a framework for HEs, it is, therefore, necessary to provide a consensus definition of standard diet. Subject to the constraints of collective catering, standard nutrition must enable meeting the needs of the greatest number of hospitalized individuals who do not require a therapeutic diet. In addition, due to the need for both educational and pedagogical actions in the nutritional sphere of patients and their family members, as recommended by the High Authority of Health, the French High Council of Public Health and the National Food Council, it would hence seem appropriate that this standard diet be offered in coherence with the nutritional policy of prevention and health promotion. There have been, for several years, recommendations regarding nutrition from a public health perspective. In France, the main example is the National Nutrition Health Program (PNNS, Programme National Nutrition Santé) launched in 2001 and its recommendations for a healthy and balanced diet. As a result, the High Council of Public Health has defined a nutritional policy compiling objectives of food consumption, nutritional intake, and nutritional status for the general population as well as for hospitalized patients. The implementation of a standard diet in HEs meeting consumption benchmarks defined for the general population would appear to be consistent with the decrease in the prevalence of nutritional disorders (undernutrition and/or overweight). Whereas the PNNS recommends a guideline, the proposal of a standard, balanced and varied diet meeting nutritional benchmarks requires compliance with precise specifications in terms of quality, frequency and acceptability, while also meeting the constraints of collective catering. The nutrition recommendations of the Public Catering and Nutrition Markets Study Group (GEM-RCN, Groupe d'Etude des Marchés de Restauration Collective et Nutrition) allow HEs to define and apply such specifications. Standard food provision, offered in HEs in accordance with the recommendations of the GEM-RCN, favors a balanced and varied diet. The objective of this provision is to respond to the increase in the prevalence of overweight and obesity, but also to counter undernutrition in elderly and/or dependent individuals. ## Recommendation 3: Outside of a personalized adaptation, it is recommended that the standard diet provide a minimum of 2000 kcal/d. ## Comment: The nutritional needs of the patient must be established according to his/her weight, metabolic condition and appetite. However, the majority of current meal distribution systems do not allow meal trays to be personalized by adapting the size of the portions served. A simple determination of nutritional requirements by applying 30 kcal/kg/day (even for the elderly, grade Bmakes it possible to establish the energy target of a nutritional day. In order to fulfill the nutritional needs of a large number of patients, we recommend a minimum of 2000 kcal per day provided by meals. This threshold takes into account the characteristics of the hospitalized population. The Nutrition-Day surveyof 15,123 hospitalized patients revealed a median weight of 70 kg. Data from 17,102 screenings in 2017 and 2018 in the medical and surgical departments of a French University Hospital Center showed very constant monthly figures, with a median of 68.2 kg and a mean of 72.4 ± 9.9 kg, respectively (unpublished data). The 2000 kcal cover the needs of half of the patients. They represent a minimum daily threshold to be provided, given that meals are not always fully consumed and, depending on the proposed menus, there can also be significant energy content differences from one day to the next. The issue of food wastemust also be taken into account when proposing strategies to improve food intake. These include the conditions of meal intake, an appetizing presentation of the dishes, the quality in the choice of foodstuffs, and the palatability of the recipes. There may also be strategies aimed at improving the nutrient density of the dishes, without increasing their volume. Snacks can also be used to reach nutritional targets, although one must ensure that they are systematically distributed to the patients. ## Recommendation 4: It is recommended that the nutritional values (energy, proteins, fats, carbohydrates) of provided food be accessible, in particular to the prescribing physician and the dietician. ## Comment: Knowledge of the nutritional values of the provided food is a prerequisite that allows the assessment of the actual provision offered to patients and guarantees its regularity. The Food and Nutrition Liaison Committee (CLAN, Comité de Liaison Alimentation Nutrition)and the dietetic service, or in the absence of such structures, the dietician of the health establishment must validate the provided foods in order to facilitate the work of the prescribers. These prescribers will hence have knowledge of the overall characteristics of the provided food (energy, proteins, etc.), in order to tailor nutritional provision to specific situations, when necessary. For therapeutic diets, the nutritional values of these dishes may target salt, fiber, potassium intake, etc., depending on the purpose of the prescription. Knowing these values allows the assessment of the patient's true intake in order to ascertain whether the prescribed diet fulfills the patient's nutritional needs and in what proportions, in order to recommend a readjustment or, if needed, nutritional support. The estimated nutritional value must be calculated: - For dishes prepared by catering services: knowledge per serving served, at minimumproteins, lipids, carbohydrates and energy. - For therapeutic diets, the nutritional values of these dishes can target salt, fiber, potassium, calcium intake, etc. - For prepared products originating directly from the food industry, suppliers must be able to provide the nutritional value of the dishes. - Special attention is required for each change in supplier, for both finished dishes and raw foodstuffs. An update of the calculations is then necessary. ## - Given that the calculations are based on recipe technical sheets as well as technical sheets of raw foodstuffs from suppliers, approximations are frequent. - Regular nutritional analyses by appropriate analysis laboratories are to be integrated into the follow-up and quality control of the catering service. They are the guarantors of the regularity and adequacy of food provision along with the nutritional target. They also allow strategies to be adjusted in terms of menus, palatability, and the reaching of nutritional goals. ## Prescription of nutritional diets at the hospital ## Recommendation 5: It is recommended that all diets (standard and therapeutic) be prescribed upon admission of the patient and adapted according to his or her clinical condition. ## Comment: The prescription includes all nutritional diets: standard and therapeutic (restrictive, fortified therapeutic diets and/or texture modified diets). Many authors agree that the provision of meals should be considered an essential component of patient treatment. The provision of meals upon admission, tailored to the patient's clinical condition, is a broad-based process involving many stakeholders in healthcare establishments (physicians, dieticians, caregivers and catering services). This process begins with the identification of the patient's nutritional status, nutritional risk, food intake possibilities, and the definition, as specific as possible, of his/her clinical condition. The act of eating, i.e., the non-contraindication to food intake, and the type of diet must be subject to a medical prescription. The nutritional prescription is a medical act which implies the physician's medico-legal responsibility. The physician prescribes the patient's nutritional diet, standard or therapeutic (including texture modified), and determines the implementation of specific measures in the event of inability, insufficiency or contraindication of an oral diet. While the responsibility for the nutritional prescription rests with the physician, the tailoring of the diet at admission can be subject to the expertise of a dietician . The training of physicians in the field of nutrition is very heterogeneous and often of average quality. In addition, not all health establishments include a physician nutritionist. Prescribing a therapeutic diet is, however, a complex technical act, the effectiveness of which is dependent on the accuracy of the indication and the patient's adherence . As such, dieticians intervene as experts in order to adjust the diet to the needs of the patients: they take part in menu creation and the adaptation from a standard diet to a therapeutic diet. Thus, through their interaction with both care and catering services, dieticians are guarantors of the quality of the food served, regardless of the disease. Dieticians also contribute to the preparation of nutritional protocols, allowing all patients to benefit from a diet tailored to his or her needs upon admission, particularly in HEs with a limited number of dieticians. The corollary of this recommendation is the following: ## Recommendation 6: It is recommended that all types of therapeutic diets be reassessed during hospitalization and upon discharge by the prescriber, and if necessary, by a dietician and/or a physician nutritionist. ## Comment: The implementation of a therapeutic diet in the case of nutritional disorder(s) is an act of care which should not derogate from the principle of re-assessment, as part of the quality process developed by the HAS. The re-assessment of therapeutic diets during hospital stay has several objectives: to ensure the effectiveness and adherence of actions implemented, to adapt food provision to changes in clinical condition, and to propose, when necessary, oral, enteral or parenteral supplementation. When the patient is discharged, this re-assessment is also useful for verifying the need for maintaining the therapeutic diet and its feasibility at home . Given the often average and heterogeneous training level of physicians in the field of nutrition [34], the possible intervention by a physician-nutritionist and/or dietician for the re-assessment and adaptation of a therapeutic diet would appear advisable. The dietary care approach, involving the re-assessment during hospital stay or when patients are discharged, has been the subject of recommendations for good practices validated by the HAS [34]. Thus, in collaboration with numerous health professionals, the dietician plays a key role in this re-assessment. Owing to the expertise provided by the qualitative and quantitative evaluation of patient nutrition, dieticians are hence qualified to control the quality of nutritional care and to propose adaptive measures. Although this dietary re-assessment should ideally target all hospitalized patients with a therapeutic diet, the lack of personnel trained in nutrition and their distributive disparity according to health establishments are likely obstacles to its application. As a result, if the re-assessment by specialized personnel cannot be generalized within an HE, prioritized and targeted actions should, therefore, be carried out in the event of initiation of a therapeutic diet during an acute clinical situation, or when implementing a restricted or texture modified diet. Conversely, patients with stable chronic illnesses without change in clinical status or medical treatment likely do not require a prioritized and regular reassessment of their therapeutic diet by nutrition specialists. In such cases, the re-assessment must, at minimum, be carried out by the prescribing physician. ## Recommendation 7: It is recommended not to combine more than two restrictive therapeutic diets due to the risk of undernutrition. ## Comment: By "combine", we imply the association (manual or computerized) of several types of prescribed diets. Combining several levels of dietary restrictions renders the designing/preparation of a meal tray in the kitchen both difficult and random and exposes the patient to the possibility of reduced consumption and an increased risk of undernutrition. It also impacts its acceptability from a visual and taste standpoint (for example, a prescribed texture-modified, no-residue, low-salt diet). It has a negative effect on the patient's appetite. Many therapeutic prescriptions reduce the variety of foods consumed and expose the patent to a more monotonous nutritional diet. It also increases the risk of specific deficiencies (example: no-residue diet and vitamin C deficiency). The prescription of a therapeutic diet is, therefore, a therapeutic medical act which encompasses the medico-legal responsibility of the prescriberand incurs changes in the dietary status of the patient concerned. Dieticians are the health professionals qualified to define, assess and control the quality of food provision. It is important to assess the benefit/risk ratio of restrictive diets, especially in the frailest patients, such as the elderlyand according to the recommendation of the French Council of Food and Nutrition (CNA, Conseil National de l'Alimentation et de la nutrition). The prioritization of needs should lead to limiting prescriptions to one or two therapeutic diets that are essential to the patient's condition. Computerized meal ordering systems must limit the cumulative amount of therapeutic diets to a maximum of two possibilities. Prescriptions incorporating more than two restrictions must be the exception and should be managed solely by physicians or dieticians. ## Adaptation of food provision Recommendation 8: It is recommended that food provision can be partitioned by offering more than three meals a day. ## Comment: The current meal distribution system systematically includes three meals: breakfast, lunch and dinner. The possibility of offering snacks should constitute an integral part of the strategies to fight undernutrition. Health facilities must endeavor to provide food intake at times other than traditional mealtimes during the day, in the form of snacks. Health facilities should be able to fulfill the specific needs of certain patient populations (pregnant or lactating women, elderly people, as well as implement strategies to fight undernutrition. Snacks should be given at coordinated time intervals with meals, but also to decrease the duration of night-time fasting. ## Recommendation 9: It is recommended that the adaptation of food texture be established according to the International Dysphagia Diet Standardization Initiative (IDDSI) recommendations. Comment: Swallowing disorders affect nearly 8% of the world's population and are particularly common in neurodegenerative diseases, stroke, cancers of the upper aerodigestive tract and in the elderly. The appropriate adaptation of foods and beverages can reduce the complications of swallowing disorders, mainly undernutrition and lung infections. The adjustments must ensure a food intake and hydration that is safe, sufficient and pleasant for the patient. Experts from the European Society for Swallowing Disorders (ESSD)conclude that a variety of choices must be available in order to adapt to the severity of the disorders, including modification of solid food texture (firmness, bite size, adhesion and consistency) and liquid thickness (transit speed). Aside from swallowing disorders, various conditions, such as locking of the jaw, dental extractions as well as certain post-ENT or post-bariatric surgery refeeding issues, may require the use of texture modifications. Within the various care structures, there is a notable absence of common terminology to qualify the various textures proposed and in which the names, number of modification levels and characteristics are attributed empirically and in an extremely variable man-ner, leading to a very heterogeneous management of swallowing disorders. The thickening of liquids reduces the risk of pulmonary inhalation but increases the risk of post-swallow residues in the pharynx, and also necessitates the application of a liquid thickening grading system logged in the medical chart. The IDDS initiative made it possible to achieve a universal, standardized terminology for adapting foods and beverages in the event of a swallowing disorder. The IDDSI recommendations were issued by a panel of international experts, including dieticians, after reviewing the international literature. These recommendations are based on a description of each adaptation level and specific measurement methods in order to foster their application in clinical practice. The recommendations are freely accessible on the https://iddsi.org/ website (accessed: 13 March 2021) and resulted in an eight-level diagram (from liquid to solid). The characteristics, indications, measurement methods and examples of corresponding foods are detailed for each level. With the objective of rationalization, the health establishments must tend toward this classification by harmonizing the terms and foods proposed at each adaptation level according to the possibilities of each establishment and the type of patients received. One of the objectives of the IDDSI is to extend this harmonization to the products distributed by the agro-food industries, which will facilitate the work of catering professionals during the various purchasing procedures and the creation of menus. Health establishments do not have to propose all variations of the textures in their menus but must identify their proposals according to the IDDSI classification. Indeed, the Health establishments do not have to propose all variations of the textures in their menus but must identify their proposals according to the IDDSI classification. Indeed, the use of consistent terminology improves patient safety and communication between the various professionals as well as during transfer to another healthcare establishment invested in the nutritional well-being of the patient. The use of an international standard tends to promote good practices and efficiency and to secure both professionals and patients alike. Given that this classification was published in 2016, it would seem legitimate to suggest establishing the texture adaptations according to IDDSI standards. It is recommended to refer to the IDDSI website, updated according to user feedback and translated into multiple languages. ## Therapeutic diets Recommendation 10: During hospitalization, aside from a specialized indication, the prescription of a therapeutic diet aimed at weight loss is not recommended. ## Comment: In 2014, nearly half of the population in France was considered overweight. The prevalence of overall obesity was 15.8% in men and 15.6% in women, while the prevalence of abdominal obesity was 41.6% and 48.5% for men and women, respectively. The increase in the prevalence of obesity affects all population age groups, including the elderly. As a result, the population of sick obese patients is also increasing in hospitals. In hospitalized obese patients, the risk of undernutrition is high and often underestimated by healthcare professionals. Sarcopenic obesity is an emerging concern with very little literature regarding the subject. Its prevalence is estimated to be between 5 and 15% in the general populationand up to 22% in the non-hospitalized elderly population. In the hospital setting, there are currently no data relative to the prevalence of sarcopenic obesity. In critically ill obese patients, it is recommended to provide 20-25 kcal/kg of ideal weight per day or <14 kcal/kg actual body weight per day as well as a protein intake of 1.2 to 2 g of protein/kg ideal weight per day. There is no clear consensus for non-critically ill obese subjects, although recent literature data suggest that intake remain hypo-energetic with 20-25 kcal per kg of adjusted weight, albeit with a high protein component of 1 to 1.1 g of protein per kg of actual weight. With regard to strategies related to sarcopenic obesity in the elderly, Batsis et al.highlight the absence of evidence of specific diets. The authors emphasize the importance of combining dietary and lifestyle measures (limiting calorie restriction for the purpose of losing weight to 0.5 kg/week for a target of 8-10% loss in 6 months, followed by a stabilization phase, protein supplementation of 1-1.2 g/kg/day (25-30 g/d) along with calcium (food-based if feasible) and vitamin D supplementation, as well as physical activity to increase functional and cardiorespiratory capacities (aerobic and resistance exercises). The 2010 recommendations for good clinical practice on preoperative nutritionspecify that obese patients are potentially malnourished patients and that an involuntary weight loss prior to surgery is an independent risk factor for complications. Thus, restrictive diets leading to a significant loss of lean mass are not recommended, particularly in patients with common obesity (BMI 30 to 40) or in elderly obese subjects. Voluntary preoperative weight loss is not recommended in the days and weeks before surgery. There is no evidence of the benefit of voluntary pre-operative weight loss regardless of the surgery. Finally, the recommendation specifies that if weight loss is necessary to facilitate the surgical procedure, a weight stabilization phase of at least 15 days is necessary before the intervention. It is also emphasized that it is probably not recommended to prescribe a low-calorie diet in an obese patient post-operatively. Food intake should be considered an essential component of the treatment of hospitalized patients, even though many patients do not consume half of the meals served in the hospital, primarily due to anorexia linked to treatment and secondly to organizational or food provision reasons. Based on calculations drawn from intake recommendations (excluding during resuscitation care), the Lausanne University Hospital team determined that both energy and protein requirements are not fulfilled when providing a standard diet of 1800 kcal and 60 g of protein per day for patients reaching the moderate obesity stage. In cases of massive obesity and conditional to the total consumption of the meal tray, the energy deficit is approximately 500 kcal while the protein deficit is at least 55 g. A study conducted by the same team showed that, on the one hand, the standard food provision was deemed not only insufficient but, in addition, under-consumption secondary to the disease worsened the protein-energy deficit; therefore, there was a risk of undernutrition and loss of lean body mass. The prescription of a therapeutic diet aimed at weight loss is not recommended for patients with acute illness, under metabolic stress or surgical procedure. On the contrary, however, the nutritional management of obese patients requires expertise and multidisciplinary management in order to assess the dietary intakes and individually adapt the latter to the calculated needs of the patients. ## Recommendation 11: It is recommended to adapt protein intake according to Chronic Kidney Disease stage and nutritional status. In chronic kidney disease (CKD), the beneficial effects of controlling protein intake are manyfold: lowering of albuminuria and proteinuria, decrease in plasma and urinary urea, decrease in phosphatemia, reduction in insulin resistance and control of acidosis. These different factors not only act on renal health but also on cardiovascular, bone and neuromuscular health. Protein intake should be adapted according to the stage of chronic kidney disease: Severe and end-stage CKD (stages IV and V): 0.6 g to 0.8 g/kg/d including 50% high biological value protein, or <0.6 g/kg/d with the addition of essential amino acids or keto-analogs. [formula] - [/formula] Dialysis treatments (hemodialysis and peritoneal dialysis) lead to loss of proteins, which require readjustment of intakes greater than 1 g of protein/kg/d. During these different periods, it is recommended to assess the nutritional status of chronic kidney disease patients by regular monitoring of weight, biological values (albumin), appetite and food consumption. Any protein-energy undernutrition during renal failure and chronic dialysis requires an increase in protein intake from 1.2 to 1.4 g/kg/d, or even above 1.5 g in the case of hypercatabolism. ## Recommendation 12: It is not recommended to prescribe a low-fat therapeutic diet < 35% of the total energy intake, with the exception of major primary hypertriglyceridemia and chylous effusions (chylothorax, chylous ascites and chyluria) in which a strict fat restriction is required (<30 g per day, excluding medium chain triglycerides (MCTs)). ## Comment: The above indication takes into account: ## - The lack of consensus and scientific literature regarding the value of a low-fat diet in instances of hypertriglyceridemia, other than its primary form. There is no consensus as to the definition of major hypertriglyceridemia or of the threshold beyond which there is risk of acute pancreatitis. ## - In the case of acute alcoholic pancreatitis, often associated with hypertriglyceridemia, the value of such a diet and the triglyceridemia threshold requiring a low-fat diet has not been established. - Substitution with medium chain triglycerides is not addressed in this recommendation. ## - The value of a low-fat diet (<35% of energy intake) is now questioned in its classic indications: prevention of obesity, prevention of cardiovascular disease. The Mediterranean-type diet (40-45% fat, rich in monounsaturated fats and omega 3) appears more effective in terms of cardiovascular risk prevention, high blood pressure, prevention of type 2 diabetes, NASH (non-alcoholic steatohepatitis), etc. Possible indications of low-fat diets, according to literature data: - Hypertriglyceridemia (hyperTG): Major hypertriglyceridemia occurring during an accumulation of chylomicrons is arbitrarily defined above a threshold of 10 to 15 mmol/L (8.8-13.4 g/L). Beyond this threshold, ingestion or infusion of triglycerides can increase hypertriglyceridemia and "clog" lipoprotein lipase (enzyme responsible for the breakdown of triglyceride-rich lipoproteins) by saturating its activity. This can lead to a rapid increase in triglyceridemia. The main objective is to avoid the occurrence of acute pancreatitis by containing triglyceridemia within a relative safe zone between 4 and 10 g/L, through a low-calorie and/or low-carbohydrate and/or alcohol-restricted diet. The value of a low-fat diet is not established in this indication with the exception of the primitive forms in which an extremely low-fat diet (limiting fat intake to 30 g or even 10 g per day) is required. However, the risk of pancreatitis increases when TG levels exceed 10 to 15 g/Lalthough concentrations between 2 and 10 g/L can be observed at the time of diagnosis of acute pancreatitis regardless of etiology. The risk of acute pancreatitis in patients with a serum TG at 10 g/L is 5% and 10-20% at 20 g/L. According to certain authors, a hyperTG > 10 g/L, therefore, requires a restriction of dietary fat to between 10% and 15% of calorie intake, with a reduction in saturated and unsaturated fat ranging from 10 to 25 g. ## - Acute pancreatitis: Hypertriglyceridemia is one of the causes of acute pancreatitis. Aside from hypertriglyceridemia linked to type 1 (hyperchylomicronemia) or type 5 dyslipidemia, which can be responsible for acute pancreatitis, hypertriglyceridemia is generally associated with alcohol consumption, even in small quantities (subject identified as "sensitive" to alcohol). According to certain authors, care should be taken to monitor the concentration of plasma triglycerides. ## - Exocrine pancreatic insufficiency: chronic pancreatitis: There is no indication for restricting the proportion of dietary fat. Increasing pancreatic enzyme replacement therapy reduces steatorrhea. Addition of a proton pump inhibitor can increase therapeutic effectiveness. On the other hand, the patient must be persuaded not to limit his or her diet. The measurement of steatorrhea under treatment makes it possible to assess the effectiveness of treatment as well as calorie loss (9 kcal/g of fat). In the case of major malabsorption (residual steatorrhea > 40 g/d) and undernutrition, medium chain triglycerides (20 to 30 g) can be introduced, although such intervention is exceptional. Eighty percent of patients can, therefore, continue a normal diet if combined with pancreatic extracts. ## - Following supramesocolic surgery (cephalic duodenopancreatectomy, gastrectomy and superior polar esogastrectomy): In contrast, an increase in calorie intake, in all forms, is strongly encouraged. Treatment with pancreatic enzymes should help control steatorrhea. Treatment should be optimized by controlling the level of steatorrhea under treatment. ## - Chylothorax: A low-fat diet (<10 g/d) is generally recommended, and typically associated with other treatments (pleurodesis). Although no case/control study was able to demonstrate its value, descriptive data in one study showed that this diet was associated with a resolution of chylothorax in two-thirds of the cases with a median follow-up of 10 days . The combination of a low-fat diet and pleurodesis resolved the chylothorax in more than 80% of cases not responding to diet alone. In this latter study, the indication retained for pleurodesis was the presence of >500 mL of chylous fluid during the first 24 h after initiation of the low-fat diet. - Chyluria: A low-fat diet, combined with or without somatostatin, allows reducing lymphatic leakage. It is sometimes necessary to combine the former with etiological treatments (antiparasitic, surgical treatment, etc.). ## - Chylous ascites: Abundant chylous ascites, greater than 1 L in volume, require a maximum reduction in lymphatic flow. Lymphatic flow increases from 1 mL/min to 200 mL/min after a fatcontaining meal. Normal food maintains lymphatic flow as a result of long-chain fatty acids entering the lymphatic pathway after their enterocytic absorption. A strict fat-free oral diet leads to a significant calorie restriction, since there are very few foods that do not contain long-chain fatty acids (fruits and vegetables) and the foreseeable duration of such management should not exceed 7-10 days and, as such, requires the indication of parenteral nutrition. In the initial phase, in the presence of large ascites, exclusive parenteral nutrition is indicated in order to significantly reduce lymphatic flow. Enteral nutrition is indicated only in cases of small-volume chylous ascites. In France, among the family of commercially available solutes intended for enteral nutrition, semi-elemental solutes are those which contain the highest concentration of medium chain triglycerides (MCT) compared to standard polymeric solutes (45-70% versus 15-25%). ## - Bile acid malabsorption: A randomized study has shown that a low-fat diet can help reduce symptoms related to bile acid malabsorption (biliary diarrhea). However, the impact of such a diet on the patients' nutritional status was not assessed. ## - Obesity and cardiovascular risk: Hospitalization in acute care is not the time to initiate a low-calorie or low-fat diet. Results of several meta-analyses of randomized studies comparing low-carbohydrate or low-fat diets (<30% of energy intake), combined or not, with a reduction in energy intake in strictly adherent populations have shown that each diet was associated with a significant weight loss and reduced predicted risk of cardiovascular events. However, the low-carbohydrate diet was associated with greater weight loss and greater improvement in cardiovascular risk. A low-fat diet is associated with a decrease in LDL-cholesterol, but an increase in triglyceridemia and a reduction in HDL-cholesterol. This reduction in HDL-cholesterol can be limited by adding monounsaturated fatty acids (e.g., olive oil). In the case of diabetes, a low-fat diet does not appear to alter blood sugar balance in the medium term, compared to a low-fat diet. ## - Cancer: Increased consumption of fruits, vegetables and grains is associated with a decrease in breast cancer mortality in a large cohort study. A fruit-and vegetable-enriched diet leads to a decrease in fat consumption. - NASH (non-alcoholic steatohepatitis): Calorie restriction leads to an improvement in fatty liver and NASH, irrespective of intake distribution. The most effective approach appears to be the implementation of a Mediterranean diet characterized by a decrease in carbohydrate intake, in particular sugars and refined carbohydrates (40% of calories compared to 50-60% in a low-fat diet), and by an increase in monounsaturated and omega-3 fatty acid intake (40% of calories in the form of fat compared to <30% in a typical low-fat diet). An isocaloric diet rich in monounsaturated fatty acids leads to a reduction in fatty liver disease. Nevertheless, a high-fat diet exacerbates fatty liver disease, while a low-lipid isocaloric diet could be of interest provided that it is not compensated by an increase in the consumption of fructose or carbohydrates with a high glycemic index. ## Recommendation 13: The standard diet is suitable for diabetic patients without exclusion of foods and desserts containing sucrose. Comment: For nutrition recommendations, France refers on the one hand to French public health data, and on the other, to the recommendations of the ADA (American Diabetes Association), which remain in agreement in both North America and Europe. The recommendations for macronutrient intake in individuals with diabetes are the same as for the general population, in the absence of diabetes complications. Sugar and sweet products can be consumed in the same quantity as the recommended intakes for the general population. As advocated by ANSES, it is more a question of "controlling" the consumption of sugar as opposed to excluding the latter. The lowest contribution identified in the literature from which an alteration in risk markers is observed has been considered. The minimum consumption for which a significant increase in blood triglyceride concentrations was observed is 50 g of fructose per day, i.e., 100 g of sucrose (ANSES, 2016). Thus, an upper limit of 100 g/d has been set for the total consumption of sugars, excluding lactose and galactose. This particular point is not required in hospital catering. For an optimization of carbohydrate distribution, their consumption should be considered in equivalence to that of other carbohydrate foods, with the exclusion of sugary drinks whose consumption should be avoided outside of adapted situations. With the exception of the consumption of sugar-sweetened beverages, there are, therefore, no recommendations which exclude sucrose from the diet of individuals with diabetes, within the framework of compliance with public health policies. From a scientific standpoint, there are no arguments to contradict these recommendations. This was aptly demonstrated over 35 years ago. Note: In gestational diabetes, there is also no systematic exclusion of sucrose. It is rather the choice of foods according to their glycemic index that is recommended. ## Recommendation 14: It is recommended that the standard diet provide a regular carbohydrate content for each meal. ## Comment: The standard diet is appropriate for patients with diabetes. For those who do not adjust their insulin dose according to carbohydrate intake (functional insulin therapy), the amount of consumed carbohydrates must be regular and at fixed times. This favors glycemic balance and minimizes glycemic excursions including the risk of hypoglycemia. The designing of menus with regular carbohydrate content allows standard food to be offered to diabetic patients. Regular intake includes the entire meal, not just starchy foods. Indeed, the amount of carbohydrates in the meal should be calculated and planned taking into account all of the components of a meal. This approach will allow more flexibility in menu creation (e.g., starchy products as appetizer, main dish, dessert or bread). ## Recommendation 15: It is recommended that the amount of carbohydrates be known and accessible for each dish served. ## Comment: Individuals under functional insulin therapy must be able to estimate the amount of carbohydrates consumed, and possibly fats and proteins, in order to define the adjusted mealtime insulin dose for better glycemic control. Recommendation 4 on accessible nutritional values will facilitate the achievement of this recommendation. Insofar as recommendations 2 (standard diet meeting the recommendations for prevention and health promotion) and 4 (known nutritional values of provided foods) are respected, the standard (so-called normal) diet may be offered to individuals hospitalized with diabetes. The meals offered should meet public health criteria with regard to diabetic diet provision on the one hand, and on the other, the amount of carbohydrates per dish should be given. ## Recommendation 16: If a low-salt therapeutic diet is indicated, it is recommended not to restrict salt intake (NaCl) from the diet to less than 5 g/day (or approx. 2 g of sodium/d), except in severe acute decompensation and for a very short duration. ## Comment: (1) In heart failure: There is insufficient scientific evidence to support sodium restriction. Several studies are ongoing to assess the effects of a restricted salt (NaCl) consumption in the setting of heart failure (GOURMET-HF, SODIUM-HF, ProhibitSodiumand should enable the providing of answers in the coming years. However, the majority of learned societies recommend a low-sodium (Na) diet, particularly in the case of acute cardiac decompensation. The European consensus recommends a moderately restricted sodium (Na) diet, without specifying the threshold. Finally, the American, New Zealand, Canadian and Australianrecommendations advocate a sodium (Na) consumption of less than 2 g per day, or 5.1 g of salt (NaCl). All of these recommendations are based on expert agreement. A diet under 5 g of salt (NaCl) or~2 g of sodium (Na) per day exposes the patient to a major risk of undernutrition by a reduction in food intakedue to the lack of flavor of the dishes: there is no indication in cardiology. (2) In the setting of ascitic cirrhosis, the European Association for the Study of Liver recommends a restricted diet of between 4.6 and 6 g of salt (NaCl) or~1.8 to 2.4 g of sodium (Na) per day. These recommendations are based on two randomized trials. It is specified that a more restricted salt diet is often associated with a reduction in oral intake and a risk of undernutrition or worsening thereof. (3) In nephrology, a sodium (Na) consumption of less than 4 g per day (or <10 g per day of NaCl salt) is recommended. In the case of volume overload (edema), sodium (Na) consumption should be less than 3 g per day (or 7.6 g of NaCl salt). ## Recommendation 17: The diet designated as "acid-free and/or spice-free" has no indication (except oral or digestive hypersensitivity or food allergy). ## Comment: The terminology of "acid-free and spice-free diet" is that reported by health establishments offering this type of diet. The purpose of the present recommendation is to eliminate this type of diet which has no scientific basis aside from oral sensitivity, particularly for certain spices, which may be related to mucosal lesions. ## Glossary Spices: A spice is an aromatic or pungent vegetation or mineral product. A spice-free diet, however, essentially targets hot spices, comprising piperine or capsaicin (pepper, chili, etc.). The digestive effects of the spices described in the literature are rather positive, although the level of evidence is low, with the exception of a few indications. Spices may improve digestion by stimulating certain digestive enzymes. They can potentially increase satiety, particularly capsaicin. A spicy, more satietogenic diet has a limiting effect on food intake and may facilitate weight gain management. Certain studies have shown that pungent spices may increase plasma concentrations of zinc, iron and calcium (piperine, capsaicin and ginger)and beta-carotene, which may explain the antioxidant effect reported in certain studies. The negative association between spicy food consumption and LDL-cholesterol has led to the suspicion of a cholesterol-lowering effect, which has been corroborated in intervention studies, although with a low level of evidence and low statistical power, particularly with ginger and turmeric. The consumption of spices may reduce salt intake, which is implicated in hypertensionand gastric carcinogenesis. An antineoplastic effect of capsaicin has been reported in several laboratory studies, prompting the testing of analogs, and anticancer effects have also been found for curcumin. Among potential negative effects, certain spices may inhibit a number of liver enzymes involved in the metabolism of drugs, cytochromes P450, in particular capsaicin (CYP2C9), piperine (CYP3A4) and curcumin. Hot spices can increase digestive permeability, which may explain an increase in allergen sensitivity in the event of food allergy, and may also be involved, according to some authors, in the modulation of certain autoimmune diseases. ## Beliefs and misconceptions ## - In irritable bowel syndrome: no study has established a link between spicy food and symptoms. ## - In gastroesophageal reflux disease (GERD): spices may induce burns, but not GERD. Spices can indeed trigger pain when there are existing lesions, such as esophagitis or gastric ulceration. Spices are not involved in the pathophysiology of lesions, but may reveal these lesions by their hyperemic effects. - Spices have no involvement in the pathophysiology of ulcers. Some studies have shown that spices may increase mucus secretion and have a protective role. Capsaicin has been reported to inhibit acid secretion, stimulate mucus secretion and gastric mucosal blood flow, thereby helping in the prevention and healing of gastric ulcers. The metabolic pathway involves prostaglandin E 2 and prostacyclins in conjunction with EP1 and the IP receptor. Spices (pepper, chili) thus appear to have a protective effect on the gastric mucosa. ## Oral mucositis In the case of oral mucositis, a study has shown that the symptoms are significantly correlated with the consumption of spicy and/or hot-temperature foods. ## Regarding the acidity of food There are a number of misconceptions and beliefs regarding the acidity of food. For example, honey has a more acidic pH than tomatoes (3.7-4.2 vs. 4.3-4.9) and grenadine syrup has a lower pH (2.31) than vinegar (2.40-3.40), lemon juice (2.4-2.6) or cola . No food reaches a gastric pH equal to 2. No study has established a link between the pH of food and digestive lesions or diseases. As is the case with spices, certain beverages or foods can trigger pain in the event of a preexisting lesion (esophagitis for example), although the link with the pH of the food is not established. Most acidic foods are perfectly tolerated, even with mouth lesions. Conversely, combining simple sugar with an acidic pH increases the risk of dental erosion. ## Recommendation 18: It is recommended not to exclude pulp-free fruit juices, potatoes, white bread, milk and dairy products from a "strict low-fiber" diet (10-14 g fiber/d, commonly called low-residue or no-residue diet). ## Comment: The designations pertaining to the types of food targeting residues and fibers are subject to semantic heterogeneity from one health establishment to another, both in France and worldwide. As a result, it is possible to find designations as varied as "strict no residue", "no residue", "low-residue", "no fiber", "low-fiber", "digestive restriction", "light", etc. In addition, the same designation can correspond to different levels of restriction. In practice, in clinical studies, the terms "low-fiber" and "low-residue" have the same meaning. This is, therefore, a source of confusion for both the prescriber and the patient. Regardless of the designation, the goal of this type of diet is to limit the volume and number of stools and gas. ## Definition and semantic choices In accordance with Regulation (EU) No. 1169/2011, dietary fiber means: Carbohydrate polymers with three or more monomeric units, which are neither digested nor absorbed in the human small intestine and belong one of the following categories: While it is necessary to be aware of the regulatory definition of dietary fiber, which highlights the health effect of fibers, it is also imperative, in therapeutic practice, to keep in mind that there are other compounds comparable to fibers which do not meet this definition but which, similarly to fibers, are not digested in the small intestine and can have digestive effects, including lignin, polydextroses or even, under certain conditions, lactose or fructose, etc. In its scientific opinion of 2010, l'EFSA (the European Food Safety Agency) gives a broader definition which includes this type of compound. [formula] - [/formula] A residue is defined as the food fraction, derived from fibers or assimilated to fibers, which is not degraded in the small intestine under physiological conditions, and which increases the volume of stool and or gas. The following choices are proposed and justified: 1. The elimination of the designation "no residue": this designation should no longer be used because all foods generate residues. 2. The term "low-fiber" replaces that of "low-residue". In some countries such as the United States, the learned societies in charge of reflecting on these themes have proposed since 2011 to prefer the term "low-fiber" to that of "low-residue"; indeed, unlike fiber, there is no consensus scientific methodology to accurately assess the residue content of a meal. Similarly to this search for harmonization across the Atlantic, and anxious to base itself on a quantifiable scientific definition, it is proposed to no longer use the designation "low-residue" diet. ## 3. To define fiber intake thresholds according to the level of restriction: - "strict low-fiber" corresponds to intakes of 10 to 14 g/d of fiber; - "low-fiber" corresponds to intakes of 15 to 20 g/d of fiber; - A diet consisting of less than 10 g/d of fiber has no indication since it has not been proven to have a therapeutic or diagnostic benefit additional to that of a fiber intake between 10 and 14 g/d. ## 4. As a reminder, most countries recommend that healthy adults, as part of a balanced diet, consume 25 to 35 g/d of dietary fiber daily. In France, ANSES recommends a consumption of 30 g/d while the average consumption among French adults according to the INCA3 survey is 20 g/d. The "strict low-fiber" diet (10 to 14 g/d): This diet must meet daily energy and macronutrient needs. Compared to the aforementioned definitions, the classic exclusion of white bread, potatoes, pulp-free fruit juices, milk and dairy products in the "strict low fiber" diet is currently not based on any rational argument. Fibers and, in particular, those in fruits and vegetables favor GI transit. Due to their effect on the volume of stools and gases and on transit, the following are excluded: whole grains, and vegetables and fruits including apple and prune juice (other pulpfree juices can be proposed). In light of several old studies, there is, however, no justification to prefer stale bread, toast or rusks, to fresh bread. Potatoes can be introduced in any form. Lactose can be poorly absorbed under certain conditions and induce digestive disorders. Intolerant individuals, however, represent only a small proportion of the lactosemalabsorption population. Lactose intolerance, whether primary or secondary, is managed by adapting the consumption of the products to the patient's tolerance without eliminating them(see recommendation 21). There is, therefore, no justification for systematically excluding milk and dairy products from the "strict low-fiber" diet. It is important to note that the "strict low-fiber" diet remains nonetheless restrictive and monotonous and can induce a nutritional risk. It should be prescribed for a limited period and reassessed regularly. ## Recommendation 19: It is recommended to reserve the "strict low-fiber" diet (10 to 14 g/d of fiber) for therapeutic purposes in symptomatic intestinal strictures; for diagnostic purposes in certain GI explorations (colonoscopy, CT colonography, MR enterography (MRE), etc.); or for symptomatic purposes. ## Comment: The "strict low fiber" diet provides 10 to 14 g/d of fiber, as defined in recommendation 18. The indication of a "strict low-fiber" diet for therapeutic purposes is not based on a strong scientific rationale outside the field of symptomatic intestinal strictures (subocclusion) and lower digestive fistulas (small intestine and colon). It is recommended in colonoscopies in addition to or as a replacement for purging when administration is impossible and, in such cases, constitutes an indication of diagnostic value. There is lack of consensus regarding the prescription period, which can range from 1 to 3 days, or even be limited to a meal. In the American recommendations, the duration used for such a diet in addition to the purge is equivalent to 1 day, the day before exploration. This therapeutic diet can be prescribed for other explorations, in particular for imaging, to improve the quality of images by reducing the production of intestinal gas. There is no rationale for higher restriction levels, namely a fiber intake of less than 10 g/day (see recommendation. Fibers participate in nutritional balance; furthermore, it is advisable not to unduly restrict fibers, including in gastrointestinal diseases. The prescription of a "strict low-fiber" diet for therapeutic purposes is not recommended in colonic diverticulitis, in irritable bowel syndrome, or in IBD. In case of type III chronic intestinal failure and irrespective of the type of short bowel, it is not recommended to proscribe fibers, including in type 1 short bowel (jejunostomy), since fibers slow down gastric emptying and contribute to energy recovery in type 2 and 3 short bowel via the intestinal flora of the colon. While there is no indication to prescribe a strict low-fiber diet for therapeutic purposes in these diseases, there may, however, be indications to prescribe this type of diet on a case-by-case basis, and transiently, for symptomatic relief, in order to limit intestinal distension, diarrhea, excessive flatulence or digestive pain. This can be the case in acute or chronic and active (or flare-up) enteropathies such as small bowel radiation enteritis or inflammatory bowel disease. This diet modality is aimed at improving symptoms experienced by the patient and, consequently, to improve quality of life. It must be personalized, and its relevance reassessed after treatment of the underlying disease which led to its indication. The duration should be as short as possible in order to limit nutritional risk. In the case of colonic diverticulitis, low levels of evidence do not make it possible to substantively define an optimal level of fiber intake. The HAS recommends not restricting fiber intake in such patients; however, pending recommendations based on stronger evidence, some authors suggest limiting the intake of fiber in case of pain, while other authors propose leaving the patient free to consume whatever amount he or she deems able to tolerate during the acute period. Recommendation 20: Per medical prescription, a low-fiber diet (15-20 g fiber/day) may be indicated during hospital stay, in terms of digestive symptoms. ## Comment: Although there are no or very few studies with strong scientific evidence which recommend a low-fiber diet providing between 15 and 20 g fiber/day, it can help improve quality of life in some patients. This diet aims to limit the volume and number of stools and gases to a lesser degree than the strict low-fiber diet. It is essentially based on professional expertise. It is an intermediate level between the "strict low-fiber" diet and the standard diet (fiber intake between 25 and 30 g/d). It enables the limiting of nutritional risks linked to restrictions that are too high relative to the expected benefits. These have been widely described in the literature with anorectic effects, imbalances, insufficient energy intake, etc. The strict low-fiber diet, for example, is associated with monotony and a deficiency in vitamin C intake. Conversely to the strict low-fiber diet, in addition to pulp-free fruit juices, the low-fiber diet incorporates vegetables and fruits whose fiber content is less than 3 g/100 g (while continuing to exclude whole grains, legumes and dried fruits). In Europe, a food can be considered a source of fiber if it contains at least 3 g of fiber/100 g or 1.5 g of fiber/100 kcal. It is considered high in fiber if it contains 6 g of fiber/100 g or 3 g of fiber/100 kcal. Food fiber contents are available in the CIQUAL table. Seasoning fat is not limited. This diet, therefore, allows a better diversity of proposed dishes. With regard to current compositions, the total fiber intake of this low-fiber diet is between 15 and 20 g of fiber/day. This dietary mode is similar to the most widespread diet in the French population, even though ANSES recommends a consumption of 30 g/day for healthy adults. The low-fiber diet can be indicated for therapeutic purposes for diseases requiring a moderate level of fiber restriction, such as mild or non-symptomatic intestinal stricture or gastroparesis. It can also be indicated for symptomatic relief when expanding a strict low-fiber diet, and also in GI replenishment (knowing that there is no indication to prescribe a strict low-fiber diet in this setting). This type of diet aims to preserve digestive comfort while limiting restrictions, the secondary benefit, therefore, being to improve intakes. This diet must be prescribed for a limited period, be adapted to individual tolerance and be reassessed. ## Recommendation 21: It is recommended not to exclude all dairy products in the context of lactose intolerance. ## Comment: In order to be absorbed, lactose must first be hydrolyzed by lactase. While lactase deficiency is common, we only speak of intolerance when the malabsorbed lactose is responsible for digestive disorders (by osmotic effect in the small intestine and or by fermentation in the colon). On the other hand, this component of malabsorbed lactose leads to colonic adaption by the microbiota, which could prove favorable. Lactase deficiency, common in adults, does not mean that you are lactose intolerant. Intolerance represents only a small proportion of maldigesters, the vast majority of lactosemalabsorbing individuals being asymptomatic. The Lactose Breath Test (25 g) remains the benchmark method of diagnosis. It is used to assess malabsorbed lactose. It must be accompanied by assessment of symptoms (for 8 h) which defines the level of tolerance. Lactose intolerance is not an allergy. When the diagnosis of lactose intolerance is made, management does not consist in suppressing, but in adapting the consumption of milk and dairy products according to the patient's tolerance, the objective being to eliminate annoying digestive disorders. While tolerance thresholds vary according to the individual, studies have shown that maldigesters can tolerate up to 12 g of lactose (i.e., a glass of milk) when it is consumed alone and on an empty stomach, and up to 20 g when ingested with other foods. Even with an equal lactose content, foods are not all equal in terms of tolerance due to their composition (lactose load, fat content, etc.), texture and their combination, or not, with other foods. Anything that slows down gastric emptying can improve lactose tolerance. Milk as a beverage is the least tolerated form (liquid), especially if it is skimmed and taken on an empty stomach. Whether it is a primary intolerance or disease-related intolerance, it is these concepts that should be relied upon to improve tolerance. It is not necessary to eliminate lactose from the diet. In all instances, there is no justification for eliminating yogurts and cheeses, or foods that are sources of low lactose content. Milk and dairy products are a source of calcium and protein. Their removal constitutes a risk to bone health; hence, there should be no unnecessary restriction, especially since the adaptation of the colonic microflora (colonic acidity) to digest lactose is one of the mechanisms of lactose tolerance. ## Recommendation 22: Aside from medically diagnosed celiac disease, a gluten-free diet is not recommended. ## Comment: Celiac disease is an autoimmune-mediated enteropathy. It is also called gluten intolerance, which can cause confusion regarding the nature of the condition. In adults, the diagnosis of celiac disease is based on the detection of specific serum antibodies, confirmed by a duodenal biopsy. Permanently eliminating gluten is the only treatment for celiac disease. Herpetiformis dermatitis is a skin expression of celiac disease, which also requires the monitoring of a gluten-free diet. The definition of non-celiac gluten sensitivity (NCGS) initially retained by the experts is: "syndrome characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected by either celiac disease or wheat allergy". In light of the current literature, SGNC is a disease that is still poorly understood, the mechanism of which is likely multifactorial. Other components of wheat, rye and barley are likely to be responsible for the observed disorders (ATI-amylase trypsin inhibitor-, WGA-wheat germ agglutinins-, FODMAPS-fermentable oligo-, di-and monosaccharides and polyols-, etc.). For this reason, the name SGNC is still under discussion, with some authors proposing the term "wheat sensitivity". The responsibility of fructans (FODMAPS) is often mentioned, although there is ostensibly no point in preferring gluten-free cereals to traditional cereals with regard to fructan content. In patients with irritable bowel syndrome, the current diagnosis of SGNC is a diagnosis of exclusion which, according to the recommendations of the experts, is achieved in two stages, after ensuring that the patient has a balanced diet: assessment of the effects of removing gluten (at least 6 weeks); impact of its reintroduction (at least 4 weeks). Once diagnosis has been established, the duration of exclusion and reintroduction are not defined. Insofar as the treatment aims only to limit the disorders, it would appear logical to adapt the consumption to the tolerance of the patient, and not by imposing a strict diet for life. While the link between gluten and celiac disease is well established, the responsibility of gluten in SGNC remains to be demonstrated. It is, therefore, not possible to date to state that a gluten-free diet is indicated in SGNC. Wheat protein allergy involves complex phenomena. Allergic reactions to wheat proteins are caused by various types of exposures-ingestion, inhalation, contact-and can also appear following physical exertion. Most often, this allergy is transient and can disappear with growth. Gluten proteins are not the only elements likely to be responsible for wheat allergy. A gluten-free diet is, therefore, not indicated in the context of wheat protein allergy, since the treatment is not limited to solely gluten restriction. In all instances, whether it is the application of the diagnostic protocol, or the adaptation of the diet once the diagnosis has been established, dietary management is necessary to support the patient and limit the risks of nutritional imbalance. Not only is the removal of gluten not indicated outside the diagnosis of celiac disease, this removal can also be harmful by incurring an imbalance in nutritional intake. When there is no medical indication for a gluten-free diet, it should nevertheless be possible to offer suitable and balanced food provision to patients who have deleted gluten out of habit, conviction or tolerance issues. It is indeed advisable not to induce a nutritional risk by proposing a meal to the patient which he or she will not consume. ## Recommendation 23: It is recommended to propose, in terms of food provision, an energyand/or protein-enriched diet in order to meet the requirements of prevention and management of undernutrition. Comment: Proposing an energy-or protein-enriched diet encompasses 30 to 50% of undernourished hospitalized patients or those at risk of undernutrition. Together with the standard diet, proposed by recommendation 2 (meeting the recommendations for promotion and prevention of health), this enrichment is aimed at prioritizing the prevention and management of undernutrition by making it possible to meet the needs of patients who have trouble feeding themselves properly (lack of appetite, staggered or skipped meals due to exams or fasting, etc.) through enrichment strategies. Several strategies are possible to increase the energy and/or protein density of meals and allow the increasing of both energy and protein intakes, particularly in the elderly. These strategies aim to offer: enriched meals through foods with high nutritional density (milk powder, dairy products, cheeses, fats and sugars), added to various salty or sweet preparations (soups, sauces, dessert creams, cakes and breads), and to adjust the size of the portions served. A systematic review byshowed the beneficial effects of meal fortification strategies and the provision of snacks in ten studies totaling 546 patients. Intake was significantly increased compared to current care by 250 to 698 kcal per day and 12-16 g of protein per day, according to the studies. The cost-effectiveness was favorable (measured in two studies), and patients expressed good acceptability of the enriched products while appreciating the taste (in four studies). The goal is to offer higher energy-and/or nutrient-dense meals, without increasing their volume. The other possibility is to reduce the volume of meals for patients that are small eaters, in order to favor consumption. This in turn necessitates enrichment and supplementation strategies in the form of snacks, in order to reach the daily nutritional target. This requires flexibility on the part of both the healthcare staff and catering services, and an adaptation to the patients' personal food/mealtime experience during their hospitalization. # Conclusions All efforts should be made to create meals that follow these recommendations while promoting the taste quality of the dishes and their presentation such that the patient rediscovers the pleasure of eating in the hospital. To promote the implementation of the guidelines, the AFDN and the SFNCM have just made available to health care institutions a grid for assessing current practices and deviations from the recommendations. This will allow the establishment of an implementation plan with priorities. At the same time, practical information sheets are being developed to provide practical assistance to hospitals. They are based on targeted arguments to convince both healthcare and catering professionals and are also based on the successful experiences of innovative establishments. Furthermore, we have obtained the labeling of the guidelines by learned societies in the fields of diabetes, nephrology and gastroenterology. This is a cornerstone in ensuring the acceptance of the recommendations by healthcare professionals and patients alike.	None	https://www.mdpi.com/2072-6643/13/7/2434/pdf?version=1626680473	Aim: Hospital food provision is subject to multiple constraints (meal production, organization, health safety, environmental respect) which influence the meal tray offered to the patient. Multiple diets can add complexity and contribute to non-consumption of the meal. To avoid undernutrition, it appeared necessary to propose guidelines for foods and diets in hospitals. Methods: These guidelines were developed using the Delphi method, as recommended by the HAS (French Health Authority), based on a formal consensus of experts and led by a group of practitioners and dieticians from the AFDN (French Association of Nutritionist Dieticians) and SFNCM (French Society of Clinical Nutrition and Metabolism). Results: Twenty-three recommendations were deemed appropriate and validated by a panel of 50 national experts, following three rounds of consultations, modifications and final strong agreement. These recommendations aim to define in adults: 1—harmonized vocabulary related to food and diets in hospitals; 2—quantitative and qualitative food propositions; 3—nutritional prescriptions; 4—diet patterns and patient adaptations; 5—streamlining of restrictions to reduce unnecessary diets and without scientific evidence; 6—emphasizing the place of an enriched and adapted diet for at-risk and malnourished patients. Conclusion: These guidelines will enable catering services and health-care teams to rationalize hospital food and therapeutic food prescriptions in order to focus on individual needs and tasty foods. All efforts should be made to create meals that follow these recommendations while promoting the taste quality of the dishes and their presentation such that the patient rediscovers the pleasure of eating in the hospital.
382309d62351e5bd6627a0b34929c92d17f444f4	pubmed	Clinical practice recommendations for growth hormone treatment in children with chronic kidney disease	Clinical practice recommendations for growth hormone treatment in children with chronic kidney disease ## Supplementary box 1 \| cost-effectiveness analysis Most pediatric CKD patients have advanced CKD at the time of initiation of GH treatment, and will undergo renal transplantation when GH treatment is terminated. The duration of GH treatment is mainly determined by the age at onset of CKD, its rate of progression and the availability of a renal transplant. Therefore, our cost-effectiveness analysis included two hypothetical scenarios: (i) case 1, a child with early-onset CKD requiring GH therapy at the age of 5 years, (ii) case 2, an adolescent with late onset or slowly progressive CKD requiring GH treatment at the age of 12 years. The mean duration of GH treatment in studies reporting on final height ranged between 2 and 5 years; therefore, we used this range to estimate the cumulative drug-related costs. In addition, the estimates for drug dose were based on daily GH doses of 0.045 mg/kg body weight and were calculated for the respective age-and sex-related 25 th weight percentile using the WHO reference data, assuming that patients will have a height below the 3 rd percentile at the time of initiation of GH treatment and will show catch-up growth into the lower normal range thereafter (Supplementary . Since the costs for patient monitoring are less than 3% of total treatment-related costs, only drug-related costs were taken into account for this analysis . The cost for GH differs considerably among European countries, and a price of €22 per 1 mg GH, based on the median cost in eight representative European countries, was used (Supplementary. In clinical studies the height standard deviation score (height SDS) is often used to compare growth in children differing in age and sex. Height SDS is a conversion of height (or length) that represents the number of standard deviations (SD) from the mean height for age and sex. A child with a height SDS less than -1.88, which corresponds to the 3 rd percentile, has short stature. Therefore, the mean increase in final height in GH treated patients was calculated as the difference between standardized final height (height SDS) and standardized height at the start of GH therapy for all available studies reporting on adult height with treatment periods of at least 2 years (Supplementary. The median increase in standardized height in these studies (1.1 SDS) was converted to cm (7.4 cm in boys, 7.0 cm in girls) by use of European reference values. Thus, an expected gain in final height of 7.2 cm was used in the costeffectiveness analysis; that is, a calculation of the incremental cost per centimeter gained in final height . GH 0.5: 0.5 IU/kg/wk for 12 months GH 1.0: 1.0 IU/kg/wk for 12 months CKD stage 3-5: HV significantly increased in both groups, and was higher in GH 1.0 vs. GH 0.5 (each P<0.01). CKD stage 5D: HV significantly increased in both groups, and was higher in GH 1.0 vs. GH 0.5 (each P<0.01). CKD stage 5T: HV increased increased in both groups (each P<0.05) and did not differ between groups; 7/23 patients showed acute rejection episodes.[S16] Height SDS in CKD stage 3-5: Baseline -3.4 ± 0.1 1st yr -2.6 ± 0.1 2nd yr -2.1 ± 0.2 3rd yr -1.8 ± 0.3 4th yr -1.7 ± 1.5 5th yr -1.9 ± 1.5 (each P<0.05) Height SDS in CKD stage 5D Baseline -3.6 ± 0.2 1st yr -3.1 ± 0.3 2nd yr -3.0 ± 0.4 3rd yr -3.7 ± 0. Suppl. Assumes a child aged 5 years and benefit uniformly sperad over treatment period. b Assumes a child aged 12 years and benefit uniformly sperad over treatment period. NA, not applicable. Costs were obtained from national data sources or local pharmacies; n.a., not available. Adverse effects not addressed ## Supplementary ## Supplementary Powell 1997 (CT) Kuizo 1998 (CKD VD) KTx, Kidney transplant; CT, conservative treatment (CKD prior to dialysis); CKD 5D, dialysis; N, total no. of patients randomized (no treatment group, GH group); NS, Non-significant; OGTT, Oral glucose tolerance test. We recommend that children with stage 3-5 chronic kidney disease (CKD) or on dialysis aged above 6 months should be candidates for GH therapy if they have persistent growth failure, defined as a height below the third percentile for age and sex and a height velocity below the twenty-fifth percentile, once other potentially treatable risk factors for growth failure have been adequately addressed and provided the child has growth potential. ## Supplementary B, moderate 2.3 We recommend that GH therapy is considered for children with stage 3-5 CKD or on dialysis aged above 6 months who present with a height between the third and tenth percentile but persistent low height velocity (below the twenty-fifth percentile) once other potentially treatable risk factors for growth failure have been adequately addressed.	None	https://www.nature.com/articles/s41581-019-0161-4.pdf	None
2fa84c890c147be2198bed4fff928c7e69cab696	pubmed	Guidelines on the management of acute respiratory distress syndrome	Guidelines on the management of acute respiratory distress syndrome # Abstract The Faculty of Intensive Care Medicine and Intensive Care Society Guideline Development Group have used GRADE methodology to make the following recommendations for the management of adult patients with acute respiratory distress syndrome (ARDS). The British Thoracic Society supports the recommendations in this guideline. Where mechanical ventilation is required, the use of low tidal volumes (<6 ml/kg ideal body weight) and airway pressures (plateau pressure <30 cmH 2 O) was recommended. For patients with moderate/severe ARDS (PF ratio<20 kPa), prone positioning was recommended for at least 12 hours per day. By contrast, high frequency oscillation was not recommended and it was suggested that inhaled nitric oxide is not used. The use of a conservative fluid management strategy was suggested for all patients, whereas mechanical ventilation with high positive end-expiratory pressure and the use of the neuromuscular blocking agent cisatracurium for 48 hours was suggested for patients with ARDS with ratio of arterial oxygen partial pressure to fractional inspired oxygen (PF) ratios less than or equal to 27 and 20 kPa, respectively. Extracorporeal membrane oxygenation was suggested as an adjunct to protective mechanical ventilation for patients with very severe ARDS. In the absence of adequate evidence, research recommendations were made for the use of corticosteroids and extracorporeal carbon dioxide removal. # Introduction aims The purpose of this guideline is to provide an evidence-based framework for the management of adult patients with acute respiratory distress syndrome (ARDS) that will inform both key decisions in the care of individual patients and broader policy. Our recommendations are neither dictates nor standards of care. We cannot take into account all of the features of individual patients and complex local factors; all we can do is to synthesise relevant evidence and to put it into the context of current critical care medicine. Similarly, our recommendations are not comprehensive: these guidelines have relevance to a fraction of the total number of decisions that are required of carers for these complex patients. Indeed, the current state of the art for the management of ARDS has been recently reviewed [bib_ref] Mechanisms and clinical consequences of acute lung injury, Fanelli [/bib_ref] [bib_ref] Recent advances in the management of the acute respiratory distress syndrome, Hager [/bib_ref] [bib_ref] Controversies in the management of severe ARDS: optimal ventilator management and use..., O'gara [/bib_ref] [bib_ref] Acute respiratory distress syndrome, Sweeney [/bib_ref] and comparable guidelines have been produced by national and international stakeholders. scope The topics considered were chosen by the Guideline Development Group (GDG) in the light of results from a survey carried out for the Intensive Care Society (ICS), including 556 responses from 3200 members. Popular topics were excluded by the GDG if it was felt that there was a dearth of evidence (eg, appropriate diagnostic investigations and the role of specialist centres), when the evidence was not specific to ARDS (weaning from mechanical ventilation, nutrition and the timing of tracheostomy) and if there was overlap with existing guidelines (post-ICU (intensive care unit) care and rehabilitation). definitions ARDS was first reported in a case series from Denver in 1967. [bib_ref] Acute respiratory distress in adults, Ashbaugh [/bib_ref] The American European Consensus Conference (AECC) 1994 defined ARDS as 'an acute inflammatory syndrome manifesting as diffuse pulmonary oedema and respiratory failure that cannot be explained by, but may co-exist with, left-sided heart failure'. [bib_ref] The American-European consensus Conference on ARDS. definitions, mechanisms, relevant outcomes, and clinical..., Bernard [/bib_ref] In 2012, the AECC definition was re-evaluated and minor alterations were proposed by the European Society of Intensive Care Medicine ARDS Definition Task Force. This iteration recognised 3 grades of severity depending on the degree of hypoxaemia and stipulated the application of at least 5 cmH 2 O of positive end-expiratory pressure (PEEP) or continuous positive airway pressure. This so-called Berlin definition was validated using retrospective cohorts and captures patients with a mortality of 24% in patients with mild ARDS, rising to 48% in Open access the group of patients with the most severe respiratory failure. [bib_ref] The Berlin definition of ARDS: an expanded rationale, justification, and supplementary material, Ferguson [/bib_ref] A four-point lung injury scoring system (Murray Score or LIS) is the most widely used means of quantifying ARDS severity. It is based on the level of PEEP, the ratio of the partial pressure of arterial oxygen (PaO 2 ) to the fraction of inspired oxygen (FiO 2 ), the dynamic lung compliance and the degree of radiographic infiltration. [bib_ref] Acute respiratory distress in adults, Ashbaugh [/bib_ref] Although the LIS has been widely used in clinical studies and a score of >3.0 is commonly used as a qualifying threshold for support with extracorporeal membrane oxygenation (ECMO), it cannot predict outcome during the first 24-72 hours of ARDS. [bib_ref] The American-European consensus Conference on ARDS. definitions, mechanisms, relevant outcomes, and clinical..., Bernard [/bib_ref] When the scoring system is used 4-7 days after the onset of the syndrome, scores of 2.5 or higher predicted a complicated course requiring prolonged mechanical ventilation. [bib_ref] The Berlin definition of ARDS: an expanded rationale, justification, and supplementary material, Ferguson [/bib_ref] As a syndrome rather than a disease, there is no laboratory, imaging or other 'gold standard' diagnostic investigation for ARDS. Therefore like acute kidney injury (AKI), ARDS is caused by a huge range of conditions and as a consequence patients with ARDS are heterogeneous. The outcome of these patients is determined by the underlying causes of ARDS, patient-specific factors such as comorbidities, clinical management and the severity of illness. ## Epidemiology and outcomes Using the AECC definition, several population-based studies of ARDS showed a fairly consistent picture of the age, mortality and severity of illness; however, there was almost a fourfold difference in incidence, probably contributed to by differences in study design and ICU utilisation. [bib_ref] Epidemiology and outcomes of acute lung injury, Rubenfeld [/bib_ref] In the USA, there are estimated to be 190 000 cases and 74 000 deaths annually from ARDS. [bib_ref] Incidence and outcomes of acute lung injury, Rubenfeld [/bib_ref] Whereas in a third world setting, from 1046 patients admitted to a Rwandan hospital over 6 weeks, 4% (median age 37 years) met modified ARDS criteria. Only 30.9% of patients with ARDS were admitted to an ICU, and hospital mortality was 50.0%. This study used the Kigali modification of the Berlin definition: without a requirement for PEEP, hypoxia threshold of SpO 2 /FiO 2 less than or equal to 315, and bilateral opacities on lung ultrasound or chest radiograph. [bib_ref] Hospital incidence and outcomes of the acute respiratory distress syndrome using the..., Riviello [/bib_ref] The recently published LUNG SAFE trial was designed to study prospectively the performance of the Berlin definition and to reflect modern management of ARDS. To those ends, the investigators recorded admissions over 4 weeks to 459 ICUs in 50 countries over 5 continents including patients. In total, 3022 (10.4%) cases fulfilled ARDS criteria, including almost a quarter of those supported with invasive mechanical ventilation. [bib_ref] Epidemiology, patterns of care, and mortality for patients with acute respiratory distress..., Bellani [/bib_ref] Despite this relatively high prevalence and the study's focus on ARDS, the syndrome was recognised in only half of the mild ARDS group. Furthermore, in a study that reported on 815 patients with at least one risk factor for ARDS who were admitted to one of 3 Spanish hospitals over 4 months, 15 out of 53 patients (28%) were not admitted to an ICU suggesting that LUNG SAFE may have underestimated both ARDS incidence and overlooked diagnoses. [bib_ref] Clinical risk conditions for acute lung injury in the intensive care unit..., Ferguson [/bib_ref] Survivors commonly suffer from muscle weakness and neuropsychiatric problems, such that fewer than 50% have returned to work 12 months after leaving intensive care. [bib_ref] One-year outcomes in survivors of the acute respiratory distress syndrome, Herridge [/bib_ref] However, it is unusual for ARDS survivors to be significantly limited by chronic respiratory failure. Therefore, ARDS is important both clinically and financially, because it is a not uncommon contributor to the deaths of critically ill patients of all ages and because survivors carry on suffering from the sequelae of critical illness long after they leave hospital. [bib_ref] Functional disability 5 years after acute respiratory distress syndrome, Herridge [/bib_ref] ## Pathophysiology The pathophysiology of ARDS results from acute inflammation affecting the lung's gas exchange surface, the alveolar-capillary membrane. [bib_ref] Mechanisms and clinical consequences of acute lung injury, Fanelli [/bib_ref] Increased permeability of the membrane associated with the recruitment of neutrophils and other mediators of acute inflammation into the airspace manifests as high permeability pulmonary oedema. The resulting acute inflammatory exudate inactivates surfactant leading to collapse and consolidation of distal airspaces with progressive loss of the lung's gas exchange surface area. This would be compensated for by hypoxic pulmonary vasoconstriction, if the inflammatory process did not also effectively paralyse the lung's means of controlling vascular tone, thereby allowing deoxygenated blood to cross unventilated lung units on its way to the left heart. The combination of these two processes causes profound hypoxaemia and eventually type 2 respiratory failure as hyperventilation fails to keep pace with carbon dioxide production. diagnosis Any diagnostic strategy for ARDS is sufficiently dependent on local factors, such as the prevalent causes of infectious pneumonia and access to imaging modalities, that a single protocol cannot be recommended. An exemplar from a tertiary referral centre used to dealing with complex and very severe cases is included (figure 1, p43-44). There are two main broad categories of condition that resemble ARDS but have a distinct pathophysiology: first, cardiovascular conditions of rapid onset including left heart failure, right-to-left vascular shunts usually with some lung pathology and major pulmonary embolism; second, lung conditions which develop more slowly than ARDS, for example, interstitial lung diseases (especially acute interstitial pneumonia), bronchoalveolar cell carcinoma, lymphangitis and the pulmonary vasculitides. ## Technical summary The guidelines for the management of adult patients with ARDS were created by a multidisciplinary writing group constituted by the Joint Standards Committee of the Faculty of Intensive Care Medicine and the ICS. All Open access Sixty-day and hospital mortality comparing LTV and HTV mechanical ventilation in adult patients with ARDS. ARDS, acute respiratory distress syndrome; HTV, higher tidal volume; LTV, lower tidal volume. group members, including lay members, are coauthors of the guideline. The group first met in 2013 and completed the guidelines in 2018. The guidelines have undergone both independent external peer review and input from stakeholder organisations. The process for guideline creation adhered to that of the National Institute for Health and Care Excellence (NICE). In brief, the writing group first performed a scoping exercise on the topic, having decided that the focus should be on effective treatment interventions. Ten topics were chosen based on existing guideline recommendations and the experience of committee members. These included: ► Corticosteroids. ► ECMO. ► ECCO 2 R. ► Fluid strategy. ► High-frequency oscillation ventilation (HFOV). ► Inhaled vasodilators (iVasoD). ► Lung protective ventilation: tidal volume (Vt). ► Neuromuscular blocking agents (NMBA). ► PEEP. ► Prone positioning. Each topic was developed into a full protocol using the PICO (Population, Intervention, Comparison, Outcome) formulation. Search strategies for each topic were then developed by the group information expert with a focus on systematic reviews (SR) and meta-analyses (MA). Each topic was assigned to two group members with one acting as topic lead. High-quality MA and SR were selected and the references placed in an Endnote database. Preselected outcome data were extracted from these reviews, using the most up-to-date MA where possible. Data from older MA were used if not all the preselected outcomes could be extracted from the most recent MA. The guidelines used the internationally recognised GRADE methodology. [bib_ref] Grade: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] Group members received training on the GRADE process and were given a resource pack, which included a practical guide which was created in-house. GRADE makes recommendations based on patient centred and predetermined outcomes. It does not judge the quality of individual randomised controlled trials (RCTs) but makes quality assessments on the predetermined outcomes, which, where possible, are extracted from published MA. [bib_ref] Grade guidelines: a new series of articles in the Journal of clinical..., Guyatt [/bib_ref] The following outcomes were chosen by the writing group as either of critical or high importance using the GRADE methodology: Mortality ( GRADE has a transparent methodology and guides recommendations based on the evidence collected. In reality, treatment recommendations are a graduation. However, in order to aid clinical decision-making, GRADE converts the continuum into five mutually exclusive categories. [bib_ref] Grade: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] Recommendations are therefore categorised as strongly in favour, weakly in favour (or conditional), strongly against or weakly against (conditional). Finally, a research recommendation can be made where the estimate of the magnitude of effect and its boundaries were so imprecise and wide that further research is likely to make ## Analysis of outcomes mortality A MA of hospital mortality alone was presented in two SRs, while combined data on both hospital and 60-day mortality were presented in another SR. [bib_ref] Exploring the heterogeneity of effects of corticosteroids on acute respiratory distress syndrome:..., Ruan [/bib_ref] The quality of evidence supporting the relative risk (RR) of 0.51 (95% CI 0.24 to 1.09) in hospital mortality with steroids was very low 21 (see GRADE evidence profile table 1). There was a serious risk of bias with only 75% of the Cochrane Open access risk of bias recommendations followed. Inconsistency was also serious with point estimates varying widely, confidence intervals overlapping, a lack of consistent direction of effect and significant heterogeneity (I 2 52%). Imprecision was also serious. A posthoc power calculation suggests that the pooled studies only had an approximately 65% power and a sample size calculation based on the reported effect size suggested that sample size was inadequate (predicted sample size of 474; actual pooled sample size of 341 for hospital mortality). This is likely to be an underestimate of the sample size required, as the effect size is likely to be smaller than the pooled data suggest due to heterogeneity of the studies. A further issue is the fact that the majority of these studies were performed in the prelung protection strategy era. The largest ARDS Network steroid study, LASARUS, changed its ventilation protocol during the study to reflect the results of the ARDS Network ARMA low tidal volume study. [bib_ref] Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome, Steinberg [/bib_ref] The other hospital mortality analysis also reported low-quality data with an estimated RR of 0.62 (0.23-1.26). [bib_ref] Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS)..., Peter [/bib_ref] Combining hospital and 60-day mortality gave a RR estimate of 0.91 (0.71-1.18) with serious inconsistency and indirectness issues including the fact that this was a pooled estimate of both preventative and treatment studies. [bib_ref] Exploring the heterogeneity of effects of corticosteroids on acute respiratory distress syndrome:..., Ruan [/bib_ref] Length of stay A MA of hospital length of stay was presented in one SR and MA. [bib_ref] Corticosteroid therapy for acute lung injury, acute respiratory distress syndrome, and severe..., Lamontagne [/bib_ref] A mean reduction of 4.8 days with steroid treatment was reported but the overall quality of the studies was very low. ## Quality of life This was not reported in the Included MA. ## Economic data No economic data were published in the trials included. ## Treatment harms Potential harms of treatment with steroids included excess hospital acquired infections, ICU acquired weakness and delirium. The only available MA reported a composite analysis of infection, ICU acquired weakness, diabetes, gastrointestinal bleeding and other complications. [bib_ref] Use of corticosteroids in acute lung injury and acute respiratory distress syndrome:..., Tang [/bib_ref] The RR reported was 0.82 (0.5-1.36) but the quality of the trials was low. # Grade recommendation statement The use of corticosteroids in established ARDS should be the subject of a suitably powered, multicentre RCT with long-term follow-up (GRADE Recommendation: research recommendation). ## Grade recommendation justification Current evidence includes the possibility of substantial patient benefit and the risk of harm appears small, although the group noted that the trials did not include longer term follow-up of survivors. However, the evidence is of low to very low quality from clinical trials, which were mostly conducted before the current era of lung protective ventilation. In addition, the lack of sufficient power in any individual study or in the combined MA and the heterogeneity of the dose, timing and agent used also influenced the decision. The group believed that a position of equipoise exists and the research recommendation reflects this view. As a caveat, it is worth mentioning that specific steroid responsive disorders may mimic ARDS, for example, pneumocystis jiroveci pneumonia, acute eosinophilic pneumonia and diffuse alveolar haemorrhage. Implications for future research A large, multicentre study on steroids in established ARDS is currently planned. ## Extracorporeal membrane oxygenation pico question In adults with ARDS, does the use of ECMO, compared with standard care affect survival and selected outcomes? ## Study identification The search strategy was predefined as per online appendix C. Eight, relevant SR were identified, of which three included a MA [bib_ref] Extracorporeal life support for acute respiratory failure. A systematic review and metaanalysis, Munshi [/bib_ref] [bib_ref] Extracorporeal membrane oxygenation for severe respiratory failure in adult patients: a systematic..., Zampieri [/bib_ref] (see PRISMA chart in online appendix A). When analysing results, we used the most recent SR with MA that considered the outcome in question. [bib_ref] Extracorporeal life support for acute respiratory failure. A systematic review and metaanalysis, Munshi [/bib_ref] The selected SR with MA included only two RCTs of ECMO in adults with ARDS. These RCTs were published in 1979 and 2006 and included a total of 270 participants. The older RCTs 32 did not combine the use of ECMO with protective low tidal volume mechanical ventilation and so is of little relevance to current practice. Data from this RCT and RCTs investigating the use of extracorporeal carbon dioxide removal (ECCO 2 R) were excluded. By contrast, we included in our de novo MA two quasi-RCT, which used genetic matching with replacement to identify control subjects and compared these with patients supported with ECMO in a total of 346 patients, all with pandemic H1N1 2009 influenza A. A GRADE Summary of Findings table is shown based on critical and important outcomes (table 2). A full GRADE evidence table can be found as part of the online appendix B. ## Analysis of outcomes mortality Hospital mortality was studied in two quasi-RCT in patients with H1N1 and hospital mortality was combined with mortality up to 6 months after hospital discharge in the RCT (CESAR) that recruited a general adult population with severe ARDS. [bib_ref] CESAR: conventional ventilatory support vs extracorporeal membrane oxygenation for severe adult respiratory..., Peek [/bib_ref] Point estimates consistently showed a reduction in mortality in patients supported with ECMO: the risk ratio for hospital mortality was 0.64 (0.51-0.79). However, owing to the potential bias and lack of generalisability in the quasi-RCTs, the quality of evidence was deemed to be very low. ## Length of stay This was not reported in the included MA. ## Quality of life This was not reported in the included MA. ## Economic data This was not reported in the included MA. The CESAR study alone included both cost utility and cost effectiveness analyses enabling investigators to predict a lifetime cost per quality-adjusted life year (QALY) for ECMO of £19 252 (CI 7622 to 59 200) at a discount rate of 3.5%. 31 ## Treatment harms The use of ECMO is associated with the risk of serious bleeding, although this has not been universally reported or consistently defined in published studies. The risk ratio for bleeding associated with ECMO was 11.44 . The quality of evidence was deemed to be very low because data were available from two non-randomised studies that only included patients with ARDS associated with influenza A (H1N1). Grade recommendation statement We do not recommend the routine use of ECMO for all patients with ARDS (GRADE Recommendation: weakly against). We suggest the use of ECMO with lung-protective mechanical ventilation in selected patients with severe ARDS (GRADE Recommendation: weakly in favour). ## Grade recommendation justification The use of ECMO in selected adults suffering severe ARDS (defined as a Lung Injury Score of 3 or more or pH<7.20 due to uncompensated hypercapnoea),was given a weakly positive recommendation based on very low quality evidence. The most widely used indications for ECMO are those reported in the CESAR study. [bib_ref] CESAR: conventional ventilatory support vs extracorporeal membrane oxygenation for severe adult respiratory..., Peek [/bib_ref] There is a paucity of data to make this judgement: one RCT remains after excluding studies including patients supported with ECCO 2 R and one RCT from 1979 in which mechanical ventilation was not protective. Arguably the predominant mechanism through which ECMO may confer a benefit is by enabling the dramatic reduction of ventilation volumes and pressures, thereby mitigating ventilator-associated lung injury (VALI). Scant evidence, again of very low quality, suggested an increased risk of bleeding associated with the use of ECMO: consistent with data from the extracorporeal life support organisation (ELSO), which publishes its registry data from around 300 centres world-wide. The incidence of serious bleeding (approximately 15% overall) and intracranial haemorrhage (3.9%) associated with the use of veno-venous ECMO for respiratory failure in adult patients based on data from the ELSO registry from its inception in 1989 to 2016 has recently been reported. [bib_ref] Extracorporeal life support organization registry international report 2016, Thiagarajan [/bib_ref] ExtrAcorPorEAl cArbon dIoxIdE rEmovAl PIco question In adults with ARDS, does the use of ECCO 2 R, compared with standard care affect survival and selected outcomes? ## Study identification The role of ECCO 2 R in ARDS has been studied in two RCTs in patients with ARDS enrolling 119 subjects. These trials have been analysed in SR without MA: there were significant difference between the studies in both ECCO 2 R technique and conventional ventilator strategy. Consequently, the SR was not able to perform a meaningful MA. There were two RCTs performed between 1994 and 2013. A GRADE Summary of Findings table is shown based on critical and important outcomes [fig_ref] Table 3: ECCO 2 R compared to standard care for acute respiratory distress syndrome [/fig_ref]. A full GRADE evidence table can be found as part of the online appendix B. ## Open access ## Analysis of outcomes mortality The risk of bias in the two RCTs was low. Both studies were stopped early following planned interim analyses and concluded that any difference between control and intervention groups was too small to be demonstrated. One trial enrolled 79 out of a planned 120 [bib_ref] Lower tidal volume strategy (=3 ml/kg) combined with extracorporeal CO 2 removal..., Bein [/bib_ref] and the other 40 out of a planned 60. [bib_ref] Randomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal CO2 removal..., Morris [/bib_ref] In one RCT, in-hospital mortality was 17.5% and 15.4% in the intervention and control groups, respectively. [bib_ref] Lower tidal volume strategy (=3 ml/kg) combined with extracorporeal CO 2 removal..., Bein [/bib_ref] The other RCT reported 30-day mortality in the intervention group of 66.6% and 57.9% in the control. [bib_ref] Randomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal CO2 removal..., Morris [/bib_ref] These were not significantly different. ## Length of stay This was not reported in the included SR. ## Quality of life No trial reported on quality of life. ## Economic data No trial reported on economic data. ## Treatment harms Potential harms of treatment with ECCO 2 R included bleeding and thrombosis. Complications were dependent on the type of ECCO 2 R used with approaches which required arterial cannulation reporting an incidence of arterial injury from 0% to 25%. [bib_ref] Extracorporeal carbon dioxide removal for patients with acute respiratory failure secondary to..., Fitzgerald [/bib_ref] Blood transfusion requirements were also increased in the ECCO 2 R group. [bib_ref] Extracorporeal carbon dioxide removal for patients with acute respiratory failure secondary to..., Fitzgerald [/bib_ref] Grade recommendation statement The use of ECCO 2 R in established ARDS should be the subject of a suitably powered multicentre RCT with long term follow-up and economic analysis (GRADE Recommendation: research recommendation). ## Grade recommendation justification Current evidence is extremely limited and mainly consists of non-randomised prospective and retrospective trials. [bib_ref] Low-flow CO2 removal integrated into a renal-replacement circuit can reduce acidosis and..., Forster [/bib_ref] [bib_ref] Pumpless extracorporeal lung assist -experience with the first 20 cases, Liebold [/bib_ref] [bib_ref] Arteriovenous extracorporeal lung assist as integral part of a multimodal treatment concept:..., Muellenbach [/bib_ref] [bib_ref] Tidal volume lower than 6 ml/kg enhances lung protection: role of extracorporeal..., Terragni [/bib_ref] [bib_ref] Hypercapnia in late-phase ALI/ARDS: providing spontaneous breathing using pumpless extracorporeal lung assist, Weber-Carstens [/bib_ref] The substantial differences between the techniques for both ECCO 2 R and conventional ventilation make the two RCTs incomparable. However, there is evidence that ECCO 2 R can allow ventilation with tidal volumes lower than currently recommended for ARDS and the potential benefits of this approach should be tested in an appropriately designed RCT. The group believed that a position of equipoise exists and the research recommendation reflects this view. Implications for future research A large, multicentre study evaluating veno-venous ECCO 2 R to facilitate lower tidal volume ventilation in patients with acute hypoxaemic respiratory failure is currently ongoing, the REST (protective ventilation with veno-venous lung assist in respiratory failure) trial (http://www. nictu. hscni. net/ rest-trial). NICE guidelines on the use of ECCO 2 R encourage clinicians to recruit patients to the REST trial. ## Fluid management pico question In adults with ARDS, does the use of a conservative fluid strategy, compared with a liberal fluid strategy or standard care, affect survival or selected outcomes? ## Open access ## Study identification The search strategy was predefined as per the online appendix C. Of four SR identified, [bib_ref] Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory..., Silversides [/bib_ref] [bib_ref] Guidelines for management of acute lung injury/acute respiratory distress syndrome: an evidence-based..., Society Of Critical Care [/bib_ref] [bib_ref] Albumin versus crystalloid solutions in patients with the acute respiratory distress syndrome:..., Uhlig [/bib_ref] one recent high quality SR with MA addressing the question of optimal fluid strategy in ARDS was included. [bib_ref] Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory..., Silversides [/bib_ref] This review included patients with ARDS, sepsis and SIRS, although subgroup data were available for ARDS. The review included data from five RCTs in ARDS [bib_ref] A randomized, controlled trial of furosemide with or without albumin in hypoproteinemic..., Martin [/bib_ref] [bib_ref] Albumin and furosemide therapy in hypoproteinemic patients with acute lung injury, Martin [/bib_ref] [bib_ref] Blood Institute Acute Respiratory Distress Syndrome Clinical Trials N,. Et al. Comparison..., Heart [/bib_ref] [bib_ref] Extravascular lung water and pulmonary arterial wedge pressure for fluid management in..., Hu [/bib_ref] [bib_ref] Effect of different liquid strategies on the prognosis of acute respiratory distresssyndrome, Wang [/bib_ref] performed between 2002 and 2014, and ranging from 29 to 1000 participants. Significant clinical heterogeneity was evident between these studies in terms of intervention strategies, fluid balance achieved and outcome reporting. Conservative fluid strategies included protocolised diuretic use, with or without 51 hyperoncotic albumin solutions, minimisation of fluid intake 51 and the use of extravascular lung water (EVLW) measurements to guide fluid therapy. [bib_ref] Extravascular lung water and pulmonary arterial wedge pressure for fluid management in..., Hu [/bib_ref] Liberal fluid strategies varied from a protocolised fluid administration strategy, which approximated the usual care arm of previous large trials in ARDS, [bib_ref] Blood Institute Acute Respiratory Distress Syndrome Clinical Trials N,. Et al. Comparison..., Heart [/bib_ref] use of furosemide without hyperoncotic albumin [bib_ref] Albumin and furosemide therapy in hypoproteinemic patients with acute lung injury, Martin [/bib_ref] and use of pulmonary capillary wedge pressure (PCWP) to guide fluid administration. [bib_ref] Extravascular lung water and pulmonary arterial wedge pressure for fluid management in..., Hu [/bib_ref] One study did not define conservative and liberal fluid strategies in detail. [bib_ref] Effect of different liquid strategies on the prognosis of acute respiratory distresssyndrome, Wang [/bib_ref] A GRADE summary of findings table is shown for critical and important outcomes (table 4). A full GRADE evidence table can be found as part of the online appendix B. ## Analysis of outcomes mortality Heterogeneity in outcome reporting was evident, with two studies reporting mortality at 30 days and three at 60 days; 51-53 the pooled results showed no effect of fluid balance strategy on mortality. Moderate quality evidence supported an RR of 0.91 (95% CI 0.77 to 1.08) for mortality using a conservative rather than a liberal fluid strategy. Although two of the RCTs included were at high or uncertain risk of bias, these studies included only 129 of 1206 patients, and thus overall no serious risk of bias was deemed to be present. Serious indirectness was present, in that various treatment regimens were compared, including a comparison of hyperoncotic albumin versus placebo as an adjunct to diuretic therapy, [bib_ref] Albumin and furosemide therapy in hypoproteinemic patients with acute lung injury, Martin [/bib_ref] and of EVLW-guided with PCWPguided fluid therapy. [bib_ref] Effect of different liquid strategies on the prognosis of acute respiratory distresssyndrome, Wang [/bib_ref] Exclusion of these studies made little difference to the point estimate. As confidence intervals around the point estimate were wide, neither clinically important benefit nor harm could be excluded. Length of ICU stay Very low quality evidence for a reduction in length of ICU stay with a conservative fluid strategy was provided by two small RCTs including 129 patients. Both studies were at very serious risk of bias due to lack of blinding and other methodological flaws. One study [bib_ref] Extravascular lung water and pulmonary arterial wedge pressure for fluid management in..., Hu [/bib_ref] ## Compared Open access EVLW-guided with PCWP-guided fluid therapy, neither of which is commonly used clinically, and a clinically important difference in fluid balance between groups was absent. The population, intervention and comparator in the other study were not reported in detail. [bib_ref] Effect of different liquid strategies on the prognosis of acute respiratory distresssyndrome, Wang [/bib_ref] The small number of patients in these studies also led to very serious imprecision. Length of hospital stay A single RCT 50 provided low-quality evidence for the absence of an effect of fluid strategy on length of hospital stay. Very serious imprecision was present due to a lack of statistical power to exclude a clinically important difference on this outcome. ## Quality of life No trial reported on quality of life. ## Economic data No trial reported on economic data. ## Treatment harms Acute kidney injury incidence Incidence of acute kidney injury (AKI) was felt to be important as this represents a potential harm associated with a conservative fluid strategy. A single large RCT 51 provided low quality evidence for similar numbers of AKI-free days with conservative and liberal fluid strategies, and a posthoc analysis of this trial 54 suggested a reduction in AKI incidence with a conservative fluid strategy using creatinine measurements corrected for changes in volume of distribution. ## Requirement for renal replacement therapy It was considered that requirement for renal replacement therapy (RRT) represented a potential harm from a conservative fluid strategy. Moderate quality evidence for a reduction in the requirement for RRT with a conservative fluid strategy was provided by a single large RCT 51 (RR 0.71, 95% CI 0.50 to 0.99). ## Cognitive dysfunction A posthoc analysis of a small subgroup of patients from the FACTT trial found conservative fluid strategy to be an independent risk factor for long-term cognitive dysfunction following ARDS. [bib_ref] The adult respiratory distress syndrome cognitive outcomes study: long-term neuropsychological function in..., Mikkelsen [/bib_ref] One RCT of uncertain risk of bias found better cognitive outcome scores with conservative fluid strategy than with liberal fluid strategy, [bib_ref] Effect of different liquid strategies on the prognosis of acute respiratory distresssyndrome, Wang [/bib_ref] although the duration of follow-up and details of the intervention were not described. # Grade recommendation statement We suggest the use of a conservative fluid strategy in patients with ARDS (GRADE recommendation: weakly in favour). ## Grade recommendation justification Despite the low quality of evidence for the majority of outcomes, and the results being driven largely by a single trial, [bib_ref] Blood Institute Acute Respiratory Distress Syndrome Clinical Trials N,. Et al. Comparison..., Heart [/bib_ref] conservative fluid management may be beneficial without evidence of harm. We therefore suggest that in adult patients with ARDS, clinicians consider the use of a conservative fluid strategy which uses fluid restriction, diuretics and possibly hyperoncotic albumin to avoid a positive fluid balance in preference to a liberal fluid strategy. vEntIlAtIon hIGh FrEquEncy oscIllAtory PIco question In adults with ARDS, does the use of HFOV, compared with standard care, affect survival and other selected outcomes? ## Study identification The search strategy was predefined as per online appendix C. The role of HFOV in ARDS with moderate to severe hypoxaemia has been studied in six RCTs published between 2002 and 2013. [bib_ref] High-frequency oscillatory ventilation following prone positioning prevents a further impairment in oxygenation, Demory [/bib_ref] [bib_ref] High-frequency oscillatory ventilation for acute respiratory distress syndrome in adults: a randomized,..., Derdak [/bib_ref] [bib_ref] High-frequency oscillation in early acute respiratory distress syndrome, Ferguson [/bib_ref] [bib_ref] High-frequency oscillation as a rescue strategy for brain-injured adult patients with acute..., Young [/bib_ref] Two recent RCTs enrolled a disproportionate number of patients-1343 out of 1608 patients (795 patients in one and 548 in the other). There have been an additional two RCTs of HFOV combined with tracheal gas insufflation. [bib_ref] Intermittent recruitment with high-frequency oscillation/tracheal gas insufflation in acute respiratory distress syndrome, Mentzelopoulos [/bib_ref] [bib_ref] Acute effects of combined high-frequency oscillation and tracheal gas insufflation in severe..., Mentzelopoulos [/bib_ref] These trials have been analysed in three SRs with MA.Data were analysed from two of these: the most recent MA was used first,supplemented with additional data from previous studies.One MA was excluded as it combined results of RCTs with HFOV and tracheal gas insufflation with those of RCTs with HFOV alone.A GRADE Summary of Findings table is shown below based on critical and important outcomes [fig_ref] Table 5: HFOV compared to usual care for ARDS ARDS, acute respiratory distress syndrome [/fig_ref]. A full GRADE evidence table can be found as part of online appendix B. ## Analysis of outcomes mortality The RR of death associated with HFOV was 1.218 (0.925 to 1.604). The evidence was judged to be of moderate quality.Of the RCTs contributing to the two MAs, five demonstrated no difference in mortality between HFOV and conventional ventilation, 56-61 while one of the larger RCTs demonstrated increased mortality in the HFOV arm. [bib_ref] High-frequency oscillation in early acute respiratory distress syndrome, Ferguson [/bib_ref] The overall risk of bias in included studies was low with the exception of two studies where crossovers accounted for more than 10% of the study group. Inconsistency was serious with point estimates varying widely, confidence intervals overlapping, a lack of consistent direction of effect and significant heterogeneity (I 2 =63.1%, p=0.028). ## Length of stay This was not reported in the included SR. ## Open access ## Quality of life No trial reported on quality of life. ## Economic data No trial reported on economic data. ## Treatment harms Potential harms of HFOV were reported including barotrauma, hypotension and oxygenation failure. The RR of barotrauma was reported from four studies enrolling 752 subjects as 1.205 (95% CI 0.834 to 1.742); however, the studies used a variable definition of barotrauma.The RR of hypotension was reported as 1.326 (95% CI 0.271 to 6.476) and these data were derived from three studies enrolling 237 patients.Oxygenation failure in the MA included 757 patients from three studies with a RR for HFOV of 0.557 (95% CI 0.351 to 0.884).Grade recommendation statement We do not recommend the use of HFOV in the management of patients with ARDS (GRADE recommendation: strongly against). ## Grade recommendation justification The use of HFOV for the management of ARDS was given a GRADE recommendation of strongly against based on moderate quality evidence. Current evidence from multiple RCTs demonstrated no benefit from HFOV and one RCT demonstrated an increase in mortality with HFOV. ## Inhaled vasodilators pico question In adults with ARDS, does the use of inhaled vasodilators (iVasoD), compared with standard care, affect survival and selected outcomes? ## Study identification The search strategy was predefined as per online appendix C. The role of the iVasoD nitric oxide (iNO) in the management of ARDS has been assessed in multiple RCT, which have been analysed in subsequent SR with MA. No studies examining the role of nebulised prostacyclin in adults with ARDS were identified by Cochrane reviewers in 2010. [bib_ref] Aerosolized prostacyclin for acute lung injury (ali) and acute respiratory distress syndrome..., Afshari [/bib_ref] Three SR with MA were identified from which data were analysed (see PRISMA chart in online appendix A). [bib_ref] Effect of nitric oxide on oxygenation and mortality in acute lung injury:..., Adhikari [/bib_ref] [bib_ref] Inhaled nitric oxide therapy and risk of renal dysfunction: a systematic review..., Ruan [/bib_ref] [bib_ref] Inhaled nitric oxide does not reduce mortality in patients with acute respiratory..., Adhikari [/bib_ref] Mortality data were analysed from nine RCTs [bib_ref] Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome:..., Dellinger [/bib_ref] [bib_ref] Dose-response characteristics during long-term inhalation of nitric oxide in patients with severe..., Gerlach [/bib_ref] [bib_ref] Inhalation of nitric oxide in acute lung injury: results of a European..., Lundin [/bib_ref] [bib_ref] Acute oxygenation response to inhaled nitric oxide when combined with highfrequency oscillatory..., Mehta [/bib_ref] [bib_ref] Inhaled nitric oxide versus conventional therapy: effect on oxygenation in ARDS, Michael [/bib_ref] [bib_ref] Combined effects of inhaled nitric oxide and A recruitment maneuver in patients..., Park [/bib_ref] [bib_ref] Inhaled nitric oxide and acute lung injury, Payen [/bib_ref] [bib_ref] Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized..., Taylor [/bib_ref] [bib_ref] Inhaled nitric oxide in acute respiratory distress syndrome: a pilot randomized controlled..., Troncy [/bib_ref] published between 1998 and 2004, including 1142 participants. Exclusion criteria for RCT included: >50% crossover between iNO and placebo groups and unequal distribution of other rescue therapies between treatment and control groups. Limited information on possible harms was available: data from four RCTs 71 73 77 78 provided specific information regarding nephrotoxicity associated with the use of iNO. ## Analysis of outcomes mortality Mortality at hospital discharge was used for analysis where available. Otherwise these data were combined with mortality at discharge from the ICU or 28-30 days after randomisation. The quality of evidence supporting the RR of 1.10 (95% CI 0.94 to 1.29: p=0.24) in the first treatment analysis was low (see GRADE evidence profile table). In only 3/9 studies 72 78 79 was placebo gas (nitrogen) administered to the control group, creating a serious risk of bias in the other six studies. There was serious indirectness in the nine studies analysed owing to variability in inclusion criteria including marked deviation from AECC criteria for diagnosing ALI/ARDS and variable iNO treatment regimens. Data from studies using different doses of iNO were combined. These variable doses and duration of treatment, which may be considered to be too high and too long respectively, constitute a serious source of indirectness. Consistency was good with confidence intervals overlapping, a consistent direction of effect and a very low heterogeneity. [bib_ref] Inhaled nitric oxide does not reduce mortality in patients with acute respiratory..., Adhikari [/bib_ref] Subgroup analysis from 7/9 trials did not support the hypothesis that iNO conferred a survival benefit in patients with severe ARDS (PaO 2 to FiO 2 ratio of <20 kPa). ## Length of stay No MA available. ## Quality of life No trial reported on quality of life. ## Economic data No trial reported on economic data. ## Treatment harms The administration of iNO was associated with an increased incidence of renal dysfunction in four trials representing 80% of the patients recruited into the nine studies analysed above (risk ratio 1.50, 1.11 to 2.02). The quality of the evidence supporting the association was judged to be low based on the factors outlined above and the variable criteria used to define renal dysfunction, although the consistency between trials was good. # Grade recommendation statement We do not suggest using iNO in patients with ARDS (GRADE Recommendation: weakly against). ## Grade recommendation justification The recommendation that iNO is not used for adult patients with ARDS is based on low quality but consistent evidence suggesting a lack of mortality benefit and an association with renal dysfunction. While the studies examining the role of iNO in ARDS are imperfect, further trials would be given a low priority. The possible use of Open access iNO in patients with severe right ventricular dysfunction or extreme hypoxaemia for short periods, while more long-term rescue strategies (such as ECMO) are instituted, fall outside the scope of this guideline. ## Mechanical ventilation at lower tidal volume pico question In mechanically ventilated adult patients with ARDS, do lower tidal volumes compared with higher, conventional tidal volumes affect survival and other related outcomes? ## Study identification The search strategy was predefined as per online appendix C. Seven, full text, SR were assessed for eligibility. We excluded four reviews: three did not contain the full complement of published trials [bib_ref] Meta-analysis of acute lung injury and acute respiratory distress syndrome trials testing..., Eichacker [/bib_ref] [bib_ref] Ventilation with smaller tidal volumes: a quantitative systematic review of randomized controlled..., Petrucci [/bib_ref] and one contained studies of patients without ARDS. [bib_ref] Lower tidal volume at initiation of mechanical ventilation may reduce progression to..., Fuller [/bib_ref] The remaining three reviews [bib_ref] Pressure and volume limited ventilation for the ventilatory management of patients with..., Burns [/bib_ref] [bib_ref] Cochrane Emergency and Critical Care Group. Lung protective ventilation strategy for the..., Petrucci [/bib_ref] [bib_ref] Meta-analysis: ventilation strategies and outcomes of the acute respiratory distress syndrome and..., Putensen [/bib_ref] each contained the six RCT that met the PICO inclusion criteria. We extracted the mortality data provided by Petrucci 2013 85 (the most recent published review) to the GRADE profiler. In addition, we reviewed the published papers and extracted additional outcomes that were relevant to the guidelines, but not reported in the three SR. The Petrucci 2013 review included six multi-centre RCT published from 1998 to 2006 that included a total of 1297 patients. Within-trial sample sizes ranged from 52 to 861 patients. Trials were conducted in North and South America and Europe. Four trials 87-90 compared lower tidal volumes (range <6-8 mL/kg) and restricted airway pressures (plateau pressure<30 cmH 2 O) with higher tidal volumes (range 9-15 mL/kg) and airway pressures (plateau pressure <50-60 cmH 2 O). The Amato 1998 92 and Villar 2006 93 trials compared lower tidal volume with higher PEEP, where possible set just above the lower inflection point of a pressure-volume curve, and higher tidal volume with lower PEEP: these studies investigating the composite intervention of lower tidal volume and higher PEEP were analysed separately. We provide Forest plots to show the separate MA for the comparisons of (1) lower versus higher tidal volumes with similar PEEP and (b) lower tidal volumes with higher PEEP versus higher tidal volume with lower PEEP. A GRADE Summary of Findings table is shown based on critical and important outcomes [fig_ref] Table 7: Lower tidal volume compared with higher tidal volume [/fig_ref]. A full GRADE evidence table can be found as part of online appendix B. # Analysis of outcomes Lower versus higher tidal volume with similar PEEP Mortality In this comparison, four studies reported mortality at varying time-points: 60 days 91 and hospital discharge (figure 1). [bib_ref] Ventilation with lower tidal volumes as compared with traditional tidal volumes for..., Brower [/bib_ref] [bib_ref] Tidal Volume Reduction for Prevention of Ventilator-induced Lung Injury in Acute Respiratory..., Brochard [/bib_ref] [bib_ref] Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation..., Brower [/bib_ref] Pooled data from the four trials showed no significant difference between lower and higher tidal volume groups in risk of death including all time-points (RR 0.87, 95% CI 0.75 to 1.01, p=0.07) with moderate, but non-significant heterogeneity (I 2 48%, p=0.13). Pooled data for hospital mortality showed a statistically significant reduction in risk of death (RR 0.83, 95% CI 0.71 to 0.98, p=0.02) associated with lower tidal volume ventilation, whereas a non-significant increase in risk was found at 60 days (RR 1.23, 95% CI −0.80 to 1.89, p=0.35) based on data from a single study with relatively few patients, in which body weight was not corrected according to the ideal or predicted standard (http://www. ardsnet. org/ files/ pbwtables_ 2005-02-02. pdf). ## Icu length of stay The pooled effect from two studies showed no significant difference in length of ICU stay (mean difference 4.79 days, 95% CI −2.06 to 11.63, p=0.17) (figure 2). ## Hospital length of stay There was no difference in hospital length of stay reported by one study [bib_ref] Evaluation of a ventilation strategy to prevent barotrauma in patients at high..., Stewart [/bib_ref] (mean difference 6.30 days, 95% CI −7.53 to 20.13, p=0.37). ## Quality of life No trial reported on quality of life. ## Economic data No trial reported on economic data. lower tidal volume with higher PEEP versus higher, conventional tidal volume with lower PEEP Mortality: 28-day, ICU and hospital Two studies reported mortality. At 28 days, one study [bib_ref] Effect of a protectiveventilation strategy on mortality in the acute respiratory distress..., Amato [/bib_ref] showed a significant reduction in risk of death in the lower tidal volume and higher PEEP group (RR 0.54, 95% CI 0.31 to 0.91, p=0.02). Similarly, pooled data from two studies showed a significant reduction in risk of ICU mortality (RR 0.57, 95% CI 0.40 to 0.82, p=0.002) and hospital mortality (RR 0.62, 95% CI 0.44 to 0.87, p=0.006). In both cases, the evidence was downgraded to low because of imprecision (relatively few patients, 156 in total), and indirectness of evidence (methodological flaws-body weight was not corrected in one study; and lack of generalisability based on the unusually high mortality rate of the conventional ventilation group). # Grade recommendation statement We recommend the routine use of lower tidal volumes for the management of patients with ARDS (GRADE Recommendation: strongly in favour). ## Grade recommendation justification The recommendation to use lower tidal volume (less than or equal to 6 mL/kg predicted body weight) ventilation with a plateau pressure less than or equal to 30 cmH 2 O is strong despite moderate quality of evidence for hospital mortality and barotrauma, but low quality of Open access evidence for 60-day mortality. The evidence was downgraded for serious indirectness for hospital mortality, and for inconsistency and imprecision for 60 day mortality. For example, the beneficial effects of low tidal volume ventilation were only seen in one large trial and the means of managing respiratory acidosis in the ARDS Network ARMA trial [bib_ref] Ventilation with lower tidal volumes as compared with traditional tidal volumes for..., Brower [/bib_ref] is not generally applied. However, a lack of adverse effects associated with the intervention, strong mechanistic rationale for its use [bib_ref] Ventilator-induced lung injury, Slutsky [/bib_ref] and supportive data from ARDS prevention studies [bib_ref] A meta-analysis of intraoperative ventilation strategies to prevent pulmonary complications: is low..., Yang [/bib_ref] have resulted in its universal acceptance as a gold standard of care. ## Neuromuscular blocking agents pico question In adults with ARDS, does the use of NMBA, compared with standard care, affect survival and selected outcomes? ## Analysis of outcomes mortality Mortality (pooled 28 day, ICU and hospital mortality) was reported in all three RCTs 100-102 with point estimates showing a reduction in mortality at each of these time points. However, in each of these RCT, the 95% CI for the risk ratio reached or crossed the no effect line. When mortality data from these RCTs were pooled in MA (with a total of 431 participants), the CI was narrowed to show a significant reduction in mortality at each of these time points. The risk ratios for 28 day, ICU and hospital mortality were 0.66, 0.70 and 0.72, respectively, ## Open access suggesting a significant reduction in the risk of mortality with this intervention. Although these results showed a good level of consistency and precision, there are important concerns over the risk of bias and indirectness in the contributing RCT. All three studies, which were conducted by the same team of investigators in France, have been criticised for the lack of effective blinding of caregivers to study group allocation. In two of the studies, no attempt was made to blind caregivers while, in the third, [bib_ref] Neuromuscular blockers in early acute respiratory distress syndrome, Papazian [/bib_ref] it is questionable whether blinding was effective. It has also been noted that there is considerable overlap of authorship of the most recent SR and the contributing RCT. One of the contributing RCTs 101 included only patients with severe ARDS (P/F ratio<20 kPa) within the first 48 hours, leading to our assessment of 'serious' indirectness of the findings for ARDS as a whole. ## Length of stay This was not reported in the included SR. ## Quality of life This was not reported in the included SR. ## Economic data This was not reported in the included SR. ## Treatment harms A key concern for the use of NMBA in ICU is the presumed risk of increased ICU-acquired weakness with their use. Although the risk of ICU-acquired weakness was not found to be significantly increased on MA (RR 1.08; 95% CI 0.83 to 1.41), these findings are severely limited by the lack of robust screening measures in two of the contributing RCT, and by the lack of follow-up beyond ICU discharge in the final RCT [bib_ref] Neuromuscular blockers in early acute respiratory distress syndrome, Papazian [/bib_ref] Grade recommendation statement We do not suggest using NMBAs for all patients with ARDS (GRADE Recommendation: weakly against). We suggest the use of cisatracurium besylate by continuous 48 hours infusion in patients suffering early moderate/ severe ARDS (P/F<20 kPa: GRADE Recommendation: weakly in favour). ## Grade recommendation justification The use of cisatracurium besylate in adults suffering early, severe ARDS was given a weakly positive recommendation based on moderate evidence quality. The group felt it was appropriate to recommend this management protocol because it was the only one studied by RCT. Due to the nature of this intervention, it should only be given to patients who are adequately sedated and receiving invasive ventilation. As such, it would have been difficult to recruit patients with mild ARDS. Although it is reassuring that in all three RCTs the point estimate of treatment effect indicated a survival benefit, it was only by pooling these data in MA that these findings reached statistical significance. There are also concerns over the ineffective blinding of caregivers to study group allocation in the clinical trials and concerns that the potential association of NMBA and ICU-acquired weakness was not studied in a robust manner. ## Positive end-expiratory pressure pico question In adult patients with ARDS, does mechanical ventilation with higher PEEP, compared with standard (lower) PEEP improve survival, and selected outcomes? ## Study identification The search strategy was predefined as per online appendix C. Six high-quality SR with MA were identified (see PRISMA chart in online appendix A). These used data from a total of seven clinical trials, published between 1998 and 2009. The largest single study enrolled 983 patients. [bib_ref] Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory..., Meade [/bib_ref] Data from three MA form the basis of the recommendation, [bib_ref] Higher vs lower positive endexpiratory pressure in patients with acute lung injury..., Briel [/bib_ref] [bib_ref] High levels of PEEP may improve survival in acute respiratory distress syndrome:..., Oba [/bib_ref] [bib_ref] High versus low positive end-expiratory pressure (PEEP) levels for mechanically ventilated adult..., Cruz [/bib_ref] with the most recent used where possible for outcomes of interest. Where this MA did not provide information on relevant outcomes, alternative MA were used. A GRADE summary of findings table is shown based on critical and important outcomes (table 9). A full GRADE evidence table can be found as part of online appendix B. ## Analysis of outcomes mortality A MA of hospital mortality alone was presented in the most recent SR assessing the impact of higher PEEP in ARDS. [bib_ref] High versus low positive end-expiratory pressure (PEEP) levels for mechanically ventilated adult..., Cruz [/bib_ref] The quality of evidence supporting the RR of 0.90 (0.81-1.01) was deemed moderate, as there were different strategies used between the trials to set PEEP. The mean PEEP levels in each arm of the three studies are presented in table [bib_ref] Epidemiology and outcomes of acute lung injury, Rubenfeld [/bib_ref]. Mortality within 28 days of randomisation was presented in the same MA, and the quality of evidence supporting the RR of 0.83 (0.67-1.01) was low, as the analysis included trials which incorporated low tidal volume ventilation in the high PEEP arm, while the control group were ventilated with a low PEEP, high tidal volume strategy. Individual patient data MA of three RCT (table 10) evaluating high vs low PEEP showed a reduction in ICU mortality (up to day 60) in patients with moderate or severe ARDS (P/F<27 kPa): RR 0.85 (0.76 to 0.95). There is moderate quality of evidence supporting this assessment, again because different strategies to set PEEP levels were used. This analysis is supported by a MA of three randomised trials that, with low quality of evidence, reported a reduced ICU mortality in patients with moderate or severe ARDS (RR 0.67 (0.48 to 0.95). [bib_ref] High versus low positive end-expiratory pressure (PEEP) levels for mechanically ventilated adult..., Cruz [/bib_ref] Additional individual patient data MA evaluating the effect of high PEEP on hospital mortality in three studies Open access reported a RR 0.90 (0.81 to 1), with evidence supporting this finding regarded as moderate (see GRADE evidence profile table). [bib_ref] Higher vs lower positive endexpiratory pressure in patients with acute lung injury..., Briel [/bib_ref] Length of stay In a MA of two trials, a high PEEP strategy was not associated with a significant reduction in ICU-free days (0.04 (95% CI −1.03 to 1.1)). This is supported by a moderate evidence base given the wide confidence interval that extends beyond the 25% threshold. ## Open access Quality of life This was not reported in the included SRs. ## Economic data This was not reported in the included SRs. ## Treatment harms A higher PEEP ventilation strategy was not associated with increased rates of air leaks (RR 0.97 (0.66 to 1.42)), with the evidence supporting this finding deemed very low because of the difference in tidal volume strategies assessed between the intervention and control arms of some studies, and the imprecision of the results. 110 ## Grade recommendations We suggest the use of high PEEP strategies for patients with moderate or severe ARDS (P/F ratio <27 kPa: GRADE Recommendation: weakly in favour). ## Grade justification We identified low-quality evidence to support the use of higher PEEP strategies in the ventilation of patients with moderate or severe ARDS. Evidence was downgraded because of inconsistency caused by differences between individual studies in the strategy to set the level of PEEP, while some trials compared lower tidal volume ventilation as part of a ventilator strategy that incorporated higher PEEP levels. The recommendation to consider the use of higher PEEP in patients with at least moderate ARDS is based on subgroup and individual patient data MA, providing less robust evidence than a RCT investigating higher PEEP in this patient group. The risk of barotrauma as a result of the use of higher PEEP for patients with at least moderate or severe ARDS cannot be excluded because this risk has not been quantified in this population. The quality of this evidence is also limited by inconsistency as the MA included trials of high PEEP with different tidal volume strategies. ## Prone positioning pico question In adults with ARDS, does the use of prone positioning, compared with standard care, affect survival and selected outcomes? ## Study identification The search strategy was predefined as per online appendix C. Fourteen eligible SRs investigating the effect of prone positioning in ARDS (see PRISMA chart in online appendix A) were identified. Twelve reviews included a MA. The most recently published of these was used for data extraction. [bib_ref] The efficacy and safety of prone positioning in adults patients with acute..., Park [/bib_ref] A GRADE Summary of Findings table is shown based on available evidence for critical and important outcomes [fig_ref] Table 11: Prone positioning compared with standard care for ARDS [/fig_ref]. A full GRADE evidence table can be found as part of online appendix B. ## Analysis of outcomes mortality Mortality (defined as overall mortality at the longest available follow-up) was significantly reduced with prone positioning (RR 0.9; 95% CI 0.82 to 0.96, 8 studies, 2141 patients) with very low quality of evidence supporting this RR. All trials demonstrated performance bias, because of the impossibility of blinding patients and carers with respect to the intervention. All trials also demonstrated detection bias, where outcome assessors were not blinded to intervention allocation. One RCT additionally demonstrated selection bias [bib_ref] Effects of prone position on inflammatory markers in patients with ARDS due..., Chan [/bib_ref] and three separate trials suffered from attrition bias [bib_ref] Effects of systematic prone positioning in hypoxemic acute respiratory failure: a randomized..., Guerin [/bib_ref] [bib_ref] A multicenter trial of prolonged prone ventilation in severe acute respiratory distress..., Mancebo [/bib_ref] [bib_ref] Prone positioning in patients with moderate and severe acute respiratory distress syndrome:..., Taccone [/bib_ref] according to the Cochrane risk of bias recommendations.Inconsistency was very serious, with varied point estimates, overlapping confidence intervals with high and significant levels of heterogeneity. There was also serious indirectness as the cohort of trials included subgroups receiving additional interventions known to demonstrate a mortality benefit. Subgroup analysis demonstrated that prone positioning in combination with lung-protective ventilation (low tidal volume ventilation, 6-8 mL/kg body weight) demonstrated a significant reduction in mortality (RR 0.73; 95% CI 0.62 to 0.86) compared with patients receiving prone positioning and no lung-protective ventilation (RR 1.01; 95% CI 0.9 to 1.13), supported by moderate quality evidence. These findings may be influenced by inclusion of one trial enrolling a sizeable patient cohort with more severe ARDS (P/F ratio <20 kPa, FiO 2 >0.6) 129 which showed larger differences in mortality rates between patients managed prone and supine in the setting of lung-protective ventilation. Subgroup analysis based on the duration of prone positioning found that over 12 hours of prone positioning was associated with significantly reduced mortality (>12 hour, RR 0.75, 95% CI 0.65 to 0.87;<12 hour, RR 1.03, 95% CI 0.91 to 1.17), again supported by moderate quality evidence. Length of stay ICU length of stay was only examined in two older MAs. However, these data could not be extracted, as pooled analyses included either confirmed or potential paediatric data. No other trial examined hospital length of stay. ## Quality of life No trial reported on health-related quality of life. ## Economic data No trial reported on economic data. ## Treatment harms Overall, the pooled risk of any adverse event with prone positioning was significantly increased (RR 1.10; 95% CI 1.01 to 1.12). Where a more detailed analysis of adverse events was conducted, endotracheal tube displacement (RR 1.33; 95% CI 1.02 to 1.74), the incidence of pressure sores (1.23; 95% CI 1.07 to 1.41) and loss of venous access (RR 1.98; 95% CI 1.11 to 3.55) were significantly increased. ## Open access ## Continued ## Open access However, this evidence was down-graded based on the risk of bias and imprecision in the trials evaluated. # Grade recommendation statement We do not recommend the use of prone positioning for all patients with ARDS. We recommend the use of prone positioning for at least 12 hours per day in patients with moderate/severe ARDS (P/F ratio<20 kPa: GRADE recommendation: strongly in favour). ## Grade recommendation justification Current evidence includes the possibility of substantial patient benefit in terms of reduced mortality when combined with lung-protective ventilation and when delivered for at least 12 hours to patients with moderate/severe ARDS. Evidence for these findings was of moderate quality. The GDG noted the relative improvements in study design over the time course of publication of all eight trials, such that the most recently published focused enrolment on the most severe strata of patients with ARDS, and involved a multimodal intervention comprising lung-protective ventilation with prolonged prone positioning producing highly favourable outcomes. [bib_ref] Prone positioning in severe acute respiratory distress syndrome, Guérin [/bib_ref] This observation provides the rationale for the strong classification of recommendation. The possibility for substantial patient benefit must be considered in the context of a significant risk of occurrence of adverse events including endotracheal tube displacement, pressure sores and loss of venous access, although the evidence to support these findings was either low or very low. However, the GDG felt that these adverse events could be mitigated by ensuring that sufficient skilled personnel were in place to deliver and monitor the intervention. conclusIon summary [fig_ref] Table 2: ECMO compared to standard care for ARDS [/fig_ref] outlines the GDG's synthesis of data for the Management of ARDS from relevant clinical trials. # Discussion The summary of the group's recommendations emphasises the importance of avoiding VALI in patients with ARDS, as all of the interventions with positive recommendations apart from maintaining a conservative fluid balance, arguably act through this process. Despite at best moderate quality evidence by MA, we have strongly supported the use of low tidal volume and low airway pressure mechanical ventilation. This ventilation strategy is supported by results of the ARDS Network ARMA study, 87 data from studies whose primary outcome was the prevention of ARDS and a large volume of evidence from preclinical and mechanistic studies. It is now so universally accepted that it is mandated for all patients in clinical trials of ARDS. When applied to patients with moderate/severe ARDS for at least 12 hours per day, prone positioning was also strongly recommended because the most recent studies focused enrolment on the most severe strata of patients with ARDS and involved a multimodal intervention comprising lung-protective ventilation with prolonged prone positioning producing highly favourable outcomes. [bib_ref] Prone positioning in severe acute respiratory distress syndrome, Guérin [/bib_ref] By contrast, despite a strong theoretical rationale as a means of preventing VALI, high frequency oscillatory ventilation was ineffective or deleterious in two large studies leading to our recommendation strongly against its use. While broadly similar recommendations for the management of ARDS have been produced, many questions remain. Fundamentally the parameters characterising optimal protective mechanical ventilation are unknown, as are the optimal means of achieving them. We have recommended targeting <6 mL/kg ideal body weight (IBW), but, based on the absence of evidence of a safe tidal volume threshold on retrospective reanalysis of the ARMA study [bib_ref] Tidal volume reduction in patients with acute lung injury when plateau pressures..., Hager [/bib_ref] and a dose-response effect seen in observational studies, [bib_ref] Lung protective mechanical ventilation and two year survival in patients with acute..., Needham [/bib_ref] it would be reasonable to recommend minimising tidal volume as far as possible. Similarly, analysing individual patient data from RCT concluded that driving pressure (plateau pressure minus PEEP) was a better predictor of outcome than tidal volume or plateau pressure alone. [bib_ref] Driving pressure and survival in the acute respiratory distress syndrome, Amato [/bib_ref] Open access consensus regarding the means used to optimise PEEP (oxygenation or various lung mechanical parameters) or to manage the respiratory acidosis that commonly accompanies protective ventilation. In certain details, recent guidelines have diverged. We felt that the evidence supporting the role of recruitment manoeuvres was so poor and the concept so ill-defined that we were unable to make a recommendation. By contrast, the American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine group has given a conditional recommendation, although with low-to-moderate confidence. [bib_ref] An official American thoracic Society/European Society of intensive care Medicine/Society of critical..., Fan [/bib_ref] Similarly, our group did not consider airway pressure release ventilation owing to the paucity of high quality, relevant evidence, despite the knowledge that this ventilatory mode is widely used. Hopefully there will be sufficient evidence to justify including these interventions in the next version of the guidelines. We have synthesised available evidence with the clinical practice of the GDG into a management algorithm . Hence, for a patient presenting with for example severe ARDS, low tidal volume (<6 ml/kg IBW) and low plateau pressure (<30 cmH 2 O), mechanical ventilation using higher PEEP is recommended with the addition of neuromuscular blockade for the first 48 hours and prone positioning for at least 12 hours per day. After initial resuscitation of the circulation, a neutral or, if tolerated, a negative fluid balance target should be set. Consideration of escalation to extracorporeal lung support (ECMO or ECCO 2 R) is indicated by the failure to achieve adequate gas exchange using protective ventilatory settings as described above. To what extent is this synthesis evidence-based? While the individual components are to an extent evidence-based, the combination of interventions has evolved rather than being formally tested. For example, attempts have been made to test a so-called 'open lung approach', by combining higher PEEP levels with low tidal volume ventilation both in early studies concentrating on low tidal volume ventilation, in subsequent PEEP trials and more recently in studies combining the use of recruitment manoeuvres and high levels of PEEP. The rationale for the open lung approach is that increasing airway pressure will increase the volume of ventilatable lung, thereby decreasing VALI and a large clinical trial was supported by encouraging pilot data. This Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) carried out in 1010 patients with severe ARDS surprisingly showed significantly higher 6-month mortality (65.3% vs 59.9%) in the intervention group. [bib_ref] Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) vs low..., Cavalcanti [/bib_ref] These data demonstrate the enduring value of large well-conducted clinical trials of complex interventions in this challenging patient group. ## Unmet needs, research and future directions We have made research recommendations for two interventions for adult patients with ARDS: corticosteroids and ECCO 2 R. Two international studies are currently examining the effects of ECCO 2 R combined with ultralow tidal volume ventilation (pRotective vEntilation with Veno-ve-nouS Lung Assi (pRotective vEntilation With Veno-ve-nouS Lung assisT in Respiratory Failure (REST, Clinical-Trials. gov NCT02654327) and SUPERNOVA: A Strategy of UltraProtective lung ventilation with Extracorporeal CO 2 Removal for New-Onset moderate to seVere ARDS, whose pilot study has just been reported. There are no disease modifying, drug therapies for ARDS. Drug development in this area is notoriously Open access difficult, partly because ARDS is not a disease but a syndrome describing acute respiratory failure occurring de novo as a result of a wide variety of conditions. One strategy designed to increase the likelihood of positive clinical trials in ARDS is to select a less heterogeneous patient population-a step on the road to a personalised approach made at the expense of having a smaller pool of patients from which to recruit. Such splitting can be envisaged on the basis of readily identifiable predisposing causes (eg, influenza pneumonia, transfusion-related acute lung injury (TRALI) or systemic sepsis) or inherent patient characteristics, such as alcoholism or the expression of particular single nucleotide polymorphisms known to be associated with a predisposition to ARDS. The ultimate aim is to identify subgroups, so-called endotypes of ARDS that will predict a positive response to a certain class of therapy. [bib_ref] Toward smarter lumping and smarter splitting: rethinking strategies for sepsis and acute..., Prescott [/bib_ref] Current management of ARDS is hampered by failure to diagnose the condition and to prevent iatrogenic harms. We need to heighten awareness of the diagnosis, particularly outside ICU, so that the opportunity to prevent progression of the syndrome is not missed. Research into prevention and treatment needs to be translated more effectively into the clinic. Biomarkers that confirmed the diagnosis highlighted patients with a poor prognosis and predicted that a positive response to a particular therapy would be invaluable in research and clinical care. For example, a validated bedside biomarker of VALI would facilitate the fine tuning of mechanical ventilation and could guide related decisions during the recovery phase of ARDS, for example, assessing the risk-benefit relationship between allowing spontaneous ventilatory modes with associated larger tidal volumes. In order to discover effective drug therapies, continued investment in human studies that aim to elucidate the pathogenesis of ARDS is essential to identify clinically useful biomarkers and surrogate outcome measures. These investigations need to be performed with a view to designing a stepwise approach to testing novel therapeutics in this particularly challenging patient group. [bib_ref] A stepwise approach to justify phase III randomized clinical trials and enhance..., Mcauley [/bib_ref] Finally, standardisation of outcome measures will help in the conduct and comparison of clinical trials and such work is underway, for example, the Core Outcomes for Ventilation Trials: the COVenT Delphi study (COMET registration: http://www. comet-initiative. org/ studies/ details/ 292). As reflected in the outcome prioritisation exercise carried out by the GDG, there is an increasing emphasis on the health of survivors of critical illness, which mandates that clinical trials include long-term outcomes and economic analysis that will inform the societal impact of intensive care medicine. ## Management of ards in practice management The essence of management of ARDS consists of optimising the diagnosis and treatment of underlying conditions, and the deployment of supportive measures that minimise iatrogenic injury and the consequences of severe critical illness (ie, secondary and tertiary prevention). We have combined these strategies with the outcome of the analysis of evidence relating to the topics selected in [fig_ref] Figure 3: Analysis of evidence relating to the topics selected in this figure [/fig_ref]. ## Primary prevention A common theme of research into critical illness has been the increasing appreciation of the contribution of iatrogenic factors, most notably: fluid overload, VALI from mechanical ventilation, transfusion of blood products and hospital acquired infection. [bib_ref] Strategies to reduce ventilatorassociated lung injury (VALI), Salman [/bib_ref] While it is sobering to appreciate the negative role that healthcare systems have played, it has at least indicated the potential to prevent ARDS through simple quality improvement interventions. Similarly, while causes of ARDS that act directly on the lung, including pneumonia and gastric aspiration, are associated with a rapid progression to ARDS, indirect causes typified by severe sepsis commonly evolve into ARDS as part of a multiorgan dysfunction syndrome over 2-4 days. [bib_ref] Clinical risk conditions for acute lung injury in the intensive care unit..., Ferguson [/bib_ref] Scoring systems have been developed to predict progression to ARDS both in patients at risk and those with early lung injury. The Lung Injury Prediction Score (LIPS: table 13) is the product of a series of epidemiological studies. LIPS was designed to identify a population of patients at high risk of ARDS for prevention studies to be carried out by the National Institutes of Health's Prevention and Early Treatment of Acute Lung Injury (PETAL) Network (http:// petalnet. org/). LIPS-A was a large multicentre study to address the question of whether ARDS can be prevented with a drug, in this case aspirin, the latest in a succession of promising therapeutics for ARDS, which was supported by a plethora of positive preclinical data. Disappointingly, the study was negative and one contributing factor was that the score threshold for study inclusion produced only half the predicted number of ARDS cases, the study's primary outcome. [bib_ref] Effect of aspirin on development of ARDS in at-risk patients presenting to..., Kor [/bib_ref] This raises concerns about the ability of LIPS to identify an enriched population of patients at risk for ARDS without the addition of factors such as biomarkers that can predict deterioration from at risk, to mild, to severe ARDS, and to death. Similarly, by characterising patients early in their clinical course before they develop ARDS, it has been possible to refine the parameters to the need for supplemental oxygen, an elevated respiratory rate and bilateral infiltrates on the chest radiograph to identify patients with early acute lung injury (EALI). [bib_ref] Clinical evidence of early acute lung injury often precedes the diagnosis of..., Rackley [/bib_ref] Validation by means of a multicentre study prospectively evaluating the positive predictive value of a score comprising these variables would be required to generate a EALI score that could have a similar role to LIPS in future trials. secondary and tertiary prevention Transfusion of blood products has been associated with the incidence of ARDS, nosocomial infection and mortality in critical illness. TRALI is defined as the onset of ARDS within 6 hours of the transfusion of any blood product in the absence of another risk factor. [bib_ref] Transfusion-related acute lung injury: a clinical review, Vlaar [/bib_ref] The most important mechanism of injury appears to be the interaction of preformed antibodies in the product with the host pulmonary vascular endothelium. Hence, products containing the most plasma confer the highest risk and the exclusion of female donors of products with high plasma volume has resulted in a decrease of roughly two-thirds in the incidence of TRALI. Transfusion of packed red cells using a threshold of 7 was non-inferior to a threshold of 9 g/dL and corresponding protocols Open access restricting unnecessary transfusion should be introduced locally and practices audited. There is a lack of evidence-based practices that decrease hospital acquired infection. An effective local antibiotic policy should aim to optimise antibiotic treatment according to local surveillance data and to ensure rapid de-escalation based on culture results. Recent evidence suggests that enteral nutrition is preferable to parenteral, and that underfeeding is less dangerous than overprovision. Finally, active rehabilitation, specialist outpatient follow-up and psychological support have been recommended for all survivors of severe critical illness in order to mitigate the associated neuropsychological effects and weakness.Author affiliations [bib_ref] Mechanisms and clinical consequences of acute lung injury, Fanelli [/bib_ref] Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK contributors Each author contributed elements to the final text. 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. competing interests Each author contributed elements to the final text. Patient consent for publication Not required. Provenance and peer review Not commissioned; internally peer reviewed. open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http:// creativecommons. org/ licenses/ by-nc/ 4. 0/. [fig] Figure 2: ICU length of stay comparing LTV and HTV mechanical ventilation in adult patients with ARDS. ARDS, acute respiratory distress syndrome; HTV, higher tidal volume; ICU, intensive care unit; LTV, lower tidal volume. [/fig] [fig] Figure 3: Analysis of evidence relating to the topics selected in this figure. ARDS, acute respiratory distress syndrome; CPAP, continuous positive airway pressure; ECMO, extracorporeal membrane oxygenation; PEEP, positive end-expiratory pressure. [/fig] [table] Open access Table 1: Corticosteroids compared to placebo for ARDS GRADE evidence table can be found as part of the online appendix B (https://www. ficm. ac. uk/ sites/ default/ files/ appendix_ b_-_ grade_ evidence_ tables. pdf). [/table] [table] Table 2: ECMO compared to standard care for ARDS [/table] [table] Table 3: ECCO 2 R compared to standard care for acute respiratory distress syndrome [/table] [table] Table 4: Conservative compared to liberal fluid management for ARDS AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; RRT, renal replacement therapy. [/table] [table] Table 5: HFOV compared to usual care for ARDS ARDS, acute respiratory distress syndrome; HFOV, high-frequency oscillatory ventilation. A GRADE Summary of Findings table is shown below based on critical and important outcomes (table 6). A full GRADE evidence table can be found as part of online appendix B. [/table] [table] Table 6: iVasoD compared to placebo or usual care for ARDS Patient or population: adults with ARDS Settings: intensive care Intervention: iNO for all studies Comparison: placebo or usual care ARDS, acute respiratory distress syndrome; iNO, iVasoD, inhaled nitric oxide; iVasoD, inhaled vasodilators. [/table] [table] Table 7: Lower tidal volume compared with higher tidal volume (at similar PEEP) for ARDS Patient or population: adults with ARDS Settings: intensive care Intervention: lower tidal volume Comparison: higher, conventional tidal volume GRADE Summary of Findings table is shown based on critical and important outcomes (table 8). A full GRADE evidence table can be found as part of online appendix B. [/table] [table] Table 8: NMBAs compared to placebo for ARDS [/table] [table] Table 9: Higher PEEP compared to lower PEEP for ARDS [/table] [table] Table 10: PEEP values at day 1 in clinical trials [/table] [table] Table 11: Prone positioning compared with standard care for ARDS [/table] [table] Table 12: Summary of the FICM/ICS Guidelines for the management of ARDS in adult patients ARDS, acute respiratory distress syndrome; ECCO2R, extracorporeal carbon dioxide removal; ECMO, extracorporeal membrane oxygenation; FICM, Faculty of Intensive Care Medicine; HFOV, high frequency oscillation; ICS, Intensive Care Society; NMBA, neuromuscular blocking agents; PEEP, peek end-expiratory pressure. [/table] [table] Table 13: The lung injury prediction score High-risk surgery *Add 1.5 points in case of emergency surgery. †Only in cases of sepsis. BMI, body mass index; RR, respiratory rate; SpO2, oxygen saturation by pulse oximetry. [/table]	None	https://bmjopenrespres.bmj.com/content/bmjresp/6/1/e000420.full.pdf	The Faculty of Intensive Care Medicine and Intensive Care Society Guideline Development Group have used GRADE methodology to make the following recommendations for the management of adult patients with acute respiratory distress syndrome (ARDS). The British Thoracic Society supports the recommendations in this guideline. Where mechanical ventilation is required, the use of low tidal volumes (<6 ml/kg ideal body weight) and airway pressures (plateau pressure <30 cmH2O) was recommended. For patients with moderate/severe ARDS (PF ratio<20 kPa), prone positioning was recommended for at least 12 hours per day. By contrast, high frequency oscillation was not recommended and it was suggested that inhaled nitric oxide is not used. The use of a conservative fluid management strategy was suggested for all patients, whereas mechanical ventilation with high positive end-expiratory pressure and the use of the neuromuscular blocking agent cisatracurium for 48 hours was suggested for patients with ARDS with ratio of arterial oxygen partial pressure to fractional inspired oxygen (PF) ratios less than or equal to 27 and 20 kPa, respectively. Extracorporeal membrane oxygenation was suggested as an adjunct to protective mechanical ventilation for patients with very severe ARDS. In the absence of adequate evidence, research recommendations were made for the use of corticosteroids and extracorporeal carbon dioxide removal.
b3dc69b4036ecc2b54bde48eb15b9497b4217372	pubmed	Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach	Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach [bib_ref] Type 2 diabetes: assessing the relative principles for applying the Users' Guides..., Bergenstal [/bib_ref] [bib_ref] N of 1 trials in diabetes: making individual therapeutic decisions, Tsapas [/bib_ref] [bib_ref] Translating comparative effectiveness into practice: the case of diabetes medications, Shah [/bib_ref] # Background Epidemiology and health care impact Both the prevalence and incidence of type 2 diabetes are increasing worldwide, particularly in developing countries, in conjunction with increased obesity rates and westernization of lifestyle. The attendant economic burden for health care systems is skyrocketing, owing to the costs associated with treatment and diabetes complications. Type 2 diabetes remains a leading cause of cardiovascular disorders, blindness, end-stage renal failure, amputations, and hospitalizations. It is also associated with increased risk of cancer, serious psychiatric illness, cognitive decline, chronic liver disease, accelerated arthritis, and other disabling or deadly conditions. Effective management strategies are of obvious importance. ## Relationship of glycemic control to outcomes It is well established that the risk of microvascular and macrovascular complications is related to glycemia, as measured by HbA 1c ; this remains a major focus of therapy [bib_ref] Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes..., Stratton [/bib_ref]. Prospective randomized trials have documented reduced rates of microvascular complications in type 2 diabetic patients treated to lower glycemic targets. In the UK Prospective Diabetes Study (UKPDS) [bib_ref] UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or..., Turner [/bib_ref] [bib_ref] UK Prospective Diabetes Study VIII: study design, progress and performance, Ukpds Group [/bib_ref] , patients with newly diagnosed type 2 diabetes were randomized to two treatment policies. In the standard group, lifestyle intervention was the mainstay with pharmacological therapy used only if hyperglycemia became severe. In the more intensive treatment arm, patients were randomly assigned to either a sulfonylurea or insulin, with a subset of overweight patients randomized to metformin. The overall HbA 1c achieved was 0.9% lower in the intensive policy group compared with the conventional policy arm (7.0% vs. 7.9%). Associated with this difference in glycemic control was a reduction in the risk of microvascular complications (retinopathy, nephropathy, neuropathy) with intensive therapy. A trend toward reduced rates of myocardial infarction in this group did not reach statistical significance [bib_ref] UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or..., Turner [/bib_ref]. By contrast, substantially fewer metformintreated patients experienced myocardial infarction, diabetes-related and all-cause mortality [bib_ref] UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with..., Turner [/bib_ref] , despite a mean HbA 1c only 0.6% lower than the conventional policy group. The UKPDS 10-year follow-up demonstrated that the relative benefit of having been in the intensive management policy group was maintained over a decade, resulting in the emergence of statistically significant benefits on cardiovascular disease (CVD) end points and total mortality in those initially assigned to sulfonylurea/ insulin, and persistence of CVD benefits with metformin [bib_ref] 10-year follow-up of intensive glucose control in type 2 diabetes, Holman [/bib_ref] , in spite of the fact that the mean HbA 1c levels between the groups converged soon after the randomized component of the trial had concluded. In 2008, three shorter-term studies [Action to Control Cardiovascular Risk in Diabetes (ACCORD) [bib_ref] Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive..., Gerstein [/bib_ref] , Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) [bib_ref] ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients..., Patel [/bib_ref] , Veterans Affairs Diabetes Trial (VADT) [bib_ref] Intensive glucose control and macrovascular outcomes in type 2 diabetes, Turnbull [/bib_ref] ] reported the effects of two levels of glycemic control on cardiovascular end points in middleaged and older individuals with wellestablished type 2 diabetes at high risk for cardiovascular events. ACCORD and VADT aimed for an HbA 1c ,6.0% using complex combinations of oral agents and insulin. ADVANCE aimed for an HbA 1c #6.5% using a less intensive approach based on the sulfonylurea gliclazide. None of the trials demonstrated a statistically significant reduction in the primary combined cardiovascular end points. Indeed, in ACCORD, a 22% increase in total mortality with intensive therapy was observed, mainly driven by cardiovascular mortality. An explanation for this finding has remained elusive, although rates of hypoglycemia were threefold higher with intensive treatment. It remains unclear, however, if hypoglycemia was responsible for the adverse outcomes, or if other factors, such as more weight gain, or simply the greater complexity of therapy, contributed. There were suggestions in these trials that patients without overt CVD, with shorter duration of disease, and lower baseline HbA 1c , benefited from the more intensive strategies. Modest improvements in some microvascular end points in the studies were likewise demonstrated. Finally, a meta-analysis of cardiovascular outcomes in these trials suggested that every HbA 1c reduction of ;1% may be associated with a 15% relative risk reduction in nonfatal myocardial infarction, but without benefits on stroke or all-cause mortality [bib_ref] Intensive glucose control and macrovascular outcomes in type 2 diabetes, Turnbull [/bib_ref]. Overview of the pathogenesis of type 2 diabetes Any rise in glycemia is the net result of glucose influx exceeding glucose outflow from the plasma compartment. In the fasting state, hyperglycemia is directly related to increased hepatic glucose production. In the postprandial state, further glucose excursions result from the combination of insufficient suppression of this glucose output and defective insulin stimulation of glucose disposal in target tissues, mainly skeletal muscle. Once the renal tubular transport maximum for glucose is exceeded, glycosuria curbs, though does not prevent, further hyperglycemia. Abnormal islet cell function is a key and requisite feature of type 2 diabetes. In early disease stages, insulin production is normal or increased in absolute terms, but disproportionately low for the degree of insulin sensitivity, which is typically reduced. However, insulin kinetics, such as the ability of the pancreatic b-cell to release adequate hormone in phase with rising glycemia, are profoundly compromised. This functional islet incompetence is the main quantitative determinant of hyperglycemia (37) and progresses over time. In addition, in type 2 diabetes, pancreatic a-cells hypersecrete glucagon, further promoting hepatic glucose production [bib_ref] Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications, Nauck [/bib_ref]. Importantly, islet dysfunction is not necessarily irreversible. Enhancing insulin action relieves b-cell secretory burden, and any intervention that improves glycemiad from energy restriction to, most strikingly, bariatric surgerydcan ameliorate b-cell dysfunction to an extent [bib_ref] The stunned beta cell: a brief history, Ferrannini [/bib_ref]. More recently recognized abnormalities in the incretin system (represented by the gut hormones, glucagon-like peptide 1 [GLP-1], and glucose-dependent insulinotropic peptide are also found in type 2 diabetes, but it remains unclear whether these constitute primary or secondary defects [bib_ref] Unraveling the science of incretin biology, Nauck [/bib_ref]. In most patients with type 2 diabetes, especially the obese, insulin resistance in target tissues (liver, muscle, adipose tissue, myocardium) is a prominent feature. This results in both glucose overproduction and underutilization. Moreover, an increased delivery of fatty acids to the liver favors their oxidation, which contributes to increased gluconeogenesis, whereas the absolute overabundance of lipids promotes hepatosteatosis [bib_ref] Insulin action and substrate competition, Groop [/bib_ref]. Antihyperglycemic agents are directed at one or more of the pathophysiological defects of type 2 diabetes, or modify physiological processes relating to appetite or to nutrient absorption or excretion. Ultimately, type 2 diabetes is a disease that is heterogeneous in both pathogenesis and in clinical manifestationda point to be considered when determining the optimal therapeutic strategy for individual patients. ## Antihyperglycemic therapy ## Glycemic targets The ADA's "Standards of Medical Care in Diabetes" recommends lowering HbA 1c to ,7.0% in most patients to reduce the incidence of microvascular disease. This can be achieved with a mean plasma glucose of ;8.3-8.9 mmol/L (;150-160 mg/dL); ideally, fasting and premeal glucose should be maintained at ,7.2 mmol/L (,130 mg/dL) and the postprandial glucose at ,10 mmol/L (,180 mg/dL). More stringent HbA 1c targets (e.g., 6.0-6.5%) might be considered in selected patients (with short disease duration, long life expectancy, no significant CVD) if this can be achieved without significant hypoglycemia or other adverse effects of treatment (20,43). Conversely, less stringent HbA 1c goalsde.g., 7.5-8.0% or even slightly higherdare appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced complications, extensive comorbid conditions and those in whom the target is difficult to attain despite intensive self-management education, repeated counseling, and effective doses of multiple glucose-lowering agents, including insulin (20,44). The accumulated results from the aforementioned type 2 diabetes cardiovascular trials suggest that not everyone benefits from aggressive glucose management. It follows that it is important to individualize treatment targets (5, [bib_ref] Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive..., Gerstein [/bib_ref] [bib_ref] ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients..., Patel [/bib_ref] [bib_ref] Intensive glucose control and macrovascular outcomes in type 2 diabetes, Turnbull [/bib_ref]. The elements that may guide the clinician in choosing an HbA 1c target for a specific patient are shown in . As mentioned earlier, the desires and values of the patient should also be considered, since the achievement of any degree of glucose control requires active participation and commitment [bib_ref] Current treatment of non-alcoholic fatty liver disease, Ahmed [/bib_ref] [bib_ref] We need minimally disruptive medicine, May [/bib_ref]. Indeed, any target could reflect an agreement between patient and clinician. An important related concept is that the ease with which more intensive targets are reached influences treatment decisions; logically, lower targets are attractive if they can be achieved with less complex regimens and no or minimal adverse effects. Importantly, utilizing the percentage of diabetic patients who are achieving an HbA 1c ,7.0% as a quality indicator, as promulgated by various health care organizations, is inconsistent with the emphasis on individualization of treatment goals. ## Therapeutic options Lifestyle. Interventions designed to impact an individual's physical activity levels and food intake are critical parts of type 2 diabetes management [bib_ref] Importance of weight management in type 2 diabetes: review with meta-analysis of..., Anderson [/bib_ref]. All patients should receive standardized general diabetes education (individual or group, preferably using an approved curriculum), with a specific focus on dietary interventions and the importance of increasing physical activity. While encouraging therapeutic lifestyle change is important at diagnosis, periodic counseling should also be integrated into the treatment program. Weight reduction, achieved through dietary means alone or with adjunctive medical or surgical intervention, improves glycemic control and other cardiovascular risk factors. Modest weight loss (5-10%) contributes meaningfully to achieving improved glucose control. Accordingly, establishing a goal of weight reduction, or at least weight maintenance, is recommended. Dietary advice must be personalized [bib_ref] Nutrition recommendations and interventions for diabetes: a position statement of the American..., Bantle [/bib_ref]. Patients should be encouraged to eat healthy foods that are consistent with the prevailing population-wide dietary recommendations and with an individual's preferences and culture. Foods high in fiber (such as vegetables, fruits, whole grains, and of the elements of decision making used to determine appropriate efforts to achieve glycemic targets. Greater concerns about a particular domain are represented by increasing height of the ramp. Thus, characteristics/predicaments toward the left justify more stringent efforts to lower HbA 1c , whereas those toward the right are compatible with less stringent efforts. Where possible, such decisions should be made in conjunction with the patient, reflecting his or her preferences, needs, and values. This "scale" is not designed to be applied rigidly but to be used as a broad construct to help guide clinical decisions. Adapted with permission from Ismail-Beigi et al. . ? activation of farnesoid X receptor (FXR) in liver legumes), low-fat dairy products, and fresh fish should be emphasized. High-energy foods, including those rich in saturated fats, and sweet desserts and snacks should be eaten less frequently and in lower amounts [bib_ref] A self-regulation program for maintenance of weight loss, Wing [/bib_ref]. Patients who eventually lose and keep weight off usually do so after numerous cycles of weight loss and relapse. The health care team should remain nonjudgmental but persistent, revisiting and encouraging therapeutic lifestyle changes frequently, if needed. As much physical activity as possible should be promoted, ideally aiming for at least 150 min/week of moderate activity including aerobic, resistance, and flexibility training [bib_ref] Effects of exercise on glycemic control and body mass in type 2..., Boulé [/bib_ref]. In older individuals, or those with mobility challenges, so long as tolerated from a cardiovascular standpoint, any increase in activity level is advantageous. At diagnosis, highly motivated patients with HbA 1c already near target (e.g., ,7.5%) could be given the opportunity to engage in lifestyle change for a period of 3-6 months before embarking on pharmacotherapy (usually metformin). Those with moderate hyperglycemia or in whom lifestyle changes are anticipated to be unsuccessful should be promptly started on an antihyperglycemic agent (also usually metformin) at diagnosis, which can later be modified or possibly discontinued if lifestyle changes are successful. Oral agents and noninsulin injectables. Important properties of antihyperglycemic agents that play a role in the choice of drug(s) in individual patients are summarized in . Ultimately, the aims of controlling glycemia are to avoid acute osmotic symptoms of hyperglycemia, to avoid instability in blood glucose over time, and to prevent/delay the development of diabetes complications without adversely affecting quality of life. Information on whether specific agents have this ability is incomplete; an answer to these questions requires long-term, largescale clinical trialsdnot available for most drugs. Effects on surrogate measures for glycemic control (e.g., HbA 1c ) generally reflect changes in the probability of developing microvascular disease but not necessarily macrovascular complications. Particularly from a patient standpoint, stability of metabolic control over time may be another specific goal. Metformin, a biguanide, remains the most widely used first-line type 2 diabetes drug; its mechanism of action predominately involves reducing hepatic glucose production [bib_ref] Effect of metformin on cardiovascular events and mortality: a metaanalysis of randomized..., Lamanna [/bib_ref]. It is generally considered weight-neutral with chronic use and does not increase the risk of hypoglycemia. Metformin is associated with initial gastrointestinal side effects, and caution is advised to avoid its use in patients at risk for lactic acidosis (e.g., in advanced renal insufficiency, alcoholism), a rare complication of therapy. As noted earlier, there may be some cardiovascular benefits from this drug, but the clinical trial data are not robust. The oldest oral agent class is the sulfonylurea insulin secretagogues. Through the closure of ATP-sensitive potassium channels on b-cells, these drugs stimulate insulin release [bib_ref] Insulin secretagogues, sulfonylurea receptors and K(ATP) channels, Bryan [/bib_ref]. While effective in controlling glucose levels, their use is associated with modest weight gain and risk of hypoglycemia. In addition, studies have demonstrated a secondary failure rate that may exceed other drugs, ascribed to an exacerbation of islet dysfunction [bib_ref] Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy, Kahn [/bib_ref]. Shorter-acting secretagogues, the meglitinides (or glinides), stimulate insulin release through similar mechanisms but may be associated with less hypoglycemia [bib_ref] PRESERVE-b: two-year efficacy and safety of initial combination therapy with nateglinide or..., Gerich [/bib_ref]. They require more frequent dosing, however. Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor g activators (59) that improve insulin sensitivity in skeletal muscle and reduce hepatic glucose production (54,55). They do not increase the risk of hypoglycemia and may be more durable in their effectiveness than sulfonylureas and metformin [bib_ref] Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy, Kahn [/bib_ref]. Pioglitazone appeared to have a modest benefit on cardiovascular events as a secondary outcome in one large trial involving patients with overt macrovascular disease [bib_ref] PROactive investigators. Secondary prevention of macrovascular events in patients with type 2..., Dormandy [/bib_ref]. Another agent of this class, rosiglitazone, is no longer widely available owing to concerns of increased myocardial infarction risk [bib_ref] Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular..., Nissen [/bib_ref]. Pioglitazone has recently been associated with a possible increased risk of bladder cancer [bib_ref] Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report..., Lewis [/bib_ref]. Recognized side effects of TZDs include weight gain, fluid retention leading to edema and/or heart failure in predisposed individuals, and increased risk of bone fractures [bib_ref] Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy, Kahn [/bib_ref] [bib_ref] PROactive investigators. Secondary prevention of macrovascular events in patients with type 2..., Dormandy [/bib_ref]. Drugs focused on the incretin system have been introduced more recently (63). The injectable GLP-1 receptor agonists mimic the effects of endogenous GLP-1, thereby stimulating pancreatic insulin secretion in a glucose-dependent fashion, suppressing pancreatic glucagon output, slowing gastric emptying, and decreasing appetite. Their main advantage is weight loss, which is modest in most patients but can be significant in some. A limiting side effect is nausea and vomiting, particularly early in the course of treatment. Concerns regarding an increased risk of pancreatitis remain unresolved. The oral dipeptidyl peptidase 4 (DPP-4) inhibitors enhance circulating concentrations of active GLP-1 and GIP [bib_ref] Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative..., Deacon [/bib_ref]. Their major effect appears to be in the regulation of insulin and glucagon secretion; they are weight neutral. Typically, neither of the incretinbased classes cause hypoglycemia by themselves. Two agents that are used infrequently in the U.S. and Europe are the a-glucosidase inhibitors (AGIs), which retard gut carbohydrate absorption [bib_ref] Alpha-glucosidase inhibitors for people with impaired glucose tolerance or impaired fasting blood..., Van De Laar [/bib_ref] , and colesevelam, a bile acid sequestrant whose mechanism of glucose-lowering action remains poorly understood and whose major additional benefit is LDL-cholesterol reduction [bib_ref] Colesevelam lowers glucose and lipid care.diabetesjournals.org DIABETES CARE, Fonseca [/bib_ref]. Both have gastrointestinal effects, mainly flatulence with AGIs and constipation with colesevelam. The dopamine agonist bromocriptine is only available in the U.S. as an antihyperglycemic agent [bib_ref] Bromocriptine: a sympatholytic, D2-dopamine agonist for the treatment of type 2 diabetes, Defronzo [/bib_ref]. Its mechanism of action and precise role are unclear. The amylin agonist, pramlintide, is typically reserved for patients treated with intensive insulin therapy, usually in type 1 diabetes mellitus; it decreases postprandial glucose excursions by inhibiting glucagon secretion and slowing gastric emptying [bib_ref] Pramlintide acetate injection for the treatment of type 1 and type 2..., Singh-Franco [/bib_ref]. The glucose-lowering effectiveness of noninsulin pharmacological agents is said to be high for metformin, sulfonylureas, TZDs, and GLP-1 agonists (expected HbA 1c reduction ;1.0-1.5%) [bib_ref] Incretin-based therapies: review of current clinical trial data, Peters [/bib_ref] [bib_ref] Comparative effectiveness and safety of medications for type 2 diabetes: an update..., Bennett [/bib_ref] , and generally lower for meglitinides, DPP-4 inhibitors, AGIs, colesevelam, and bromocriptine (;0.5-1.0%). However, older drugs have typically been tested in clinical trial participants with higher baseline HbA 1c , which is itself associated with greater treatment emergent glycemic reductions, irrespective of therapy type. In head-to-head studies, any differential effects on glucose control are small. So agent-and patient-specific properties, such as dosing frequency, side-effect profiles, cost, and other benefits often guide their selection. Insulin. Due to the progressive b-cell dysfunction that characterizes type 2 diabetes, insulin replacement therapy is frequently required [bib_ref] Primary care physicians and insulin initiation: multiple barriers, lack of knowledge or..., Jabbour [/bib_ref]. Importantly, most patients maintain some endogenous insulin secretion even in late stages of disease. Accordingly, the more complex and intensive strategies of type 1 diabetes are not typically necessary [bib_ref] Adjust to target in type 2 diabetes: comparison of a simple algorithm..., Bergenstal [/bib_ref] Ideally, the principle of insulin use is the creation of as normal a glycemic profile as possible without unacceptable weight gain or hypoglycemia [bib_ref] Hypoglycaemia: the limiting factor in the glycaemic management of Type I and..., Cryer [/bib_ref]. As initial therapy, unless the patient is markedly hyperglycemic and/or symptomatic, a "basal" insulin alone is typically added [bib_ref] 4-T Study Group. Three-year efficacy of complex insulin regimens in type 2..., Holman [/bib_ref]. Basal insulin provides relatively uniform insulin coverage throughout the day and night, mainly to control blood glucose by suppressing hepatic glucose production in between meals and during sleep. Either intermediate-acting (neutral protamine Hagedorn [NPH]) or long-acting (insulin glargine [A21Gly,B31Arg,B32Arg human insulin] or insulin detemir [B29Lys (´-tetradecanoyl),desB30 human insulin]) formulations may be used. The latter two are associated with modestly less overnight hypoglycemia (insulin glargine, insulin detemir) than NPH and possibly slightly less weight gain (insulin detemir), but are more expensive [bib_ref] A 26-week, randomized, parallel, treatto-target trial comparing insulin detemir with NPH insulin..., Hermansen [/bib_ref] [bib_ref] The Treat-to-Target Trial and related studies, Riddle [/bib_ref]. Of note, the dosing of these basal insulin analogs may differ, with most comparative trials showing a higher average unit requirement with insulin detemir [bib_ref] A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when..., Rosenstock [/bib_ref]. Although the majority of patients with type 2 diabetes requiring insulin therapy can be successfully treated with basal insulin alone, some, because of progressive diminution in their insulin secretory capacity, will require prandial insulin therapy with shorter-acting insulins. This is typically provided in the form of the rapid insulin analogs, insulin lispro (B28Lys,B29Pro human insulin), insulin aspart (B28Asp human insulin), or insulin glulisine (B3Lys,B29Glu human insulin), which may be dosed just before the meal. They result in better postprandial glucose control than the less costly human regular insulin, whose pharmacokinetic profile makes it less attractive in this setting. Ideally, an insulin treatment program should be designed specifically for an individual patient, to match the supply of insulin to his or her dietary/exercise habits and prevailing glucose trends, as revealed through self-monitoring. Anticipated glucoselowering effects should be balanced with the convenience of the regimen, in the context of an individual's specific therapy goals . Proper patient education regarding glucose monitoring, insulin injection technique, insulin storage, recognition/ treatment of hypoglycemia, and "sick day" rules is imperative. Where available, certified diabetes educators can be invaluable in guiding the patient through this process. ## Implementation strategies Initial drug therapy. It is generally agreed that metformin, if not contraindicated and if tolerated, is the preferred and most cost-effective first agent (42) and Supplementary Figs.). It is initiated at, or soon after, diagnosis, especially in patients in whom lifestyle intervention alone has not achieved, or is unlikely to achieve, HbA 1c goals. Because of frequent gastrointestinal side effects, it should be started at a low dose with gradual titration. Patients with a high baseline HbA 1c (e.g., $9.0%) have a low probability of achieving a nearnormal target with monotherapy. It may therefore be justified to start directly with a combination of two noninsulin agents or with insulin itself in this circumstance [bib_ref] International Diabetes Center treatment of type 2 diabetes glucose algorithm, Simonson [/bib_ref]. If a patient presents with significant hyperglycemic symptoms and/or has dramatically elevated plasma glucose concentrations (e.g., .16.7-19.4 mmol/L [.300-350 mg/dL]) or HbA 1c (e.g., $10.0-12.0%), insulin therapy should be strongly considered from the outset. Such treatment is mandatory when catabolic features are exhibited or, of course, if ketonuria is demonstrated, the latter reflecting profound insulin deficiency. Importantly, unless there is evidence of type 1 diabetes, once symptoms are relieved, glucotoxicity resolved, and the metabolic state stabilized, it may be possible to taper insulin partially or entirely, transferring to noninsulin antihyperglycemic agents, perhaps in combination. If metformin cannot be used, another oral agent could be chosen, such as a sulfonylurea/glinide, pioglitazone, or a DPP-4 inhibitor; in occasional cases where weight loss is seen as an essential aspect of therapy, initial treatment with a GLP-1 receptor agonist might be useful. Where available, less commonly used drugs (AGIs, colesevelam, bromocriptine) might also be considered in selected patients, but their modest glycemic effects and side-effect profiles make them less attractive candidates. Specific patient preferences, characteristics, susceptibilities to side effects, potential for weight gain and hypoglycemia should play a major role in drug selection (20,21). (See for adaptations of that address specific patient scenarios.) Advancing to dual combination therapy. (and Supplementary Figs.) also depicts potential sequences of escalating glucose-lowering therapy beyond metformin. If monotherapy alone does not achieve/maintain an HbA 1c target over ;3 months, the next step would be to add a second oral agent, a GLP-1 receptor agonist, or basal insulin (5,10). Notably, the higher the HbA 1c , the more likely insulin will be required. On average, any second agent is typically associated with an approximate further reduction in HbA 1c of ;1% [bib_ref] Comparative effectiveness and safety of medications for type 2 diabetes: an update..., Bennett [/bib_ref] [bib_ref] Effect of antihyperglycemic agents added to metformin and a sulfonylurea on glycemic..., Gross [/bib_ref]. If no clinically meaningful glycemic reduction (i.e., "nonresponder") is demonstrated, then, adherence having been investigated, that agent should be discontinued, and another with a different mechanism of action substituted. With a distinct paucity of long-term comparative-effectiveness trials available, uniform recommendations on the best agent to be combined with metformin cannot be made [bib_ref] Dipeptidyl peptidase-4 inhibitors for type 2 diabetes mellitus in the clinical setting:..., Karagiannis [/bib_ref]. Thus, advantages and disadvantages of specific drugs for each patient should be considered . Some antihyperglycemic medications lead to weight gain. This may be associated with worsening markers of insulin resistance and cardiovascular risk. One exception may be TZDs (57); weight gain associated with this class occurs in association with decreased insulin resistance. Although there is no uniform evidence that increases in weight in the range observed with certain therapies translate into a substantially increased cardiovascular risk, it remains important to avoid unnecessary KEY POINTS c Glycemic targets and glucose-lowering therapies must be individualized. c Diet, exercise, and education remain the foundation of any type 2 diabetes treatment program. c Unless there are prevalent contraindications, metformin is the optimal first-line drug. c After metformin, there are limited data to guide us. Combination therapy with an additional 1-2 oral or injectable agents is reasonable, aiming to minimize side effects where possible. c Ultimately, many patients will require insulin therapy alone or in combination with other agents to maintain glucose control. c All treatment decisions, where possible, should be made in conjunction with the patient, focusing on his/her preferences, needs, and values. c Comprehensive cardiovascular risk reduction must be a major focus of therapy. weight gain by optimal medication selection and dose titration. For all medications, consideration should also be given to overall tolerability. Even occasional hypoglycemia may be devastating, if severe, or merely irritating, if mild [bib_ref] Severe iatrogenic hypoglycemia in type 2 diabetes mellitus, Cryer [/bib_ref]. Gastrointestinal side effects may be tolerated by some, but not others. Fluid retention may pose a clinical or merely an aesthetic problem [bib_ref] Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies, Loke [/bib_ref]. The risk of bone fractures may be a specific concern in postmenopausal women [bib_ref] Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy, Kahn [/bib_ref]. It must be acknowledged that costs are a critical issue driving the selection of glucose-lowering agents in many environments. For resource-limited settings, less expensive agents should be chosen. However, due consideration should be also given to side effects and any necessary monitoring, with their own cost implications. Moreover, prevention of morbid In most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis (unless there are explicit contraindications). If the HbA 1c target is not achieved after ;3 months, consider one of the five treatment options combined with metformin: a sulfonylurea, TZD, DPP-4 inhibitor, GLP-1 receptor agonist, or basal insulin. (The order in the chart is determined by historical introduction and route of administration and is not meant to denote any specific preference.) Choice is based on patient and drug characteristics, with the over-riding goal of improving glycemic control while minimizing side effects. Shared decision making with the patient may help in the selection of therapeutic options. The figure displays drugs commonly used both in the U.S. and/or Europe. Rapid-acting secretagogues (meglitinides) may be used in place of sulfonylureas. Other drugs not shown (a-glucosidase inhibitors, colesevelam, dopamine agonists, pramlintide) may be used where available in selected patients but have modest efficacy and/or limiting side effects. In patients intolerant of, or with contraindications for, metformin, select initial drug from other classes depicted and proceed accordingly. In this circumstance, while published trials are generally lacking, it is reasonable to consider three-drug combinations other than metformin. Insulin is likely to be more effective than most other agents as a third-line therapy, especially when HbA 1c is very high (e.g., $9.0%). The therapeutic regimen should include some basal insulin before moving to more complex insulin strategies . Dashed arrow line on the left-hand side of the figure denotes the option of a more rapid progression from a twodrug combination directly to multiple daily insulin doses, in those patients with severe hyperglycemia (e.g., HbA 1c $10.0-12.0%). DPP-4-i, DPP-4 inhibitor; Fx's, bone fractures; GI, gastrointestinal; GLP-1-RA, GLP-1 receptor agonist; HF, heart failure; SU, sulfonylurea. a Consider beginning at this stage in patients with very high HbA 1c (e.g., $9%). b Consider rapid-acting, nonsulfonylurea secretagogues (meglitinides) in patients with irregular meal schedules or who develop late postprandial hypoglycemia on sulfonylureas. c See for additional potential adverse effects and risks, under "Disadvantages." d Usually a basal insulin (NPH, glargine, detemir) in combination with noninsulin agents. e Certain noninsulin agents may be continued with insulin (see text). Refer to long-term complications will likely reduce long-term expenses attributed to the disease. Advancing to triple combination therapy. Some studies have shown advantages of adding a third noninsulin agent to a two-drug combination that is not yet or no longer achieving the glycemic target [bib_ref] Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients..., Kendall [/bib_ref] [bib_ref] Triple therapy with glimepiride in patients with type 2 diabetes mellitus inadequately..., Roberts [/bib_ref] [bib_ref] Triple oral fixed-dose diabetes polypill versus insulin plus metformin efficacy demonstration study..., Bell [/bib_ref]. Not surprisingly, however, at this juncture, the most robust response will usually be with insulin. Indeed, since diabetes is associated with progressive b-cell loss, many patients, especially those with long-standing disease, will eventually need to be transitioned to insulin, which should be favored in circumstances where the degree of hyperglycemia (e.g., $8.5%) makes it unlikely that another drug will be of sufficient benefit [bib_ref] Triple therapy in type 2 diabetes: insulin glargine or rosiglitazone added to..., Rosenstock [/bib_ref]. If triple combination therapy exclusive of insulin is tried, the patient should be monitored closely, with the approach promptly reconsidered if it proves to be unsuccessful. Many months of uncontrolled hyperglycemia should specifically be avoided. In using triple combinations the essential consideration is obviously to use agents with complementary mechanisms of action . Increasing the number of drugs heightens the potential for side effects and drug-drug interactions, raises costs, and negatively impacts patient adherence. The rationale, benefits, and side effects of each new medication should be discussed with the patient. The clinical characteristics of patients more or less likely to respond to specific combinations are, unfortunately, not well defined. ## Transitions to and titrations of insulin. Most patients express reluctance to beginning injectable therapy, but, if the practitioner feels that such a transition is important, encouragement and education can usually overcome such reticence. Insulin is typically begun at a low dose (e.g., 0.1-0.2 U kg 21 day 21 ), although larger amounts (0.3-0.4 U kg 21 day 21 ) are reasonable in the more severely hyperglycemic. The most convenient strategy is with a single injection of a basal insulin, with the timing of administration dependent on the patient's schedule and overall glucose profile . Although extensive dosing instructions for insulin are beyond the scope of this statement, most patients can be taught to uptitrate their own insulin dose based on several algorithms, each essentially involving the addition of a small dose increase if hyperglycemia persists [bib_ref] 4-T Study Group. Three-year efficacy of complex insulin regimens in type 2..., Holman [/bib_ref] [bib_ref] The Treat-to-Target Trial and related studies, Riddle [/bib_ref] [bib_ref] Initiate Insulin by Aggressive Titration and Education (INITIATE): a randomized study to..., Yki-Järvinen [/bib_ref]. For example, the addition of 1-2 units (or, in those already on higher doses, increments of 5-10%) to the daily dose once or twice weekly if the fasting glucose levels are above the preagreed target is a reasonable approach [bib_ref] Improvement of glycemic control in subjects with poorly controlled type 2 diabetes:..., Davies [/bib_ref]. As the target is neared, dosage adjustments should be more modest and occur less frequently. Downward adjustment is advisable if any hypoglycemia occurs. During self-titration, frequent contact (telephone, e-mail) with the clinician may be necessary. Practitioners themselves can, of course, also titrate basal insulin, but this would involve more intensive contact with the patient than typically available in routine clinical practice. Daily self-monitoring of blood glucose is of obvious importance during this phase. After the insulin dose is stabilized, the frequency of monitoring should be reviewed [bib_ref] The importance of titrating starting insulin regimens in patients with type 2..., Garber [/bib_ref]. Consideration should be given to the addition of prandial or mealtime insulin coverage when significant postprandial glucose excursions (e.g., to .10.0 mmol/L [.180 mg/dL]) occur. This is suggested when the fasting glucose is at target but the HbA 1c remains above goal after 3-6 months of basal insulin titration [bib_ref] Effects of initiation and titration of a single pre-prandial dose of insulin..., Owens [/bib_ref]. The same would apply if large drops in glucose occur during overnight hours or in between meals, as the basal insulin dose is increased. In this scenario, the basal insulin dose would obviously need to be simultaneously decreased as prandial insulin is initiated. Although basal insulin is titrated primarily against the fasting glucose, generally irrespective of the total dose, practitioners should be aware that the need for prandial insulin therapy will become likely the more the daily dose exceeds 0.5 U kg 21 day 21 , especially as it approaches 1 U kg 21 day 21 . The aim with mealtime insulin is to blunt postprandial glycemic excursions, insulin strategies in type 2 diabetes. Basal insulin alone is usually the optimal initial regimen, beginning at 0.1-0.2 units/kg body weight, depending on the degree of hyperglycemia. It is usually prescribed in conjunction with one to two noninsulin agents. In patients willing to take more than one injection and who have higher HbA 1c levels ($9.0%), twicedaily premixed insulin or a more advanced basal plus mealtime insulin regimen could also be considered (curved dashed arrow lines). When basal insulin has been titrated to an acceptable fasting glucose but HbA 1c remains above target, consider proceeding to basal plus mealtime insulin, consisting of one to three injections of rapid-acting analogs (see text for details). A less studied alternativedprogression from basal insulin to a twice-daily premixed insulindcould be also considered (straight dashed arrow line); if this is unsuccessful, move to basal plus mealtime insulin. The figure describes the number of injections required at each stage, together with the relative complexity and flexibility. Once a strategy is initiated, titration of the insulin dose is important, with dose adjustments made based on the prevailing glucose levels as reported by the patient. Noninsulin agents may be continued, although insulin secretagogues (sulfonylureas, meglitinides) are typically stopped once more complex regimens beyond basal insulin are utilized. Comprehensive education regarding self-monitoring of blood glucose, diet, exercise, and the avoidance of, and response to, hypoglycemia are critical in any patient on insulin therapy. Mod., moderate. which can be extreme in some individuals, resulting in poor control during the day. Such coverage may be provided by one of two methods. The most precise and flexible prandial coverage is possible with "basal-bolus" therapy, involving the addition of premeal rapid-acting insulin analog to ongoing basal insulin. One graduated approach is to add prandial insulin before the meal responsible for the largest glucose excursiondtypically that with the greatest carbohydrate content, often, but not always, the evening meal [bib_ref] A stepwise approach to insulin therapy in patients with type 2 diabetes..., Davidson [/bib_ref]. Subsequently, a second injection can be administered before the meal with the next largest excursion (often breakfast). Ultimately, a third injection may be added before the smallest meal (often lunch) [bib_ref] Options for the intensification of insulin therapy when basal insulin is not..., Raccah [/bib_ref]. The actual glycemic benefits of these more advanced regimens after basal insulin are generally modest in typical patients [bib_ref] A stepwise approach to insulin therapy in patients with type 2 diabetes..., Davidson [/bib_ref]. So, again, individualization of therapy is key, incorporating the degree of hyperglycemia needing to be addressed and the overall capacities of the patient. Importantly, data trends from self-monitoring may be particularly helpful in titrating insulins and their doses within these more advanced regimens to optimize control. A second, perhaps more convenient but less adaptable method involves "premixed" insulin, consisting of a fixed combination of an intermediate insulin with regular insulin or a rapid analog. Traditionally, this is administered twice daily, before morning and evening meals. In general, when compared with basal insulin alone, premixed regimens tend to lower HbA 1c to a larger degree, but often at the expense of slightly more hypoglycemia and weight gain [bib_ref] Prandial premixed insulin analogue regimens versus basal insulin analogue regimens in the..., Ilag [/bib_ref]. Disadvantages include the inability to titrate the shorter-from the longer-acting component of these formulations. Therefore, this strategy is somewhat inflexible but may be appropriate for certain patients who eat regularly and may be in need of a simplified approach beyond basal insulin [bib_ref] A stepwise approach to insulin therapy in patients with type 2 diabetes..., Davidson [/bib_ref] [bib_ref] Options for the intensification of insulin therapy when basal insulin is not..., Raccah [/bib_ref]. (An older and less commonly used variation of this two-injection strategy is known as "split-mixed," involving a fixed amount of intermediate insulin mixed by the patient with a variable amount of regular insulin or a rapid analog. This allows for greater flexibility in dosing.) The key messages from dozens of comparative insulin trials in type 2 diabetes include the following: 1. Any insulin will lower glucose and HbA 1c . 2. All insulins are associated with some weight gain and some risk of hypoglycemia. 3. The larger the doses and the more aggressive the titration, the lower the HbA 1c , but often with a greater likelihood of adverse effects. 4. Generally, long-acting insulin analogs reduce the incidence of overnight hypoglycemia, and rapid-acting insulin analogs reduce postprandial glucose excursions as compared with corresponding human insulins (NPH, Regular), but they generally do not result in clinically significantly lower HbA 1c . Metformin is often continued when basal insulin is added, with studies demonstrating less weight gain when the two are used together [bib_ref] Effects of metformin in patients with poorly controlled, insulin-treated type 2 diabetes..., Avilés-Santa [/bib_ref]. Insulin secretagogues do not seem to provide for additional HbA 1c reduction or prevention of hypoglycemia or weight gain after insulin is started, especially after the dose is titrated and stabilized. When basal insulin is used, continuing the secretagogue may minimize initial deterioration of glycemic control. However, secretagogues should be avoided once prandial insulin regimens are employed. TZDs should be reduced in dose (or stopped) to avoid edema and excessive weight gain, although in certain individuals with large insulin requirements from severe insulin resistance, these insulin sensitizers may be very helpful in lowering HbA 1c and minimizing the required insulin dose [bib_ref] Combination therapy using metformin or thiazolidinediones and insulin in the treatment of..., Strowig [/bib_ref]. Data concerning the glycemic benefits of incretin-based therapy combined with basal insulin are accumulating; combination with GLP-1 receptor agonists may be helpful in some patients [bib_ref] Type 2 diabetes mellitus in 2010: individualizing treatment targets in diabetes care, Buse [/bib_ref] [bib_ref] Efficacy and safety of sitagliptin when added to insulin therapy in patients..., Vilsbøll [/bib_ref]. Once again, the costs of these more elaborate combined regimens must be carefully considered. ## Other considerations ## Age Older adults (.65-70 years) often have a higher atherosclerotic disease burden, reduced renal function, and more comorbidities [bib_ref] Treatment of patients over 64 years of age with type 2 diabetes:..., Prato [/bib_ref] [bib_ref] Relation between age and cardiovascular disease in men and women with diabetes..., Booth [/bib_ref]. Many are at risk for adverse events from polypharmacy and may be both socially and economically disadvantaged. Life expectancy is reduced, especially in the presence of long-term complications. They are also more likely to be compromised by hypoglycemia; for example, unsteadiness may result in falls and fractures [bib_ref] The relationship between glycemic control and falls in older adults, Nelson [/bib_ref] , and a tenuous cardiac status may deteriorate into catastrophic events. It follows that glycemic targets for elderly with long-standing or more complicated disease should be less ambitious than for the younger, healthier individuals (20). If lower targets cannot be achieved with simple interventions, an HbA 1c of ,7.5-8.0% may be acceptable, transitioning upward as age increases and capacity for self-care, cognitive, psychological and economic status, and support systems decline. While lifestyle modification can be successfully implemented across all agegroups, in the aged, the choice of antihyperglycemic agent should focus on drug safety, especially protecting against hypoglycemia, heart failure, renal dysfunction, bone fractures, and drug-drug interactions. Strategies specifically minimizing the risk of low blood glucose may be preferred. In contrast, healthier patients with long life expectancy accrue risk for vascular complications over time. Therefore, lower glycemic targets (e.g., an HbA 1c ,6.5-7.0%) and tighter control of body weight, blood pressure, and circulating lipids should be achieved to prevent or delay such complications. This usually requires combination therapy, the early institution of which may have the best chance of modifying the disease process and preserving quality of life. ## Weight The majority of individuals with type 2 diabetes are overweight or obese (;80%) [bib_ref] Associations between general and abdominal adiposity and mortality in individuals with diabetes..., Sluik [/bib_ref]. In these, intensive lifestyle intervention can improve fitness, glycemic control, and cardiovascular risk factors for relatively small changes in body weight [bib_ref] Look AHEAD Research Group. Effectiveness of lifestyle interventions for individuals with severe..., Unick [/bib_ref]. Although insulin resistance is thought of as the predominate driver of diabetes in obese patients, they actually have a similar degree of islet dysfunction to leaner patients [bib_ref] Betacell function in subjects spanning the range from normal glucose tolerance to..., Ferrannini [/bib_ref]. Perhaps as a result, the obese may be more likely to require combination drug therapy (20,104). While common practice has favored metformin in heavier patients, because of weight loss/weight neutrality, this drug is as efficacious in lean individuals [bib_ref] A 26-week, randomized, parallel, treatto-target trial comparing insulin detemir with NPH insulin..., Hermansen [/bib_ref]. TZDs, on the other hand, appear to be more effective in those with higher BMIs, although their associated weight gain makes them, paradoxically, a less attractive option here. GLP-1 receptor agonists are associated with weight reduction [bib_ref] Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications, Nauck [/bib_ref] , which in some patients may be substantial. Bariatric surgery is an increasingly popular option in severe obesity. Type 2 diabetes frequently resolves rapidly after care.diabetesjournals.org DIABETES CARE, VOLUME 35, JUNE 2012 1373 these procedures. The majority of patients are able to stop some, or even all, of their antihyperglycemic medications, although the durability of this effect is not known [bib_ref] Weight and type 2 diabetes after bariatric surgery: systematic review and metaanalysis, Buchwald [/bib_ref]. In lean patients, consideration should be given to the possibility of latent autoimmune diabetes in adults (LADA), a slowly progressive form of type 1 diabetes. These individuals, while presenting with mild hyperglycemia, often responsive to oral agents, eventually develop more severe hyperglycemia and require intensive insulin regimens [bib_ref] Islet autoantibodies in clinically diagnosed type 2 diabetes: prevalence and relationship with..., Davis [/bib_ref]. Measuring titres of isletassociated autoantibodies (e.g., anti-GAD) may aid their identification, encouraging a more rapid transition to insulin therapy. Sex/racial/ethnic/genetic differences While certain racial/ethnic features that increase the risk of diabetes are well recognized [greater insulin resistance in Latinos (107), more b-cell dysfunction in East Asians (108)], using this information to craft optimal therapeutic strategies is in its infancy. This is not surprising given the polygenic inheritance pattern of the disease. Indeed, while matching a drug's mechanism of action to the underlying causes of hyperglycemia in a specific patient seems logical, there are few data that compare strategies based on this approach [bib_ref] The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology..., Kahn [/bib_ref]. There are few exceptions, mainly involving diabetes monogenic variants often confused with type 2 diabetes, such as maturity-onset diabetes of the young (MODY), several forms of which respond preferentially to sulfonylureas [bib_ref] Monogenic diabetes: implications for therapy of rare types of disease, Malecki [/bib_ref]. While there are no prominent sex differences in the response to various antihyperglycemic drugs, certain side effects (e.g., bone loss with TZDs) may be of greater concern in women. ## Comorbidities Coronary artery disease. Given the frequency with which type 2 diabetic patients develop atherosclerosis, optimal management strategies for those with or at high risk for coronary artery disease (CAD) are important. Since hypoglycemia may exacerbate myocardial ischemia and may cause dysrhythmias [bib_ref] The case for hypoglycaemia as a proarrhythmic event: basic and clinical evidence, Nordin [/bib_ref] , it follows that medications that predispose patients to this adverse effect should be avoided, if possible. If they are required, however, to achieve glycemic targets, patients should be educated to minimize risk. Because of possible effects on potassium channels in the heart, certain sulfonylureas have been proposed to aggravate myocardial ischemia through effects on ischemic preconditioning [bib_ref] Sulfonylureas and cardiovascular effects: from experimental data to clinical use. Available data..., Riveline [/bib_ref] , but the actual clinical relevance of this remains unproven. Metformin may have some cardiovascular benefits and would appear to be a useful drug in the setting of CAD, barring prevalent contraindications [bib_ref] UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with..., Turner [/bib_ref]. In a single study, pioglitazone was shown to reduce modestly major adverse cardiovascular events in patients with established macrovascular disease. It may therefore also be considered, unless heart failure is present [bib_ref] PROactive investigators. Secondary prevention of macrovascular events in patients with type 2..., Dormandy [/bib_ref]. In very preliminary reports, therapy with GLP-1 receptor agonists and DPP-4 inhibitors has been associated with improvement in either cardiovascular risk or risk factors, but there are no long-term data regarding clinical outcomes. There are very limited data suggesting that AGIs [bib_ref] Acarbose: oral anti-diabetes drug with additional cardiovascular benefits, Hanefeld [/bib_ref] and bromocriptine (115) may reduce cardiovascular events. Heart failure. With an aging population and recent decreases in mortality after myocardial infarction, the diabetic patient with progressive heart failure is an increasingly common scenario [bib_ref] Diabetes mellitus and heart failure: epidemiology, mechanisms, and pharmacotherapy, Masoudi [/bib_ref]. This population presents unique challenges given their polypharmacy, frequent hospitalizations, and contraindications to various agents. TZDs should be avoided [bib_ref] Congestive heart failure and cardiovascular death in patients with prediabetes and type..., Lago [/bib_ref] [bib_ref] Review article: Thiazolidinediones and heart failure, Chaggar [/bib_ref]. Metformin, previously contraindicated in heart failure, can now be used if the ventricular dysfunction is not severe, if patient's cardiovascular status is stable, and if renal function is normal [bib_ref] Metformin, heart failure, and lactic acidosis: is metformin absolutely contraindicated?, Tahrani [/bib_ref]. As mentioned, cardiovascular effects of incretin-based therapies, including those on ventricular function, are currently under investigation [bib_ref] New drugs for the treatment of diabetes: part II: Incretin-based therapy and..., Inzucchi [/bib_ref]. Chronic kidney disease. Kidney disease is highly prevalent in type 2 diabetes, and moderate to severe renal functional impairment (eGFR ,60 mL/min) occurs in approximately 20-30% of patients [bib_ref] Glycemic control, complications, and death in older diabetic patients: the Diabetes and..., Huang [/bib_ref] [bib_ref] Antidiabetic medication use and prevalence of chronic kidney disease among patients with..., Koro [/bib_ref]. The individual with progressive renal dysfunction is at increased risk for hypoglycemia, which is multifactorial. Insulin and, to some degree, the incretin hormones are eliminated more slowly, as are antihyperglycemic drugs with renal excretion. Thus, dose reduction may be necessary, contraindications need to be observed, and consequences (hypoglycemia, fluid retention, etc.) require careful evaluation. Current U.S. prescribing guidelines warn against the use of metformin in patients with a serum creatinine $133 mmol/L ($1.5 mg/dL) in men or 124 mmol/L ($1.4 mg/dL) in women. Metformin is eliminated renally, and cases of lactic acidosis have been described in patients with renal failure [bib_ref] Contraindications can damage your healthdis metformin a case in point?, Holstein [/bib_ref]. There is an ongoing debate, however, as to whether these thresholds are too restrictive and that those with mild-moderate renal impairment would gain more benefit than harm from using metformin [bib_ref] Use of metformin in the setting of mild-to-moderate renal insufficiency, Lipska [/bib_ref] [bib_ref] Metformin: the safest hypoglycaemic agent in chronic kidney disease?, Nye [/bib_ref]. In the U.K., the National Institute for Health and Clinical Excellence (NICE) guidelines are less proscriptive and more evidencebased than those in the U.S., generally allowing use down to a GFR of 30 mL/min, with dose reduction advised at 45 mL/min (14). Given the current widespread reporting of estimated GFR, these guidelines appear very reasonable. Most insulin secretagogues undergo significant renal clearance (exceptions include repaglinide and nateglinide) and the risk of hypoglycemia is therefore higher in patients with chronic kidney disease (CKD). For most of these agents, extreme caution is imperative at more severe degrees of renal dysfunction. Glyburide (known as glibenclamide in Europe), which has a prolonged duration of action and active metabolites, should be specifically avoided in this group. Pioglitazone is not eliminated renally, and therefore there are no restrictions for use in CKD. Fluid retention may be a concern, however. Among the DPP-4 inhibitors, sitagliptin, vildagliptin, and saxagliptin share prominent renal elimination. In the face of advanced CKD, dose reduction is necessary. One exception is linagliptin, which is predominantly eliminated enterohepatically. For the GLP-1 receptor agonists exenatide is contraindicated in stage 4-5 CKD (GFR ,30 mL/min) as it is renally eliminated; the safety of liraglutide is not established in CKD though pharmacokinetic studies suggest that drug levels are unaffected as it does not require renal function for clearance. More severe renal functional impairment is associated with slower elimination of all insulins. Thus doses need to be titrated carefully, with some awareness for the potential for more prolonged activity profiles. Liver dysfunction. Individuals with type 2 diabetes frequently have hepatosteatosis as well as other types of liver disease [bib_ref] Epidemiology and natural history of NAFLD and NASH, Ong [/bib_ref]. There is preliminary evidence that patients with fatty liver may benefit from treatment with pioglitazone [bib_ref] Current treatment of non-alcoholic fatty liver disease, Ahmed [/bib_ref] [bib_ref] Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy..., Musso [/bib_ref] [bib_ref] Incretin mimetics as a novel therapeutic option for hepatic steatosis, Tushuizen [/bib_ref]. It should not be used in an individual with active liver disease or an alanine transaminase level above 2.5 times the upper limit of normal. In those with steatosis but milder liver test abnormalities, this insulin sensitizer may be advantageous. Sulfonylureas can rarely cause abnormalities in liver tests but are not specifically contraindicated; meglitinides can also be used. If hepatic disease is severe, secretagogues should be avoided because of the increased risk of hypoglycemia. In patients with mild hepatic disease, incretin-based drugs can be prescribed, except if there is a coexisting history of pancreatitis. Insulin has no restrictions for use in patients with liver impairment and is indeed the preferred choice in those with advanced disease. Hypoglycemia. Hypoglycemia in type 2 diabetes was long thought to be a trivial issue, as it occurs less commonly than in type 1 diabetes. However, there is emerging concern based mainly on the results of recent clinical trials and some crosssectional evidence of increased risk of brain dysfunction in those with repeated episodes. In the ACCORD trial, the frequency of both minor and major hypoglycemia was high in intensively managed patientsdthreefold that associated with conventional therapy [bib_ref] ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes, Gerstein [/bib_ref]. It remains unknown whether hypoglycemia was the cause of the increased mortality in the intensive group [bib_ref] The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes:..., Bonds [/bib_ref] [bib_ref] Counterpoint: Intensive glucose control and mortality in ACCORDd still looking for clues, Riddle [/bib_ref]. Clearly, however, hypoglycemia is more dangerous in the elderly and occurs consistently more often as glycemic targets are lowered. Hypoglycemia may lead to dysrhythmias, but can also lead to accidents and falls (which are more likely to be dangerous in the elderly) (132), dizziness (leading to falls), confusion (so other therapies may not be taken or taken incorrectly), or infection (such as aspiration during sleep, leading to pneumonia). Hypoglycemia may be systematically underreported as a cause of death, so the true incidence may not be fully appreciated. Perhaps just as importantly, additional consequences of frequent hypoglycemia include work disability and erosion of the confidence of the patient (and that of family or caregivers) to live independently. Accordingly, in at-risk individuals, drug selection should favor agents that do not precipitate such events and, in general, blood glucose targets may need to be moderated. FUTURE DIRECTIONS/ RESEARCH NEEDSdFor antihyperglycemic management of type 2 diabetes, the comparative evidence basis to date is relatively lean, especially beyond metformin monotherapy [bib_ref] Comparative effectiveness and safety of medications for type 2 diabetes: an update..., Bennett [/bib_ref]. There is a significant need for high-quality comparativeeffectiveness research, not only regarding glycemic control, but also costs and those outcomes that matter most to patientsd quality of life and the avoidance of morbid and life-limiting complications, especially CVD [bib_ref] Comparative effectiveness and safety of medications for type 2 diabetes: an update..., Bennett [/bib_ref]. Another issue about which more data are needed is the concept of durability of effectiveness (often ascribed to b-cell preservation), which would serve to stabilize metabolic control and decrease the future treatment burden for patients. Pharmacogenetics may very well inform treatment decisions in the future, guiding the clinician to recommend a therapy for an individual patient based on predictors of response and susceptibility to adverse effects. We need more clinical data on how phenotype and other patient/disease characteristics should drive drug choices. As new medications are introduced to the type 2 diabetes pharmacopeia, their benefit and safety should be demonstrated in studies versus best current treatment, substantial enough both in size and duration to provide meaningful data on meaningful outcomes. It is appreciated, however, that head-to-head comparisons of all combinations and permutations would be impossibly large [bib_ref] The combinatorics of medications precludes evidence-based algorithms for therapy, Rodbard [/bib_ref]. Informed judgment and the expertise of experienced clinicians will therefore always be necessary. The Endocrine Society, and several other organizations who wished to remain anonymous nominated reviewers who provided input on the final draft. Such feedback does not constitute endorsement by these groups or these individuals. The final draft was also peer reviewed and approved by the Professional Practice Committee of the ADA and the Panel for Overseeing Guidelines and Statements of the EASD. We are indebted to Dr. Sue Kirkman of the ADA for her guidance and support during this process. We also thank Carol Hill and Mary Merkin for providing administrative assistance. # Funding The three face-to-face meetings and the travel of some of the writing group were supported by the EASD and ADA. D.R. Matthews acknowledges support from the National Institute for Health Research. ## Duality of interest During the past 12 months, the following relationships with companies whose products or services directly relate to the subject matter in this document are declared: R.M. [fig] Figure 2dAntihyperglycemic: therapy in type 2 diabetes: general recommendations. Moving from the top to the bottom of the figure, potential sequences of antihyperglycemic therapy. [/fig] [table] Table 1dProperties of: currently available glucose-lowering agents that may guide treatment choice in individual patients with type 2 diabetes mellitus [/table]	None	https://care.diabetesjournals.org/content/diacare/35/6/1364.full.pdf	Glycemic management in type 2 diabetes mellitus has become increasingly complex and, to some extent, controversial, with a widening array of pharmacological agents now available (1–5), mounting concerns about their potential adverse effects and new uncertainties regarding the benefits of intensive glycemic control on macrovascular complications (6–9). Many clinicians are therefore perplexed as to the optimal strategies for their patients. As a consequence, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) convened a joint task force to examine the evidence and develop recommendations for antihyperglycemic therapy in nonpregnant adults with type 2 diabetes. Several guideline documents have been developed by members of these two organizations (10) and by other societies and federations (2,11–15). However, an update was deemed necessary because of contemporary information on the benefits/risks of glycemic control, recent evidence concerning efficacy and safety of several new drug classes (16,17), the withdrawal/restriction of others, and increasing calls for a move toward more patient-centered care (18,19). This statement has been written incorporating the best available evidence and, where solid support does not exist, using the experience and insight of the writing group, incorporating an extensive review by additional experts (acknowledged below). The document refers to glycemic control; yet this clearly needs to be pursued within a multifactorial risk reduction framework. This stems from the fact that patients with type 2 diabetes are at increased risk of cardiovascular morbidity and mortality; the aggressive management of cardiovascular …
be72227751df8119ca7507c140921a78f025dc12	pubmed	Committee Recommendations for Resuming Cardiac Surgery Activity in the SARS-CoV-2 Era: Guidance From an International Cardiac Surgery Consortium	Committee Recommendations for Resuming Cardiac Surgery Activity in the SARS-CoV-2 Era: Guidance From an International Cardiac Surgery Consortium [bib_ref] Precautions and procedures for coronary and structural cardiac interventions during the COVID-19..., Wood [/bib_ref] [bib_ref] Triage considerations for patients referred for structural heart disease intervention during the..., Shah [/bib_ref] [bib_ref] Adult cardiac surgery during the COVID-19 pandemic: a tiered patient triage guidance..., Haft [/bib_ref] [bib_ref] Cardiac surgery in Canada during the COVID-19 pandemic: a guidance statement from..., Hassan [/bib_ref] [bib_ref] ASE statement on protection of patients and echocardiography service providers during the..., Kirkpatrick [/bib_ref] [bib_ref] Society of Cardiovascular Computed Tomography guidance for use of cardiac computed tomography..., Choi [/bib_ref] [fig_ref] 1: The cardiovascular service line, including cardiac surgery, should be among the first... [/fig_ref] ## A. guidance on restarting cardiac surgery activity Class I Recommendations The incremental mortality associated with suspending all elective cardiac surgery within a wide geographic region for 6 to 8 weeks may be estimated from studies of health care systems where surgery is routinely deferred for many weeks because of lack of capacity. For example, in 5864 patients waiting for elective or urgent coronary bypass surgery in Sweden, the risk of death increased by 11% per month. [bib_ref] Mortality on the waiting list for coronary artery bypass grafting: incidence and..., Rexius [/bib_ref] A New Zealand study demonstrated significant incremental operative mortality in the nearly 20% of patients readmitted with acute coronary syndromes while waiting for bypass surgery. 14 A coordinated approach with cardiology services, including invasive cardiology is essential, because these are an integral part of the cardiovascular patient evaluation and management. Supporting references: 13, 14. 2. Triggers and contingency plans for modifying cardiac service line activity in response to government regulations, hospital capacity, and disease burden should be agreed upon and clearly communicated with clinicians to minimize adverse events due to abrupt changes in clinical practice. (Level of evidence: C) A clear response framework, such as the one outlined in [fig_ref] Table 2: Guidance for Adapting Cardiac Surgery Care Delivery in Response to Government Requirements,... [/fig_ref] , 4,6-10 enables the cardiac service line to adapt more safely and effectively to changes in governmental requirements, critical care capacity, and prevalence of disease in the community. If advisories conflict, federal and state mandates take priority over hospital policy and local assessment of disease burden. Cardiac specialists triaging patients within a resource allocation of critical care and floor beds, operating room, and outpatient time, may allow a more efficient response to evolving constraints than attempting to redefine which patients should be prioritized at each stage. Supporting references: 4-6. 3. Reduced cardiac critical care capacity mandates safe and effective triage of elective cardiac surgery patients. Such triage should be led by specialists in cardiac surgery, using formal guidelines as agreed by the heart team [fig_ref] Table 2: Guidance for Adapting Cardiac Surgery Care Delivery in Response to Government Requirements,... [/fig_ref]. (Level of evidence: C) The incremental mortality in patients whose cardiac surgery is deferred during this pandemic may be partially mitigated by effective triage with careful attention to risk factors such as symptoms, ventricular dysfunction, arrhythmias, and age, considering percutaneous coronary or valve intervention and optimizing medical therapy with frequent follow-up. For example, risk factors for death while waiting for coronary bypass included left main stem disease, reduced ejection fraction, unstable angina, and atrial fibrillation. [bib_ref] Mortality on the waiting list for coronary artery bypass grafting: incidence and..., Rexius [/bib_ref] Untreated aortic stenosis is associated with higher mortality. In a recent analysis of 823 patients waiting an average of 3 weeks for transcatheter or surgical aortic valve replacement, the mortality was 4% at 1 month in both groups. [bib_ref] Mortality while waiting for aortic valve replacement, Malaisrie [/bib_ref] Patients who died were significantly older and more likely to have left ventricular dysfunction or New York Heart Association Functional Classification II or IV symptoms. Involving cardiac surgeons early in the development of specific guidance and triage committees is essential, particularly when cancer, trauma, and other urgent care needs must be balanced, because the methods routinely used to allocate resources and prioritize patients across multiple specialties are aimed at optimizing normal daily resource use and are not designed to balance risks of deferring surgery. Very complex and high-risk cases should be performed when critical care capacity is adequate with resources for extended support, whereas if those resources are scarce the utility and ethics may be less justifiable. Supporting references: 4-6, 12-15. 4. Clear, accurate, and timely information on the availability of cardiovascular services and how to access them should be provided to referring physicians, patients, and the community. (Level of evidence: C) The substantial decrease in elective and emergency cardiovascular presentations to outpatients and the emergency departments observed in most centers can be attributed, firstly, to reduced access to primary care offices, and secondly, to necessary triage by emergency responders, and thirdly, to high levels of patient concern about visiting hospitals. Initial reports suggest this may account for significant incremental non-COVID cardiac mortality. [bib_ref] Reduced rate of hospital admissions for ACS during Covid-19 outbreak in Northern..., De Fillippo [/bib_ref] Consistent, accurate, and effective communication with primary care and cardiology providers is essential to ensure that their approach is aligned with the availability of inpatient cardiac care and that patient concerns are allayed. This may usefully be supported by direct patient messaging, without which news stories in the lay media provide the sole information for patients making decisions about their health care options. Supporting reference: 16. Class IIa Recommendations 1. A regional response is a reasonable strategy to ensure appropriate delivery of elective cardiac surgery. (Level of evidence: C) A regional response entails a coordinated effort to increase and optimize critical care capacity, expertise, and personnel between hospitals, preserving the ability of selected centers to provide cardiac surgery services on behalf of an expanded population while other centers divert resources to managing SARS-CoV-2. In Italy and the United Kingdom, this type of regional response has enabled continuous provision of cardiac surgery at selected high-volume centers and coordination of effort and experience for extracorporeal membrane oxygenation (ECMO) support. [bib_ref] Planning and provision of ECMO services for severe ARDS during the COVID-19..., Ramanathan [/bib_ref] In comparison, disaster planning in the United States is primarily organized at an individual hospital level, with governmental agencies issuing 2. It is reasonable to substitute a less-invasive approach when insufficient hospital capacity precludes planned cardiac surgery, and when patient preference informed by a shared-decision-making approach with the Heart Team also supports the balance of risks. (Level of evidence: C) Most low-risk elective patients may safely wait up to 4 weeks for planned cardiac surgery. [bib_ref] Adult cardiac surgery during the COVID-19 pandemic: a tiered patient triage guidance..., Haft [/bib_ref] [bib_ref] Cardiac surgery in Canada during the COVID-19 pandemic: a guidance statement from..., Hassan [/bib_ref] However, mortality and complications may occur in apparently low-risk patients. [bib_ref] Cardiac surgery in Canada during the COVID-19 pandemic: a guidance statement from..., Hassan [/bib_ref] If urgent surgery is not possible, any clinical deterioration indicating a need for more urgent intervention should trigger a discussion with the heart team to review alternative therapeutic strategies, including surgery at another peer center, transcatheter valve intervention, or percutaneous coronary intervention, or a combination of these. [bib_ref] ASE statement on protection of patients and echocardiography service providers during the..., Kirkpatrick [/bib_ref] Supporting references: 4-6, 10. ## B. guidance on adapting cardiac surgery care Class I Recommendations 1. All cardiac surgery patients should be screened preoperatively for COVID-19 and strong consideration be given to deferring care or using other care modalities for patients that test positive. (Level of evidence: C) All cardiac surgery patients should be tested 48 hours preoperatively for COVID-19, until the prevalence of asymptomatic community spread is minimal. Anecdotal reports indicate that COVID-19 infection in the perioperative period is associated with significant morbidity and mortality, so cardiac surgery should be deferred where possible until the patient tests negative. In a patient with active COVID-19 infection who cannot safely be deferred, percutaneous and transcatheter therapies may be the safer option. Lung and heart transplant donors and recipients should be screened and no transplants performed in positive patients. An important additional rationale for screening cardiac surgery patients for SARS-CoV-2 is the risk posed to health care workers during intubation, extubation, disconnection of the ventilator, and bronchoscopy from aerosolization.should therefore be dedicated to the care of cardiac surgery patients with SARS-CoV-2. Immunocompromised patients, including transplant recipients, should be cohorted in the intensive care unit area most distant from this. Epidemiology and infection protocols should guide designation of clean and contaminated space in the COVID area [fig_ref] 1: Remote working and telemedicine should be used to provide close and convenient... [/fig_ref]. Limitations on visitors, in-room rounding, and care pathways should be redesigned to minimize traffic through the COVID area. Careful and frequent education of nursing, intensivist staff, and consultant staff in use of PPE, virtual rounding, and dedicated teams for high-risk procedures, such as intubations, will minimize the risk of cross-infection. At the time of this writing, more than 19% of patients infected with SARS-CoV2 and 60 deaths in Italy alone were health care workers. Intubation and extubation, disconnection from the ventilator, bronchoscopy, and tracheostomy expose the health care team to the greatest risk of viral transmission. This was recognized at a relatively early stage in a joint position statement from the American Society of Anesthesiologists, which recommended full-powered air-purifying respirators for induction and extubation of patients in endemic areas.There are noticeable disparities between PPE protocols between different centers in different regions and countries.The American College of Surgeons recommends N95 respirators, particularly when operating on patients with confirmed or suspected COVID-19.Thus, for individuals at highest risk of exposure at institutions that are unable to provide N95 masks to all members of the operating team, the American College of Surgeons recommends that all surgeons and other personnel who are not wearing N95s leave the operating room during intubation, extubation, and other necessary adjunct procedures that can generate aerosolized small particles.Team simulations to practice in advance of these common clinical scenarios may improve safety. Procedural aspects of the procedures should be modified in patients with SARS CoV-2 to decrease aerosolization, including using lower coagulation settings for electrocautery, avoiding endoscopic vein harvesting to minimize aerosolization with CO 2 insufflation and avoiding ventilator tubing disconnection. Supporting references: Class III Recommendation 1. It may be harmful to discharge postoperative cardiac surgery patients to nursing facilities where increased prevalence of SARS-CoV-2 infection and mortality has been observed. (Level of evidence: C) The prevalence of SARS-CoV-2 and associated mortality in long-term community nursing facilities in the United States was especially high, and it is therefore not advisable to discharge postoperative patients to facilities where increased risk of SARS-CoV-2 remains a concern. Where institutions have relied on these facilities, it will be necessary to develop new discharge strategies to avoid the risk of community infection after hospital discharge. These should include extended hospital admission to maximize independence and planning for skilled home nursing support. Educating all patients and family members preoperatively in social distancing, use of PPE, and recognizing when to seek medical advice is essential. ## C. guidance on managing cardiac surgery research and education Class I Recommendations Telemedicine for outpatient visits and remote working, including video conferencing, is a potentially helpful practice change to emerge from the pandemic response. In the United States, many states and health care payers approved payment for clinical consultations and followup conducted by video (although not phone only). Effective, early roll-out of secure, patient confidentialitycompliant video consultations will help mitigate the reluctance of patients with advanced cardiac morbidity to seek appropriate care and allow closer follow-up of patients deferred for surgery. For postoperative patients, community primary care or cardiology practices may be willing to provide in-person visits where suture removal and incision checks can be performed. Hospital workflow may also use remote working in the form of video rounds and conferences that facilitate team-based decision making, education, and administrative meetings while social distancing. ## Class iia recommendation 1. It is reasonable to revise resident rotations to address reduced operative experience, and support research programs halted or suspended during the pandemic response. (Level of evidence: C) Educational activity was suspended or reduced in 50% of cardiac surgery centers that responded to a survey that also showed a reduction of 50% to 75% in operative cases.This may have the greatest effect in countries such as the United States where the total time spent in cardiac surgery training may be as little as 12 months and could explain why half of centers were still allowing residents to operate, even at the expense of prolonging surgery times. Research activity was similarly impacted, which may hamper efforts to obtain early data and underlines the need for real-time data collection and analysis that could inform practice in real time. The reallocation of funding activity and journal focus to research on SARS-CoV-2 may divert resources from equally impactful cardiac research. Coordinated follow-up of all cardiac surgery patients to quantify the incidence and outcomes of the COVID-19 infection and the outcomes related to deferred surgery in this population is essential to inform future policy and individual consent. # Conclusions The above practice recommendations provide an expertbased framework for restarting cardiac surgery in the outpatient and inpatient settings in a health care environment characterized by a low-grade long-term prevalence of SARS-CoV-2. Although the applicability of these recommendations may vary according to local context and as new information becomes available, we anticipate that this guidance document will assist centers in managing the 2 simultaneous threats-COVID-19 and death/ morbidity in patients awaiting cardiac surgery-that institutions providing cardiac surgical care must now constantly balance. [fig] 1: Remote working and telemedicine should be used to provide close and convenient patient follow-up and minimize exposure of patients and health care workers to infection. (Level of evidence: C) [/fig] [table] Table 2: Guidance for Adapting Cardiac Surgery Care Delivery in Response to Government Requirements, Hospital Capacity, and Infectious Disease Burden 4-6,10 [/table]	None	http://www.annalsthoracicsurgery.org/article/S0003497520307220/pdf	None
fb04c9024e81a26279efa45271923877e4eae116	pubmed	SEDAR-SEMICYUC consensus recommendations on the management of haemostasis disorders in severely ill patients with COVID-19 infection	SEDAR-SEMICYUC consensus recommendations on the management of haemostasis disorders in severely ill patients with COVID-19 infection The infection by the coronavirus SARS-CoV-2, which causes the disease called COVID-19, mainly causes alterations in the respiratory system. In severely ill patients, the disease often evolves into an acute respiratory distress syndrome that can predispose patients to a state of hypercoagulability, with thrombosis at both venous and arterial levels. This predisposition presents a multifactorial physiopathology, related to hypoxia as well as to the severe inflammatory process linked to this pathology, including the additional thrombotic factors present in many of the patients. ଝ Please cite this article as: Llau JV, Ferrandis R, Sierra P, Hidalgo F, Cassinello C, Gómez-Luque A, et al. Recomendaciones de consenso SEDAR-SEMICYUC sobre el manejo de las alteraciones de la hemostasia en los pacientes graves con infección por COVID(J.V. Llau). 1 The names of the components of the Reading and Review Committee are listed in Appendix 1. 2341-1929/© 2020 Published by Elsevier España, S.L.U. on behalf of Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor.Recomendaciones de consenso SEDAR-SEMICYUC sobre el manejo de las alteraciones de la hemostasia en los pacientes graves con infección por COVID-19Resumen La infección por el coronavirus SARS-CoV-2, causante de la enfermedad denominada COVID-19, provoca alteraciones fundamentalmente en el sistema respiratorio. En los pacientes graves, con frecuencia la enfermedad evoluciona a un síndrome de distrés respiratorio agudo que puede predisponer a los pacientes a un estado de hipercoagulabilidad, con trombosis tanto a nivel venoso como arterial. Esta predisposición presenta una fisiopatología multifactorial, relacionada tanto con la hipoxia como con el grave proceso inflamatorio ligado a esta patología, además de los factores trombóticos adicionales presentes en muchos de los pacientes. Ante la necesidad de optimizar el manejo de la hipercoagulabilidad, los grupos de trabajo de las Sociedades Científicas de Anestesiología-Reanimación y Terapéutica del Dolor (SEDAR) y de Medicina Intensiva, Crítica y de Unidades Coronarias (SEMICYUC), han desarrollado un consenso para establecer unas pautas de actuación frente a las alteraciones de la hemostasia observadas en los pacientes graves con infección por COVID-19. Estas recomendaciones incluyen la profilaxis de la enfermedad tromboembólica venosa en pacientes graves y en el periparto, el manejo de los pacientes en tratamiento crónico con fármacos antiagregantes o anticoagulantes, de las complicaciones hemorrágicas en la evolución de la enfermedad y de la interpretación de las alteraciones generales de la hemostasia. ## Anti-platelets; thrombosis; pregnancy complications In view of the need to optimise the management of hypercoagulability, the working groups of the Scientific Societies of Anaesthesiology-Resuscitation and Pain Therapy (SEDAR) and of Intensive, Critical Care Medicine and Coronary Units (SEMICYUC) have developed a consensus to establish guidelines for actions to be taken against alterations in haemostasis observed in severely ill patients with COVID-19. These recommendations include prophylaxis of venous thromboembolic disease in these patients, and in the peripartum, management of patients on long-term antiplatelet or anticoagulant treatment, bleeding complications in the course of the disease, and the interpretation of general alterations in haemostasis. © 2020 Published by Elsevier España, S.L.U. on behalf of Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Infecciones por coronavirus; Heparina de bajo peso molecular; Anticoagulantes; Antitrombóticos; Trombosis; Complicaciones del embarazo Introduction SARS-CoV-2 coronavirus infection, when it progresses to COVID-19, is frequently associated with characteristic alterations of certain haematological parameters, as shown in [fig_ref] Table 1: Frequent haematological changes in patients with COVID-19 [/fig_ref]. Several hypotheses have been put forward to explain this pattern of haematological behavior,including a hypercoagulable state, a reactivity typical of severe inflammation with endothelitis as a direct consequence of the action of the virus, and the respiratory distress-induced hypoxia frequently found in these cases. [bib_ref] Endothelial cell infection and endotheliitis in COVID-19, Varga [/bib_ref] In any event, patients with severe COVID-19 appear to be at high risk of developing cardiovascular complications. Thrombotic events are particularly frequent ----some studies have reported an overall incidence of venous thromboembolism of around 25% [bib_ref] Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia, Cui [/bib_ref] and an incidence of thrombotic complications in critically ill patients of 31%. [bib_ref] Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Klok [/bib_ref] Furthermore, an increase in microvascular thrombosis in the pulmonary circulation could play an important role in the course of respiratory failure. [bib_ref] Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia, Cui [/bib_ref] The presence of previous cardiovascular disease, on the other hand, is a risk factor for severe disease and mortality. In addition, when treating these patients clinicians must take into account that the drugs used to treat COVID-19 might interact with their background treatment, which may need to be adjusted accordingly. ## Palabras clave In these circumstances, it is important to establish prophylactic or therapeutic anticoagulant therapy that may benefit these patients. The aim of this study is to put forward recommendations for the management of these patients. Taking into account the lack of available evidence, these recommendation should be reviewed and modified on the basis of clinical experience and the emergence of new evidence. ## Thrombotic risk in patients with covid-19 An analysis of the characteristic pattern of increased ddimer and fibrinogen appears to suggest an increase in procoagulant activity leading to an increase in fibrinolytic activity. In terms of pathophysiology, disseminated intravascular coagulation (DIC) can coexist with what has been called ''sepsis-induced coagulopathy'' (SIC) 14---16. The literature is all but silent in this respect, and the presence of DIC has been described in only 8.7% of cases (16 of 183 patients) after applying the d-dimer cut-off points previously proposed for critically ill patients 17 ; however, it was found in 71% of patients who died. [bib_ref] Abnormal coagulation parameters are associated with poor prognosis in patients with novel..., Tang [/bib_ref] The d-dimer increase has been associated not only with greater clinical severity (deterioration of respiratory failure), but also with an increase in microclots in the pulmonary vascularisature.Patients with severe disease related to SARS-CoV-2 infection, particularly those admitted to intensive care units (ICU), are usually bedridden, connected to mechanical ventilation, under sedation, and frequently receiving neuromuscular blockers. Furthermore, the hypoxia and inflammatory activity characteristic of this disease can lead to a hypercoagulable state involving multiple mediators, which has been documented in cases of sepsis. [bib_ref] Anticoagulant modulation of inflammation in severe sepsis, Allen [/bib_ref] Therefore, it can be said that these patients are at particularly high risk of developing venous thromboembolism (VTE), and this complication must be evaluated in all cases. [bib_ref] Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia, Cui [/bib_ref] The results of some studies currently suggest a trend towards an increase in VTE among patients with COVID-19. 12,21---24 Some studies published so far suggest that these cases can benefit from the administration of low molecular weight heparins (LMWH), 2,12 albeit probably only in selected patients. Benefit from LMWH increases in parallel with an increase in D-dimer levels, regardless of whether or not the patients met DIC criteria. [bib_ref] Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019..., Tang [/bib_ref] In this study, the multivariate analysis concluded that the 3 independent risk factors for 28-day mortality were d-dimer increase, PT prolongation, and low platelet count. The authors also observed lower mortality in patients treated with LMWH or unfractionated heparin (UFH) at 28 days, in those with d-dimer levels more than 6 times the upper limit of normal, or with sepsis-induced coagulopathy (SIC scale ≥4). There is no evidence to show the superiority of a particular LMWH dose, pending the results of studies currently underway. ## Recommendations (fig. 1) -In hospitalised patients with COVID-19 [fig_ref] Figure 1: Outline of thromboprophylaxis and management of anticoagulant and antiplatelet drugs in patients... [/fig_ref] , we recommend administering pharmacological thromboprophylaxis, preferably LMWH. We suggest adjusting the dose based on weight and kidney function. ## Risk of thrombosis in pregnant patients with covid-19 Pregnant women have a 4---5 times higher risk of presenting VTE than non-pregnant women due to hormonal and mechanical changes (because the increased size of the pregnant uterus impairs venous return in the lower limbs and pelvis) and decreased mobility secondary to weight gain. Therefore, the risk of thrombosis during pregnancy and the puerperium is usually evaluated, and prophylactic treatment with LMWH is established accordingly. There are very few data on SARS-CoV-2 infection during pregnancy. However, the possible effect of COVID-19 in pregnant women can be inferred from data on infection by other similar coronaviruses (severe acute respiratory syndrome [SARS-CoV] or middle east respiratory syndrome [MERS-CoV]). Reports suggest that SARS-CoV-2 infection is associated with a hypercoagulable state, and although no studies have provided sufficient evidence to establish firm recommendations in infected pregnant patients, it has been suggested that these should be based on thrombotic risk factors and lab data that are known predictors of poor evolution. However, for obvious reasons, it is not possible to consider d-dimer in the context of the peripartum, so in this context only fibrinogen (given that fibrinogen levels are usually higher during pregnancy and postpartum, the cut point of thrombotic risk could be 7 g/l instead of 5 g/l), plasma ferritin and platelet count can be considered predictors of a hypercoagulable state The recommendations for thromboprophylaxis in pregnant women with COVID-19 have been based on a review of recommendations on thrombophilia in pregnant women, given that antithrombotic therapy is not mentioned in specific studies on the management of pregnant patients. At the end of pregnancy, both the route and time of delivery should be evaluated individually by a multidisciplinary team. [bib_ref] Pregnancy, thrombophilia, and the risk of a first venous thrombosis: systematic review..., Croles [/bib_ref] According to the multidisciplinary technical document ''Management of pregnant patients and infants with COVID-19'',if delivery can be performed by caesarean section, neuraxial anaesthesia (spinal, epidural or combined) should be the technique of choice, provided it is not contraindicated. ## Thromboprophylaxis in pregnant patients with covid-19 -We recommend evaluating thrombotic risk factors during pregnancy and postpartum. and ensure that all patients are monitored carefully to detect early signs indicative of spinal compression. -We recommend restarting antithrombotic prophylaxis with LMWH after delivery, administering the first dose at 6---8 h (depending on the risk of bleeding and the difficulty involved in performing neuraxial puncture). -After delivery, we suggest adjusting the LMWH dose on the basis of the thrombotic risk markers indicated above. -We recommend monitoring thrombotic risk markers (plasma ferritin, fibrinogen, and platelet count). If plasma fibrinogen level are greater than 7 g/l or thrombocytosis is observed (platelets > 500 × 10 9 /l), we suggest considering increasing LMWH to therapeutic doses (100 IU/kg/12 h or 150 IU/kg/24 h). -In patients admitted to the ICU after delivery, we recommend following the treatment guidelines established for other patients. -If pharmacological prophylaxis is contraindicated, we recommend using mechanical methods (intermittent pneumatic compression). ## Adjustment of chronic anticoagulant and antiplatelet medication in patients with covid-19 Various pharmacological interactions between anticoagulant or antiplatelet drugs and drugs routinely administered to treat COVID-19 have been described.shows the most significant interactions, although more detailed information can be found on the website of reference. 32 ## Anticoagulation The indications for chronic anticoagulation therapy are well known, and include atrial fibrillation, stroke, recent history of VTE, or mechanical heart valve. [bib_ref] Manejo perioperatorio y periprocedimiento del tratamiento antitrombótico, Vivas [/bib_ref] Patients with COVID-19 infection who are being treated with an oral anticoagulant, either antivitamin K or direct oral anticoagulant, should continue with the therapy regardless of the course of the disease, provided it is not associated with bleeding, and a switch to the parenteral route should be considered. [bib_ref] Recomendaciones sobre el tratamiento antitrombótico durante la pandemia COVID-19. Posicionamiento del Grupo..., Vivas [/bib_ref] Nevertheless, given the large number of interactions between orally administered anticoagulant drugs and drugs used to treat COVID-19 and the changes in their bioavailability in critically ill patients, the anticoagulation regimen should be based on the administration of parenteral drugs. Although both UFH and LMWH can be used, LMWH is preferred because the regimen is easy to manage and anticoagulation monitoring is only required in patients presenting kidney failure. Recommendations-We recommend maintaininganticoagulants in patients requiring this therapy, according to their indications. -For anticoagulation maintenance, we do not recommend using drugs with antivitamin K action or direct oral anticoagulants, either due to their interactions or to the difficulty involved in managing or monitoring anticoagulant activity. ## Anti-platelet treatment Antiplatelet therapy with acetylsalicylic acid (ASA) should be continued in patients previously receiving it or who develop a disease requiring this therapy. No important interactions between ASA and drugs commonly used in these patients have been described. However, due to interactions with lopinavir/ritonavir, 32 clopidogrel (decreased conversion of the drug to its active metabolite, and therefore decreased pharmacological effect) and ticagrelor (increased plasma concentration) are not recommended. In patients requiring dual therapy (ASA plus a P2Y12 receptor inhibitor), prasugrel, which has fewer interactions, is recommended. ## Recommendations ( ## Interpretation of coagulation tests and bleeding management SARS-CoV-2 infection has not so far been associated with a significant incidence of bleeding complications, despite the reported alterations in standard clinical coagulation tests. PT alterations can generally be classed as minor, since prolongation, if present, has little clinical significance. It is interesting to note that aPTT is within normal ranges in the vast majority of critically ill patients with COVID-19. This suggests that haemostasis is not affected and there is no bleeding tendency; therefore, empirical treatment should not be given on the basis of coagulation tests. A moderate decrease in plasma antithrombin concentration to around 80% of activity has been observed. [bib_ref] Abnormal coagulation parameters are associated with poor prognosis in patients with novel..., Tang [/bib_ref] Given that this decrease does not generally imply a clinically significant alteration, we do not recommend the systematic use of replacement therapy. The fibrinolysis observed in this clinical setting, which is caused by an almost systematic increase in plasma d-dimer levels, as mentioned above, appears to derive from the lysis of microthrombi in the context of an inflammatory reaction involving multiple cellular and biochemical mediators. In the absence of experience with antifibrinolytics in COVID-19, it would be prudent to discourage the use of any such therapy in COVID-19 patient presenting bleeding. There is no experience in the use of viscoelastic tests for the management of bleeding complications in seriously ill patients with COVID-19, therefore no recommendations can be established in this scenario. However, in cases of severe acute bleeding, parameters used in patients with severe acute bleeding in other clinical settings can be used to aid in decision-making. On the basis of the foregoing and on recently published guidelines, we propose the following recommendations. [bib_ref] ISTH interim guidance on recognition and management of coagulopathy in COVID-19, Thachil [/bib_ref] Recommendations -We recommend not administering anticoagulants to correct the results of coagulation tests in the absence of significant bleeding. -If bleeding is present, we suggest administering plasma as the first option to treat bleeding (10−15 ml/kg), provided the PT-ratio is greater than 1.5. -We recommend not administering prothrombin complex concentrate as the first treatment option for bleeding in these patients due to the lack of experience and lack of safety data. -In patients with acute bleeding, we recommend maintaining plasma fibrinogen levels ≥1.5 g/l, preferably administering fibrinogen concentrate or cryoprecipitate instead of fresh plasma. -In patients with acute bleeding, we recommend maintaining a platelet count of at least 50 × 10 9 /l, which is usually sufficient to achieve haemostasis, and we recommend performing platelet transfusion to achieve this level. # Conclusions Severe SARS-CoV-2 infection most frequently affects patients with various comorbidities, particularly cardiovascular disease. This means that a considerable percentage of these patients will be receiving antiplatelet or anticoagulant drugs, and these therapies must be properly managed to ensure a good outcome. In addition, changes in haemostasis observed in patients with COVID-19 may imply an increased risk of developing thrombosis, so early administration of LMWH should be part of routine treatment. Finally, any bleeding complications appearing in these patients should be treated with extreme caution, given their prothrombotic status and the multifactorial aetiology of such complications. [fig] -: We recommend administering LMWH at weightadjusted prophylactic doses in all patients with confirmed SARSCoV2 infection and no thrombotic risk factors, including asymptomatic patients. We suggest considering the administration of weightadjusted LMWH at extended or intermediate doses in all pregnant women with confirmed SARSCoV2 infection and thrombotic risk markers (increased plasma ferritin, fibrinogen > 7 g/l or thrombocytosis), based on the estimated degree of risk. In patients requiring hospital admission, we recommend following the recommendations on thromboprophylaxis for any patient admitted for COVID19. Treatment should be adjusted in each case according to the risk or the method of delivery (multidisciplinary decision). If caesarean section is indicated, we recommend using a neuraxial anaesthetic technique. If an epidural is administered, we recommend removing the catheter after caesarean delivery to facilitate anticoagulation treatment [/fig] [fig] Figure 1: Outline of thromboprophylaxis and management of anticoagulant and antiplatelet drugs in patients with COVID-19 infection. ASA: acetylsalicylic acid; AF: atrial fibrillation; AVK: antivitamin K; DD: d-dimer; DOA: direct oral anticoagulant; FIB: fibrinogen; GFR: glomerular filtration rate; HIT: heparin-induced thrombocytopaenia; IMV: invasive mechanical ventilation; LMWH: low molecular weight heparin; NR: normal range; NIMV: non-invasive mechanical ventilation; UFH: unfractionated heparin; VTE: venous thromboembolism. [/fig] [table] Table 1: Frequent haematological changes in patients with COVID-19. [/table]	None	None	None
e6a43c07c1a1d5b7fb7a42e4b62cb5dfda45407d	pubmed	Guidelines of the French Society of Otorhinolaryngology (SFORL) for teleconsultation in patients with vertigo during the COVID-19 pandemic	Guidelines of the French Society of Otorhinolaryngology (SFORL) for teleconsultation in patients with vertigo during the COVID-19 pandemic a b s t r a c tObjectives: In the context of the SARS-CoV-2 pandemic, patients may have been dissuaded from seeking consultation, thus exposing themselves to a risk of loss of chance. This guide aims to define how teleconsultation can assist in assessing vertiginous adults or children, and to gather the information needed to provide quick medical care. Methods: These recommendations rely on the authors' experience as well as on literature. A survey on otoneurologic approach via telemedicine has been conducted based on a literature search until March 2020. Results: The first clinical assessment of the vertiginous patient via teleconsultation can only be successful if the following conditions are met: initial contact to verify the feasibility of the assessment at a distance, the presence of a caregiver in order to assist the patient, the possibility of making video recordings. Medical history via telemedicine, as in a face-to-face assessment, allows to assess the characteristics, duration, frequency, and potential triggering factors of the vertigo, in both children and adults. During teleconsultation, the following tests can be carried out: oculomotricity evaluation, assessment of balance, simple neurological tests, checking for positional vertigo/nystagmus and, eventually to perform canalithrepositioning procedures. In children, the following should be searched for: history of hearing or visual impairment, a context of fever or trauma, otorrhea, signs of meningeal irritation. Conclusion: The neurotologic telemedicine relies on the accuracy of the clinical assessment, which is based on history taking and a few simple tests, encouraging the development of a decision-making algorithm adapted for teleconsultation. However, the latter has its limitations during an emergency examination of a new patient presenting vertigo, and, at least in some cases, cannot replace a face-to-face consultation. Teleconsultation is often adapted for follow-up consultations of previously selected vertiginous patients during face-to-face assessment. # Introduction Since its appearance, the objective of modern telemedicine has been to assist in providing healthcare to people geographically isolated from physicians or medical centers (https://www.who.int/ tb/areas-of-work/digital-health/definitions). In the beginning of https://doi.org/10.1016/j.anorl.2020. [bib_ref] TiTraTE: a novel approach to diagnosing acute dizziness and vertigo, Newman-Toker [/bib_ref].011 1879-7296/© 2020 Published by Elsevier Masson SAS. the 1970s, experiments with modern communication methods were designed to provide medical care to a greater number of patients [bib_ref] Telemedicine: history, applications, and impact on librarianship, Zundel [/bib_ref]. With now widespread high-speed internet access and a growing number of users, telemedicine has rapidly developed all over the world in recent years [bib_ref] Telemedicine support for the developing world, Wootton [/bib_ref]. With regard to its utility and effectiveness, recent studies have shown: - a significant degree of satisfaction from 79% [bib_ref] Patient and clinician experiences with telehealth for patient follow-up, Donelan [/bib_ref] to 87% [bib_ref] Telemedicine for ENT: Effect on quality of care during Covid-19 pandemic, Fieux [/bib_ref] among patients who have used it and; - its effectiveness in countries where it has been introduced [bib_ref] The Use of Patient-Facing Teleconsultations in the National Health Service: Scoping Review, O'cathail [/bib_ref]. The current SARS-CoV-2 pandemic (also called COVID- [bib_ref] The treatment and natural course of peripheral and central vertigo, Strupp [/bib_ref] , by imposing measures limiting the spread of the virus in the population, as well as among the medical staff, has created new indications for teleconsultation (TC). Vertigo is one of the most common reasons for seeking medical attendance in adults [bib_ref] Impact of the SARS-CoV-2 epidemic on private ENT consulting practice during the..., Rubin [/bib_ref]. It is thus essential to define how TC can assist in managing vertigo, and in particular, in assessing the signs of severity likely to impact not only the quality of life, but also the prognosis, depending on the rapidity of response to treatment. In Neurotology, the main objective in adults is to bring out the etiologies of vertigo that constitute a life-threatening emergency, particularly strokes, which represent 3-5% of vestibular emergencies [bib_ref] Diagnosing Stroke in Acute Dizziness and Vertigo Pitfalls and Pearls, Tehrani [/bib_ref]. In children, the challenge is to recognize vertigos linked to a central nervous system disorder (1-3%) [bib_ref] Vestibular disorders in children, Wiener-Vacher [/bib_ref] [bib_ref] Prevalence of vestibular and balance disorders in children, O'reilly [/bib_ref] in particular, a brain tumor whose incidence has been evaluated to be 5.6/100,000 in the 0 to 14 age range [bib_ref] CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in..., Ostrom [/bib_ref]. The goal is to identify the TC methods that are now available in neurotology and are applicable in the context of the pandemic. The TC relies on the accuracy of clinical assessment, which is based on history taking and a few simple tests [bib_ref] TiTraTE: a novel approach to diagnosing acute dizziness and vertigo, Newman-Toker [/bib_ref] [bib_ref] HINTS to diagnose stroke in the Acute Vestibular syndrome. Three-step bedside oculomotor..., Kattah [/bib_ref] [bib_ref] STANDING, a four-step beside algorithm for differential diagnosis of acute vertigo in..., Vanni [/bib_ref] , because there are evident limitations regarding imaging and laboratory tests [bib_ref] Dizziness: approach to evaluation and management, Muncie [/bib_ref] [bib_ref] Evaluating dizziness, Hoffman [/bib_ref] [bib_ref] The cost and utility of imaging in evaluating dizzy patients in the..., Ahsan [/bib_ref]. After a brief anatomical, clinical and epidemiological reminder, the methods and conditions for TC will be discussed. We will then establish the patient history taking and clinical examination and suggest simple decision-making algorithms [bib_ref] TiTraTE: a novel approach to diagnosing acute dizziness and vertigo, Newman-Toker [/bib_ref] [bib_ref] HINTS to diagnose stroke in the Acute Vestibular syndrome. Three-step bedside oculomotor..., Kattah [/bib_ref] [bib_ref] STANDING, a four-step beside algorithm for differential diagnosis of acute vertigo in..., Vanni [/bib_ref] [bib_ref] Acute vestibular syndrome: a critical review and diagnostic algorithm concerning the clinical..., Venhovens [/bib_ref]. Finally, we will outline the current limitations of TC. ## Anatomo-clinical and epidemiological background ## Anatomo-clinical reminder Vertigo is considered to have a peripheral vestibular origin (PVO) if it is caused by an inner ear or vestibular nerve impairment, and a central nervous system origin, if the lesion involves the vestibular nuclei, the vestibular connections in the brainstem, and/or the cerebellar circuits. For emergency management, it should be kept in mind that vertigo due to PVO impairment has essentially two clinical presentations. The first clinical presentation is an overall dysfunction of the inner ear or vestibular nerve: the patient complains of persistent vertigo and examination shows a peripheral vestibular syndrome, as observed in vestibular neuritis or Menière's disease (Box 1). The second clinical presentation is a dysfunction localized in a semicircular canal (by otolith debris displacement): the patient complains of brief vertigo during head movement (less than a minute), and the positional manoeuvres indicate the impaired canal, as observed in benign paroxysmal positional vertigo (BPPV). Other than these two clinical situations, the patient suffers a priori from a central neurological impairment [bib_ref] Acute vestibular syndrome: a critical review and diagnostic algorithm concerning the clinical..., Venhovens [/bib_ref]. ## Epidemiology ## Adults A meta-analysis conducted in 2019 shows the extreme variability in the distribution of vertigo etiologies depending on the speciality (ENT, Neurology, emergency medicine, etc.) and the changes in diagnostic criteria [bib_ref] A systematic review of the reported proportions of diagnoses for dizziness and..., Parker [/bib_ref]. Nevertheless, six situations [bib_ref] The treatment and natural course of peripheral and central vertigo, Strupp [/bib_ref] represent almost ¾ of vertiginous patients (the remaining ¼ corresponding to rare and often indeterminate etiologies). The first cause is BPPV (20 to 30%) with brief and positional vertigo. Neurological vertigo (excepting the vestibular migraine), represents approximatively 5 to 15% of vertiginous patients and appears as a first episode of long lasting vertigo/instability. In almost half of the cases, this type of vertigo has a vascular origin and a cerebellar stroke can be misleading (pseudo-labyrinthine forms). The remaining is represented by tumorous, inflammatory, or degenerative pathologies. Vestibular migraine represents around 10% of vertiginous patients [bib_ref] The treatment and natural course of peripheral and central vertigo, Strupp [/bib_ref] [bib_ref] Vestibular migraine. Diagnostic criteria. Consensus document of the Barany society and the..., Lempert [/bib_ref]. Diagnosis requires a history of migraine and at least 5 attacks of vertigo lasting from 5 min to 72 h, associated in at least half of the cases with headaches and/or photophobia and phonophobia and/or visual aura [bib_ref] Vestibular migraine. Diagnostic criteria. Consensus document of the Barany society and the..., Lempert [/bib_ref]. The new concept of 'Persistent Postural-Perceptual Dizziness' (PPPD)' (5 to 15%), which includes previous conditions (phobic postural vertigo, chronic subjective dizziness, space-motion discomfort and visual vertigo) is now defined by specific clinical criteria [bib_ref] Consensus document of the committee for the classification of the vestibular disorders..., Staab [/bib_ref]. The vertigo should be a disabling non-spinning sensation, lasting for more than three months, exacerbated by upright posture, active or passive motion and exposure to moving visual stimuli, noting that it often occurs after a previous peripheral or central vertigo [bib_ref] Consensus document of the committee for the classification of the vestibular disorders..., Staab [/bib_ref]. Ménière's disease (5 to 10%) must combine vertigo lasting 20 min to 12 h with fluctuating auditory manifestations on one side (fullness, tinnitus, and hearing loss documented by audiometry) [bib_ref] Diagnostic criteria for Meniere's disease, Lopez-Escamez [/bib_ref]. Finally, vestibular neuritis (5 to 10%) is characterized by a single episode of vertigo lasting several days with a typical peripheral vestibular syndrome (Box 1) [bib_ref] Vestibular neuritis, Jeong [/bib_ref]. ## Children The etiologies of vertigo in children, described in a French series of more than 2000 children [bib_ref] Vestibular disorders in children, Wiener-Vacher [/bib_ref] , are presented in [fig_ref] Figure 1: Prevalence for vertigo aetiologies in children [/fig_ref]. In terms of the distribution of the etiologies, there are some differences compared to adults. First place is occupied by vestibular migraine The migraine equivalent is in the first position (>25%), followed by the benign paroxysmal vertigo of childhood (BPVC) [bib_ref] Vestibular disorders in children, Wiener-Vacher [/bib_ref] formerly known as idiopathic paroxysmal vertigo of childhood* (15%) [bib_ref] Vertigo and dizziness in children, Jahn [/bib_ref] , and by vertigo after a head trauma (15%). There is a low incidence of "central nervous system" aetiologies (CNS tumours, epilepsies, and haemorrhages), less than 10%, as well as a very low incidence (< 5%) of endolymphatic hydrops (Menière's Disease and Delayed Vertigo). Be aware of a possible ophthalmological origin (vergence insufficiency and/or refraction problem). and migraine-equivalent vertigo (25%) and benign paroxysmal vertigo of childhood (BPVC) (15 to 20%) [bib_ref] Vestibular disorders in children, Wiener-Vacher [/bib_ref] [bib_ref] Prevalence of vestibular and balance disorders in children, O'reilly [/bib_ref] [bib_ref] Vertigo and dizziness in children, Jahn [/bib_ref] takes second place. It involves very sudden bouts of loss of balance lasting several minutes, generally in children under 4 years of age; they are typical because they are not accompanied or preceded by headaches or influenced by changes in head position. They are usually well tolerated and cure spontaneously. A very low BPPV incidence (less than 5%) is found, generally in the context of recent cranial trauma. Other peripheral etiologies are possible but rare (labyrinthitis, endolymphatic hydrops, autoimmune impairment). Posterior cranial fossa tumors should be suspected in case of worsening imbalance, progressive walking disorders, headaches or vomiting (predominantly in the morning), and visual impairments, which point to an intracranial hypertension syndrome. In the event of vertigos occurring predominantly at night and without obvious neurological signs, differential diagnosis should include childhood epilepsy. Cerebrovascular accidents are exceptional in children but should be considered in the context of cardiac or intracranial arteriovenous malformations. The most common "non-vestibular" cause (10%) of balance disorders in children is the existence of a visual impairment: uncorrected or undetected ametropia, or vergence dysfunction. At this time, it does not appear that COVID-19 infection causes specific vestibular pathologies. # Tc methods Telemedicine procedures are medical procedures performed from a distance, through a device using information and communication technologies (article L. 6313-1 of the Public Health Code). The quality of the communication between the patient and the physician is crucial, as well as the protection and security of personal data. The platforms offering the most complete services are: Doctolib, AvecMonDoc, Clickdoc, eConsult Sara (Auvergne-Rhône-Alpes region), Livi, MaQuestionMedicale.frOrdoclic, or TokTokDoc. As a reminder, throughout the coronavirus pandemic, it was not necessary for a patient to go through their attending physician and to have had a face-to-face consultation in the 12 months preceding the TC. These TC platforms are secured and approved for hosting healthcare data. The TC is invoiced by the physician; the reimbursement is the same as for a traditional consultation (https://www.ameli.fr/assure/remboursements/rembourse/ telemedecine/teleconsultation). ## Prerequisites for tc In order to enable TC, the patient must first be contacted beforehand through text message, email, or phone call to provide the necessary instructions so that they have a good understanding of how their smartphone (or their caregiver's) should be used; the proper functioning of the patient's and the physician's webcam should be ensured in case the patient is not used to handling connected devices; The patient must be accompanied by a caregiver during the TC to avoid any accident during the diagnostic manoeuvres for BPPV and assessment of postural stability (for static and dynamic balance). The patient should choose a quiet room with sufficient but not excessive lighting (good quality video image), that is private (conforming to the confidentiality terms of exchanging personal information), and with a large enough bed for examination. A short high-quality video recording will be able to provide the physician consulting via TC essential clinical information to make the diagnosis. For example, video sequences in the event of suspected BPVC will stereotypically show children that are unbalanced, putting their head into their hands while crying and/or sitting on the floor during the attacks. ## Medical history ## For adults Particularly useful in a context of vertigo and/or imbalance, it will be as effective via TC as in a traditional consultation [fig_ref] Figure 2: Decision-making algorithm based on the symptoms [/fig_ref]. A few questions will allow the practitioner to identify the personal background, both medical and surgical. From the beginning, the following are to be identified: vascular risk factors (risk of stroke), a history of migraine (vestibular migraine), the psychological context (PPPD, Meniere's disease), previous tumors (risk of cerebellar metastasis), or trauma (labyrinthine fracture and/or concussion, BPPV). Current medication should be systematically checked, paying particular attention to aminoglycosides (risk of bilateral vestibular areflexia) and antiepileptics including carbamazepine or Tegretol ® (risk of central cerebellar-vestibular syndrome in the event of overdose identified by blood test). The patient's medical history will provide information useful for the identification of the cause. Rotatory vertigo can correspond to a cause of PVO, while a minimal sensation of dizziness, in contrast to a significant imbalance, pertains more to a neurological cause. Imminent feeling of fainting/loss of consciousness supports a cardiac cause, orthostatic hypotension or vagal malaise. Atypical vertiginous sensations such as floating or weightlessness are potentially of psychogenic origin. It is often difficult to accurately identify vertigo and criteria such as duration (seconds, more than 20 min, several days), frequency/recurrence, the potential trigger (positional? loud noise? coughing? sneezing? etc.) are more pertinent [bib_ref] TiTraTE: a novel approach to diagnosing acute dizziness and vertigo, Newman-Toker [/bib_ref]. As such, vertigo lasting a few seconds, triggered by movement, especially at night, suggests a BPPV, while a sensation of vertigo/fainting occurring electively while standing up would suggest orthostatic hypotension. More rarely, vertigo caused by variations in pressure (coughing, sneezing) and/or loud noise favors an inner ear abnormality such as superior canal dehiscence, enlarged vestibular aqueduct or perilymph fistula. Vertigo occurring spontaneously and recurrently, in a context of migraines could suggest a vestibular migraine, but attention should be given to unusual headaches with acute onset and/or prolonged duration. A recurring vertigo associated with unilateral auditory manifestations suggests Menière's disease, but may also indicate a tumor of the cerebellopontine angle. A disabling vertigo lasting several days suggests vestibular neuritis, but a stroke should be eliminated, particularly a cerebellar one. The presence of a vertical and/or oblique diplopia, a dysarthria, phonation and/or swallowing disorders, sensory disturbance, clumsiness of hands, a confusional component, will require emergency neurological assessment. ## Special features in children In children, medical history is crucial but difficult to obtain before the age of 5 and even more complicated when using a webcam. Therefore, talking to the parents is indispensable to identify the circumstances in which the vertigo/balance disorders appear. Indeed, vertigo secondary to a recent cranial trauma and associated with deterioration or fluctuation in hearing, should invoke a concussion of the inner ear or a perilymph fistula. The history taking should also consider recent headaches, background of fever, recent or chronic otorrhea, recent or progressive hearing loss (a progressive hearing impairment is to be suspected in a child who begins to ask their parents to repeat themselves). Children presenting sensorineural hearing loss, often have an associated unior bilateral vestibular impairment [bib_ref] Vestibular end-organ dysfunction in children with sensorineural hearing loss and cochlear implants:..., Cushing [/bib_ref] ; this can worsen during progressive flare-ups, manifesting itself through instabilities while walking accentuated by head movements. An inner ear deformity should be searched for in children presenting hearing impairment and episodes of vertigo, the most frequent being an enlarged vestibular aqueduct, isolated or in association with other abnormalities. It is also important to inquire about the age for onset of walking because a delayed posturomotor development syndrome (onset of walking after eighteen months) can be due to complete bilateral peripheral vestibular loss that can be mistaken for neurological impairment. The history taking should also gather family background information such as hereditary hearing impairment, . Decision-making algorithm based on oculomotor signs and analysis of standing position. The analysis of spontaneous nystagmus sometimes immediately permits the identification of a central (gaze-evoked, vertical, or torsional) or peripheral (horizontal-torsional) nystagmus. In the event of horizontal-torsional nystagmus, a Romberg test must be performed to ensure the patient's ability to stand upright, alone, with eyes opened (being unable to do this suggests a central nervous system impairment), then obtain one with the eyes closed (Romberg and/or Fukuda test), to ensure a postural deviation in the opposite direction of the horizontal-torsional nystagmus (peripheral-type vestibular syndrome). In the absence of spontaneous nystagmus, positional manoeuvres are performed. BPPV: Benign Paroxysmal Positional Vertigo. background of migraines or existence of familial episodic ataxia. A well-conducted interview should allow for a diagnostic, which the clinical examination will then reinforce. ## The clinical neurotologic examination adapted for tc The technical aspects of otoscopy, acoumetry and audiometry, which are essential for the etiological diagnosis of vertigo patients are developed in a specific article [bib_ref] Telemedicine in Audiology. Best Pratice recommendations from the French Society of Audiology..., Thai-Van [/bib_ref] [fig_ref] Figure 2: Decision-making algorithm based on the symptoms [/fig_ref]. ## Adults It will include the oculomotor examination followed by postural deviations as well as some simplified neurological tests [bib_ref] Consensus on virtual management of vestibular disorders: urgent versus expedited care, Shaikh [/bib_ref]. The practitioner should require video recordings of the eye mouvements of the patient when looking straight ahead for 5 to 10 s, then in different gaze directions (up, down, left, right). The patient or the caregiver should slowly swing the phone camera from left to right and vice versa, at a distance of around 25 cm (ocular pursuit). This very simple examination allows the practitioner to ensure the absence of Claude Bernard Horner syndrome, which, in a context of vertigo/imbalance, signals a Wallenberg syndrome. It can also find an abnormality in eye alignment, in particular a vertical divergence of the eyes ("skew deviation"), considered a sign of central neurological impairment as it is very rare in peripheral otolith dysfunction [bib_ref] Evaluating dizziness, Hoffman [/bib_ref]. This test highlight flutter or opsoclonus (exceptional), a gaze-evoked nystagmus, or an upbeat or downbeat nystagmus (increased and sometimes only visible in lateral gaze), which indicates central neurological impairment. If ocular pursuit is irregular or saccadic, this could also indicate a neurological dysfunction. Observation of horizontal-torsional spontaneous nystagmus responding to Alexander's law (increased intensity when the eye moves in the direction of the fast phase), is in favor of a PVO. In the absence of spontaneous nystagmus and in the event of positional vertigo, the positional manoeuvres, performed on a bed, will allow the impaired canal to be identified. Observation of a rotatory upbeating nystagmus during the Dix Hallpike Manoeuvre argues for a posterior canal BPPV, while a horizontal nystagmus during lateral rotation manoeuvres of the head, while lying down, suggests a horizontal canal BPPV. The patient is then asked to stand up with his eyes open, in close proximity to the caregiver. If it is possible to stand up with the eyes open, the patient is then asked to close his eyes (Romberg test), or even to perform a Fukuda test (walking on the spot). This is particularly useful in the event of horizontal-torsional spontaneous nystagmus to support a PVO [fig_ref] Figure 1: Prevalence for vertigo aetiologies in children [/fig_ref]. The inability to stand up alone with his eyes open should be considered a sign of central neurological impairment (in particular a stroke) [bib_ref] STANDING, a four-step beside algorithm for differential diagnosis of acute vertigo in..., Vanni [/bib_ref]. Some neurological tests can be checked: cerebellar dysmetria using the finger-to-nose test and the heel-knee test, facial asymmetry at rest and during voluntarily contractions and/or sensory facial impairment disorder (rough tactile sensations or hot/cold). At the end of this assessment, and depending on the algorithms suggested [fig_ref] Figure 2: Decision-making algorithm based on the symptoms [/fig_ref] , it is often possible to know if the practitioner is dealing with a peripheral vestibular or a central neurological impairment, and to identify most peripheral causes of vertigo (BPPV, recurring vertigo in Menière's disease, vestibular neuritis, etc.). In the event of posterior canal BPPV, Epley-type therapeutic manoeuvres are indicated because are easily selfperformed [bib_ref] Self-treatment of benign paroxysmal positional vertigo. Semont maneuver vs Epley procedure, Radtke [/bib_ref]. In any case, the patient is recommended to remain seated, in bed, for 30 min after finishing the therapeutic manoeuvre [bib_ref] Falling sensation in patients who undergo the Epley manoeuvre: a retrospective study, Uneri [/bib_ref]. This TC enables the immediate transmission of a medical and/or vestibular rehabilitation prescription. ## Special features in children Certain causes that have a potentially serious prognosis should be searched for. A background of fever and the presence of local signs ease the teleconsulting ENT specialist's etiopathogenetic reasoning. As such, in the event of an initially "trivial" otitis complicated by the appearance of a prolonged otorrhea, the diagnosis of labyrinthitis or cholesteatoma will be considered. If the child also presents with headaches, a nuchal sensitivity or rigidity during active or passive movement, vomiting, and photophobia, the diagnosis of meningitis is to be suspected. If intense vertigo is present without any other local ENT or neurological abnormality, but associated with gastrointestinal manifestations, the most probable diagnosis is vestibular neuritis, which may be mistaken with gastroenteritis. The observation of instability, always on the same side, when walking and nystagmus is essential for the diagnosis of vestibular neuritis. Finally, visual impairment is an increasing cause of dizziness/instability and/or headache with the ever-growing popularity of all types of recreational activities based on small video screens (e.g., video games, mobile phones, TV. . . It is necessary to search for refractive disorders (myopia, hyperopia and astigmatism) and/or vergence dysfunction [bib_ref] Epidemiology of Vestibular Impairments in a Pediatric Population, Wiener-Vacher [/bib_ref] [bib_ref] Dizziness and convergence insufficiency in children: screening and management, Wiener-Vacher [/bib_ref]. ## Current limitations of teleconsultation in neurotology There are at least three kinds. First of all, there is the difficulty to make a reliable video recording of the patient's eyes in complete darkness (videonystagmography), which is essential in revealing a spontaneous nystagmus of PVO. The recently developed device in the United States is very simple and adequate for this purpose. It consists in a plastic holder-https://www.dizzydoctor.com/that allows attaching a smartphone to ensure a significant reduction of the luminosity, similarly to a videonystagmoscope system. Although the visual suppression may still be insufficient to assure careful observation of spontaneous nystagmus, this system is sensible enough to detect specific nystagmus, especially in case of BPPV. However, it is hoped that the iOS or Android smartphone cameras will soon benefit from infra-red recording devices to enable filming in complete darkness. In a known patient, loaning adapted videonystagmography glasses has proved its value in observing nystagmus during a vertigo episode [bib_ref] Capturing acute vertigo. A vestibular event monitor, Young [/bib_ref]. Secondly, there is the difficulty in performing a Halmagyi test that requires the observation of catch-up ocular saccades (favoring a PVO) during quick and especially unpredictable movements of the patient's head [bib_ref] The video-head impulse test, Halmagyi [/bib_ref]. It will be noted that it is sometimes possible to observe catch-up saccades on one side during repeated horizontal movements of the head [bib_ref] Consensus on virtual management of vestibular disorders: urgent versus expedited care, Shaikh [/bib_ref]. Last but not least, there is the necessity of secure and high-capacity transfer to ensure the reception of video data while guaranteeing the confidentiality and protection of patient data. In any case, the vestibular and clinical acquired data can and should be stored only on a server located in Europe with the Healthcare Data Hosting (HDS: Hébergement des Données de Santé) accreditation from the Health Ministry and in accordance with the European regulation (EU 2016/679) on the Protection of Personal Data (GDPR). # Conclusion The current SARS-CoV-2 pandemic has led to an increasing demand in otoneurologic consultations by telemedicine. Facing a vertiginous patient in emergency, TC is sometimes sufficient but has limitations regarding clinical examination, and, in a number of cases, cannot currently fully replace a face-to-face consultation. Algorithms are proposed to help for correct decision making. Undoubtedly, TC is adapted to carry out follow-up consultation for selected vertiginous patients previously assessed face-to-face. # Disclosure of interest The authors declare that they have no competing interest. [fig] Figure 1: Prevalence for vertigo aetiologies in children. [/fig] [fig] Figure 2: Decision-making algorithm based on the symptoms (vertigo, hearing impairment or neurological complaints) focusing on the duration, frequency, and triggering factors of the vertigo. PICA: Postero-inferior cerebellar artery. AICA: Antero-inferior cerebellar artery. [/fig]	None	None	None
d924d299e283f22ad2dbb398a89882f699018c1a	pubmed	HCV Council – critical appraisal of data: recommendations for clinical practice in a rapidly evolving therapeutic landscape	HCV Council – critical appraisal of data: recommendations for clinical practice in a rapidly evolving therapeutic landscape Background & Aims: HCV Council 2014, like its predecessor HCV Council 2011, assembled leading clinicians and researchers in the field of hepatitis C to critically evaluate current data regarding best practices for managing patients with chronic hepatitis C virus (HCV). Methods: Clinical practice statements were developed that reflect the areas of potential controversy with high clinical impact. Faculty members were responsible for reviewing the literature to support or reject these statements. After a review and comprehensive discussion of the data, the HCV Council faculty voted on the nature of the evidence and the level of support for each statement. Results: The results of the detailed analysis with expert opinion are summarized in this article. Conclusion: Numerous questions regarding optimal management of certain populations and clinical scenarios remain unanswered. The discussion in the article provides a summary of evidenced-based expert opinion that may help guide clinicians as additional information is developed.Keywords direct-acting antiviral -genotype 1a and 1b -genotype 2 -genotype 3 -hepatitis C virus Abbreviations 3D, 3 DAA regimen (paritaprevir/ritonavir, ombitasvir and dasabuvir); AASLD, American Association for the Study of LiverThis 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.Liver International(2016) The therapeutic landscape for the treatment of chronic hepatitis C virus (HCV) infection has been rapidly evolving since the approval of the first direct-acting antiviral agents (DAAs), telaprevir and boceprevir, in 2011. In 2013, sofosbuvir (SOF) became the first nucleoside NS5B polymerase inhibitor to be approved and offered a potent DAA with a high genetic-barrier that led the transformation of HCV treatment to all-oral regimens. Over the last 2 years, the US Food and Drug Administration (FDA) approved four alloral regimens: (i) SOF plus ribavirin (RBV); (ii) SOF plus simeprevir (SMV), an NS3 protease inhibitor (PI); (iii) the fixed-dose combination of SOF with the NS5A inhibitor ledipasvir (LDV/SOF) (1); and (iv) a 3 DAA (3D) ± RBV regimen [paritaprevir (NS3/4A PI) boosted with ritonavir, ombitasvir (NS5A inhibitor) and dasabuvir (non-nucleoside NS5B polymerase inhibitor)]. The Phase 3 clinical trials provided guidance for the FDA labelling and informed clinicians about optimizing therapy with these drugs. However, not all patient scenarios can be anticipated, and often a more nuanced interpretation of Phase 3 trial results, coupled with rapidly evolving data from ongoing Phase 2 clinical trials, will also provide important information to guide practice. In 2013, the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA)/International Antiviral Society USA (IAS-USA) formed a task force to provide ongoing treatment recommendations incorporating the most up-to-date clinical data and to serve as an additional resource for clinicians who manage patients with HCV. Complementing this effort, the HCV Council 2014, like its predecessor HCV Council 2011 (3), assembled leading clinicians and researchers in the field of hepatitis C in July 2014, to critically evaluate current data regarding best practices for managing patients with chronic HCV. The methodology of the HCV Council has been described previously [bib_ref] Hepatitis C virus: a critical appraisal of new approaches to therapy, Nelson [/bib_ref]. Clinical practice statements (Table 1) were developed that reflect areas of potential controversy with high clinical impact. Faculty members were responsible for reviewing the literature to support or reject these statements. After a review and comprehensive discussion of the data, the HCV Council faculty voted on the nature of the evidence and the level of support for each statement [fig_ref] Table 2: Council voting schemes [/fig_ref]. Voting results were based on data available in July 2014. Additional data available from July 2014 to August 2015 have been added to supplement the findings. The results of the detailed analysis with expert opinion are summarized below. Statement 1: patients with cirrhosis have lower rates of sustained virological response compared to non-cirrhotic patients and, thus, treatment efficacy remains suboptimal for this population ## Rationale and definition of statement Patients with advanced fibrosis and cirrhosis are most in need of HCV therapy, as successful therapy has been shown to decrease liver-related mortality [bib_ref] Association between sustained virological response and all-cause mortality among patients with chronic..., Van Der Meer [/bib_ref]. Interferon (IFN)-based antiviral treatment in these patients had been challenging because of patient tolerance, the risk of serious adverse events, and hyporesponsiveness to therapy. Bridging fibrosis and cirrhosis have traditionally been negative predictors of HCV treatment outcome. ## Summary of evidence The disparity in sustained virological response (SVR) between cirrhotic and non-cirrhotic patients was evident during treatment with peginterferon (PEG-IFN) and RBV and was not mitigated by the addition of first generation PIs [bib_ref] Safety and efficacy of boceprevir/peginterferon/ribavirin for HCV G1 compensated cirrhotics: meta-analysis of..., Vierling [/bib_ref]. The advent of all-oral DAA regimens considerably altered the treatment landscape by achieving superior tolerability as well as increased SVR rates despite truncated treatment durations [fig_ref] Table 3: Sustained virological response between cirrhotic and non-cirrhotic genotype 1 patients [/fig_ref]. The combination of LDV/SOF with or without RBV given for 12 or 24 weeks, has been evaluated in subsets of genotype 1 patients with cirrhosis in both treatment-na€ ıve and treatment-experienced patients [bib_ref] Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection, Afdhal [/bib_ref]. The SVR in treatment-na€ ıve patients ranged from 94 to 100% [bib_ref] Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection, Afdhal [/bib_ref]. In cirrhotic patients who had failed therapy, including a PI, this regimen achieved an SVR of 82 to 100% with higher SVR rates noted with the 24-week regimen, regardless of the use of RBV [bib_ref] Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection, Afdhal [/bib_ref]. Further studies that were enriched with cirrhotic patients who had failed prior PIs show that 12 weeks of LDV/SOF with RBV has equivalent efficacy to 24 weeks of LDV/SOF [bib_ref] Ledipasvir/sofosbuvir fixed dose combination is safe and efficacious in cirrhotic patients who..., Bourli Ere [/bib_ref]. In a trial exclusively for patients with cirrhosis who were treatment-na€ ıve or prior PEG-IFN/RBV failures, the 3D regimen [paritaprevir/r (ritonavir boosted PI), ombitasvir (an NS5A inhibitor) and dasabuvir (a nonnucleoside inhibitor)], with RBV for 12 or 24 weeks achieved high SVR rates of 92-96% respectively. Prior null responders and those with genotype 1a had a slightly lower numerical response of 87 and 89%, respectively, with a 12-week regimen, while the 24-week regimen achieved an SVR of 95 and 94% respectively [bib_ref] ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis, Poordad [/bib_ref]. The presence of cirrhosis also lowers efficacy in non-genotype 1 patients, as highlighted below. # Discussion The panel agreed that all-oral therapy for patients with HCV and cirrhosis has been a major advancement. Although many of the traditional treatment obstacles ## Key points - HCV Council assembled leading clinicians and researchers in the field of hepatitis C to critically evaluate current data regarding best practices for managing patients with chronic hepatitis C virus. - Clinical practice statements were developed in the field of hepatitis C that reflect areas of potential controversy with high clinical impact. - After a review and comprehensive discussion of the data, the HCV Council faculty voted on the nature of the evidence and the level of support for each statement. - The discussion in the article provides a summary of evidenced-based expert opinion that may help guide clinicians as additional information is developed. have been overcome and patients with cirrhosis can expect high SVR rates, challenges remain. Subsets of patients with cirrhosis, particularly those with prior treatment failure, will require a longer duration of therapy or other modifications, such as the addition of RBV, to maximize treatment response. Benefit in patients with decompensated cirrhosis is under active investigation. Statement 2: patients with easier-to-treat characteristics can be defined and treated for shorter duration ## Rationale and definition of statement From the outset of HCV antiviral therapy, host and viral factors predicted an ability to shorten therapy without a compromise in efficacy. Low baseline viral levels, the presence of IL28B CC, and rapid on-treatment virological decay represented parameters that allowed for SVR with shorter durations of IFN-based regimens [bib_ref] Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon..., Jensen [/bib_ref] [bib_ref] Hepatitis C genotype 1 virus with low viral load and rapid virologic..., Pearlman [/bib_ref] [bib_ref] Factors that predict response of patients with hepatitis C virus infection to..., Poordad [/bib_ref]. Early-stage liver disease, likewise, reflected a cohort that was 'easier-to-treat'. Entering into the all-oral DAA era where cost and compliance will drive therapy, there have been attempts made to shorten treatment durations further. ## Summary of evidence In the ION-3 program, two 8-week regimens of LDV/ SOF were compared with one 12-week regimen among non-cirrhotic genotype 1 patients, and the SVR rates were similar in the shorter duration arms [bib_ref] Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without..., Kowdley [/bib_ref]. These results support the notion that 'easier-to-treat' noncirrhotic patients could shorten therapy. Nevertheless, there were numerically more relapsers in the 8-week arms, leading to concern that using a shorter duration for all non-cirrhotic genotype 1 patients may come with unacceptable relapse rates and without a defined salvage regimen [bib_ref] Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without..., Kowdley [/bib_ref]. Post-hoc analyses suggested that treatment na€ ıve, non-cirrhotic patients with HCV RNA levels <6 million IU did well with 8 weeks of LDV/SOF and that relapse rates were comparable to 12-week regimens, leading to the FDA recommendation that 8 weeks of treatment can be considered in this subset. Additional post-hoc analysis also found that gender and IL28B genotype were associated with favourable response. There was a numeric but not statistically significant difference in race, age and subgenotype [bib_ref] Subgroup differences in response to 8 weeks of ledipasvir/sofosbuvir for chronic hepatitis..., O'brien [/bib_ref]. The phase 2b study, AVIATOR, also demonstrated a higher relapse rate in treatment-na€ ıve non-cirrhotic patients treated with 8 weeks of 3D (88% SVR24 compared to 96% with 12 weeks) [bib_ref] Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1, Kowdley [/bib_ref]. In addition, in the 3D development program, to optimize prior null responders to PEG-IFN/RBV who had cirrhosis and genotype 1a, a longer, 24-week course offered Patients with cirrhosis have lower rates of SVR compared to non-cirrhotic patients and, thus, treatment efficacy remains suboptimal for this population Patients with easier-to-treat characteristics can be defined and treated for shorter duration Genotype 1a and 1b will be treated with different regimens The preferred approach to treatment for all subgroups of patients with genotype 3 is sofosbuvir and ribavirin for 24 weeks The preferred approach to treatment for all subgroups of patients with genotype 2 is sofosbuvir and ribavirin for 12 weeks. See the supplemental section for review of this statement Workshop II: a patient-oriented approach: addressing treatment challenges Due to the high costs of medications, only patients with advanced fibrosis should be offered treatment with all-oral regimens for HCV Given the high-efficacy and low-viral breakthrough rates, on-treatment viral load monitoring is no longer required Patients with decompensated cirrhosis should be treated with an all-oral regimen for HCV to improve survival Patients co-infected with HIV-HCV should no longer be considered a 'special population'. See the supplemental section for review of this statement Treatment of hepatitis C should remain within the domain of hepatologists, gastroenterologists and ID physicians. See the supplemental section for review of this statement higher cure rates, as compared to the 12-week group [bib_ref] ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis, Poordad [/bib_ref]. # Discussion Most Phase 3 trials of all-oral DAA therapy have focused on lengthening therapy for more 'difficult-to-treat' populations vs shortening therapy for those considered 'easy-to-treat'. While evidence shows that certain patients with mild disease can achieve high rates of SVR with shorter duration of therapy, others, such as those with cirrhosis, benefit from a longer duration of treatment. Definitively excluding cirrhosis may be challenging in the real world. Misclassifying patients with advanced fibrosis as 'non-cirrhotic' and mandating only 8 weeks of therapy could lead to higher than expected relapse rates. Thus, although the majority of the Council members agreed that the statement was supported by a well-designed randomized controlled trial, considerable controversy existed regarding whether such a blanket statement could translate into clinical practice in 2015. Statement 3: genotype 1a and 1b will be treated with different regimens ## Rationale and definition of statement Higher rates of SVR with HCV genotype 1b compared to genotype 1a were first recognized with PEG-IFN/RBV [bib_ref] Influence of the HCV subtype on the virological response to pegylated interferon..., Legrand-Abravanel [/bib_ref]. This trend was attenuated with the first DAAs, telaprevir and boceprevir [bib_ref] Telaprevir for previously untreated chronic hepatitis C virus infection, Jacobson [/bib_ref] [bib_ref] Boceprevir for untreated chronic HCV genotype 1 infection, Poordad [/bib_ref]. However, the Phase 3 registration trial of simeprevir-based triple therapy (SMV/PEG-IFN/RBV) demonstrated substantially higher rates of SVR in genotype 1b compared to genotype 1a as a result of a pre-existing resistance mutation Q80K, which occurs almost exclusively in HCV genotype 1a [bib_ref] Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatmentnaive patients with..., Jacobson [/bib_ref]. The impact of subtype was less apparent with SOF-based triple therapy. Pooled data from the Phase 3 NEUTRINO (22) and Phase 2 ATOMIC trials (23) suggested an SVR advantage in genotype 1a (92%) over genotype 1b (82%), although the latter group also had disproportionately higher frequency of negative response characteristics. ## Summary of evidence The combination of drugs or duration of therapy may vary depending on HCV subtype. The PEARL-III and -IV studies nicely demonstrated that the addition of RBV to the 12-week 3D regimen does not enhance the efficacy in genotype 1b (SVR 99.5% with RBV and 99.0% without) [bib_ref] ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV, Ferenci [/bib_ref]. However, SVR rates were significantly lower in the genotype 1a subjects that did not receive RBV (97% with compared to 90.2% without) [fig_ref] Figure 1: 3D [/fig_ref] [bib_ref] ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV, Ferenci [/bib_ref]. TURQUOISE-II found that a 24-week regimen was optimal for genotype 1a patients with cirrhosis with prior null response: SVR rates of 88.6% with 12 weeks of treatment compared to 94.2% when extended to 24 weeks (11). This improvement in efficacy was not seen in any other subgroup including those genotype 1b patients with cirrhosis and prior null response (SVR rates of 98.5% with 12 weeks compared to 100% with 24 weeks) [bib_ref] ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis, Poordad [/bib_ref]. Lastly, the need to tailor a regimen by subtype will depend on the agents utilized. The Phase 3 ION-1, ION-2 and ION-3 studies showed no difference in efficacy between genotype 1 subtypes with or without RBV for durations of 12 or 24 weeks, even when shortening therapy to 8 weeks in a non-cirrhotic treatment-na€ ıve cohort [bib_ref] Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection, Afdhal [/bib_ref] [bib_ref] Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without..., Kowdley [/bib_ref]. However, baseline testing NS5A resistance-associated variants (RAVs) may be necessary in a subset of genotype 1a patients being considered for therapy with grazoprevir-elbasvir, as the presence of a baseline RAV lowered efficacy in the 1a subgenotype but did not appear to affect outcomes in genotype 1b patients [bib_ref] Grazoprevir-Elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis..., Zeuzem [/bib_ref]. # Discussion Although relatively simple treatment algorithms will apply for most populations, the agents and length of therapy will be directed by HCV subtype and disease severity. This is reflected in the recently released AASLD-IDSA guidance document. As supported by the data above, subtype did not impact treatment recommendations when using combination LDV/SOF; however, the addition of RBV to 3D was advised in all individuals with G1a and, as well as treatment extension to 24 weeks for G1a patients with cirrhosis irrespective of prior treatment response. Other modifications such as baseline RAV testing also may be needed to optimize therapy based on subgenotype. ## Summary of evidence Studies have demonstrated that genotype 2 patients have high SVR rates with SOF + RBV for 12 weeks but that cirrhosis and prior treatment response still affect efficacy [bib_ref] Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment..., Jacobson [/bib_ref]. There are additional meta-analysis data to indicate that one needs at least five of six negative predictors in genotype 2 to see a significant decrease in the efficacy of a SOF/RBV regimen (prior treatment, gender, weight, IL28B, cirrhosis and HCV RNA levels), so most patients will likely qualify for the 12 weeks of SOF + RBV treatment [bib_ref] Sofosbuvirbased regimens are associated with high SVR rates across genotypes and among..., Foster [/bib_ref]. Treatment with daclatasvir (DCV) + SOF for 24 weeks showed a 92% SVR in genotype 2 patients, although the regimen was not tested in patients with cirrhosis and was given for 24 rather than 12 weeks [bib_ref] Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection, Sulkowski [/bib_ref]. DCV + SOF did show high efficacy in G2 HCV-HIV co-infected patients treated for 12 weeks, making this a viable alternative for individuals who cannot tolerate RBV [bib_ref] Daclatasvir plus Sofosbuvir for HCV in Patients Coinfected with HIV-1, Wyles [/bib_ref]. The recently presented BOSON study also demonstrated high SVR12 rates in genotype 2 treatment-experienced cirrhotics with 16 weeks of SOF/RBV (87%), SOF/RBV for 24 weeks (100%) and PEG-IFN/RBV + SOF for 12 weeks (94%) (31). # Discussion The opinion of the panel was split regarding the statement with fair-to-poor evidence of support vs rejecting the statement, mostly based on concerns about the efficacy in prior treatment-experienced patients with cirrhosis. All Council members agreed that there was insufficient evidence to support the statement fully, likely because of doubts about cirrhotic non-responder efficacy and the limited data that supports other therapies available to this population. Nevertheless, in the current therapeutic landscape, a 12-week regimen with SOF/RBV remains the most efficacious for the majority of patients with genotype 2. Statement 5: the preferred approach to treatment for all subgroups of patients with genotype 3 is SOF and RBV for 24 weeks ## Rationale and definition of statement Hepatitis C virus G3 is associated with an increased risk of cirrhosis and liver cancer. As a result, it has been identified as a population prioritized for therapy. Unfortunately, available treatment alternatives may not offer high rates of viral eradication. Recommended IFN-free regimens for patients with HCV genotype 3 infection include SOF/RBV administered for 24 weeks and SOF/DCV. ## Summary of evidence The first reported Phase 3 trials (FISSION, POSITRON and FUSION) predominantly evaluated 12-week treatment durations and showed substantially lower SVR rates in genotype 3 compared with genotype 2 patients [bib_ref] Sofosbuvir for previously untreated chronic hepatitis C infection, Lawitz [/bib_ref] [bib_ref] Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment..., Jacobson [/bib_ref]. Treatment-experienced patients with genotype 3 and cirrhosis were at the greatest disadvantage. The FUSION study, demonstrating a marked increment in SVR rates in genotype 3 patients when treatment was given for 16 weeks rather than 12 weeks (37 vs 63% in non-cirrhotics and 19 vs 61% in cirrhotics) [bib_ref] Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment..., Jacobson [/bib_ref] , suggested that a longer duration for genotype 3 patients would be more effective. This hypothesis was validated by the VALENCE trial, which evaluated 24-weeks of SOF/RBV in 250 genotype 3 patients, and showed SVR rates in 92-93% of treatment-na€ ıve patients and 87% of treatment-experienced non-cirrhotic patients [bib_ref] Sofosbuvir and ribavirin in HCV genotypes 2 and 3, Zeuzem [/bib_ref]. However, the SVR rate of 62% in treatment-experienced patients with cirrhosis was similar to the 61% SVR rate in a comparable population that received 16 weeks of treatment in FUSION [bib_ref] Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment..., Jacobson [/bib_ref]. Several observations suggest that a 12-week course of PEG-IFN/RBV and SOF may offer comparable or even superior efficacy to that attained with 24 weeks of SOF/ RBV in some genotype 3 patients. Thirty-nine genotype 3 treatment-na€ ıve non-cirrhotic patients were treated for 12 weeks with SOF/RBV combined with 4-12 weeks of PEG-IFN, with 38 (97%) achieving SVR [bib_ref] Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients..., Lawitz [/bib_ref]. Another modest-sized study presented at the European Association for the Study of the Liver (EASL) 2014 lent credence to the potential role of a 12-week triple regimen by showing that both non-cirrhotic and cirrhotic genotype 3 patients who had failed a 12-to 16-week course of SOF and RBV had higher SVR rates with 12 weeks of PEG-IFN, RBV and SOF than with 24 weeks of SOF and RBV [bib_ref] Successful retreatment with sofosbuvir-containing regimens for HCV genotype 2 or 3 infected..., Esteban [/bib_ref]. More recently, the BOSON trial showed superior efficacy with 12 weeks of triple therapy (n = 168/ 181 with SVR12 93%) compared to 24 weeks of SOF/ RBV (n = 153/182 with SVR 84%) [bib_ref] Sofosbuvir + peginterferon/ribavirin for 12 weeks vs sofosbuvir + ribavirin for 16..., Foster [/bib_ref]. Importantly, PEG/RBV/SOF demonstrated higher SVR 12 rates in all arms, regardless of cirrhosis status or treatment history. Furthermore, it is possible that combinations of DAAs will improve SVR rates. The ALLY-3 study demonstrated overall SVR rates of 90 and 86% among treatment-na€ ıve and treatment-experienced patients, respectively, who were treated with a 12-week regimen of SOF and DCV [bib_ref] All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C..., Nelson [/bib_ref]. However, the SVR rate fell to 63% among genotype 3 cirrhotic patients treated with this regimen. Two 'real world' studies presented at EASL 2015 clearly indicate that extension of this regimen, with or without RBV, to 24 weeks confers superior results in this population [bib_ref] On treatment HCV RNA as a predictor of virologic response in the..., Welzel [/bib_ref] [bib_ref] Daclatasvir plus sofosbuvir with or without ribavirin in patients with HCV genotype..., Hezode [/bib_ref]. As predicted by the relative in vitro activities, realworld data from Foster et al.showed a significant benefit of DCV over ledipasvir for genotype 3 patients when each agent was combined with SOF. # Discussion Studies have demonstrated a propensity for HCV genotype 3 infection to cause progressive fibrosis, cirrhosis and hepatocellular carcinoma (HCC) more frequently than is seen in other HCV genotypes [bib_ref] HCV genotype 3 is associated with an increased risk of cirrhosis and..., Kanwal [/bib_ref]. In the light of this, some clinicians perceive that a course of therapy that leaves no resistance in the event of virological failure, as is the case with SOF/RBV, should be offered to all patients with genotype 3. Other clinicians may elect to use PEG-IFN/RBV and SOF in selected patients. However, as reflected in the updated HCV guidance documents, regimens incorporating a second DAA, such as a potent, pangenotypic NS5A inhibitor, with SOF is the preferred first-line treatment for genotype 3 [bib_ref] Safety and efficacy of treatment with the interferon-free, ribavirinfree combination of sofosbuvir..., Everson [/bib_ref]. As of August 7, 2015, SOF in combination with RBV for 24 weeks is considered only an alternative regimen. DCV/SOF for 12-24 weeks and PEG-RBV/SOF for 12 weeks are the recommended treatment options for genotype 3 patients. ## Rationale and definition of statement This statement is based on the premise that patients with advanced fibrosis have the most risk and thus the most to gain with therapy, while those with mild disease can wait. Based on wholesale acquisition cost to treat the entire US Liver International (2016) HCV population would cost in excess of $300 billion, thus the desire to prioritize and restrict access to therapy. ## Summary of evidence Hepatitis C virus has a significant effect on morbidity and mortality that is highest in patients with cirrhosis, but also impacts patients that are non-cirrhotic. In the USA, chronic HCV is the most common cause of liver disease. HCV is responsible for at least 15 000 deaths annually, with increasing mortality expected over the next decades [bib_ref] Aging of hepatitis C virus (HCV)-infected persons in the United States: a..., Davis [/bib_ref]. Despite slow progression to cirrhosis, HCV-related mortality because of liver failure and HCC has increased substantially since 1995, especially in persons 45 years and older, with the greatest increases seen in males and non-Hispanic blacks [bib_ref] Changing trends in hepatitis C-related mortality in the United States, Wise [/bib_ref]. HCV is an important cause of premature mortality [bib_ref] Changing trends in hepatitis C-related mortality in the United States, Wise [/bib_ref]. In addition, chronic HCV affects well-being in all patients, regardless of fibrosis [bib_ref] The impact of chronic hepatitis C on resource utilisation and in-patient mortality..., Younossi [/bib_ref] , although the burden is greatest in those with cirrhosis. In a recent cohort analysis of 528 cirrhotic HCV patients, baseline health-related quality of life was significantly impaired, with the most profound impairments seen in physical activity, energy, vitality and fatigue [bib_ref] Patientreported outcomes in chronic hepatitis C patients with cirrhosis treated with sofosbuvir-containing..., Younossi [/bib_ref]. Eradication of HCV improves health-related quality of life and work productivity [bib_ref] Improvement of health-related quality of life and work productivity in chronic hepatitis..., Younossi [/bib_ref]. The main goal of HCV treatment is to eradicate HCV, thereby preventing progressive liver disease. SVR is associated with reduced risk of HCC, histological reversal of liver fibrosis and reduced risk of liver-related death (4). Cure of HCV infection has also been associated with a decrease in all-cause mortality, decreased incidence of diabetes and improved insulin resistance [bib_ref] Sustained virologic response to antiviral therapy for chronic hepatitis C virus infection:..., Pearlman [/bib_ref]. A decrease in all-cause mortality was confirmed in a study of 21 000 US Veterans [bib_ref] A sustained virologic response reduces risk of all-cause mortality in patients with..., Backus [/bib_ref]. Survival advantage was seen even in those without evidence of cirrhosis, suggesting an effect on non-liver related comorbidities (cardiovascular disease, diabetes, nonliver related cancers). These results were also supported by a meta-analysis of more than 34 000 patients treated with IFN-based therapy [fig_ref] Figure 2: Effects of sustained virological response [/fig_ref] [bib_ref] Effects of sustained virological response (SVR) on the risk of liver transplant,..., Hill [/bib_ref]. This favours the treatment of all patients infected with HCV, regardless of degree of liver fibrosis. Another group prioritized for treatment includes individuals at high risk for transmission, such as healthcare workers, haemodialysis patients, incarcerated individuals, those of childbearing age, and those who engage in high-risk behaviours. Data from Phase 3 all-oral regimens suggest that cirrhosis remains a pretreatment factor that negatively affects SVR. Longer durations of therapy are required to maximize response in some cirrhotic patients, irrespective of genotype [bib_ref] ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis, Poordad [/bib_ref] [bib_ref] Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment..., Jacobson [/bib_ref] [bib_ref] Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin, Feld [/bib_ref]. Thus, restricting care to the cirrhotic population will impose higher costs per treatment regimen. A recent cost-effectiveness model examined the treatment of all patients infected with HCV vs using a fibrosis-restricted decision model (e.g. only treating F3-F4). The 'treat all' strategy was the most cost-effective [incremental cost-effectiveness ratio (ICER) of $15 709/quality-adjusted life year (QALY)] and was also associated with the lowest risk of developing advanced liver disease [bib_ref] Impact of interferon free regimens on clinical and cost outcomes for chronic..., Younossi [/bib_ref]. # Discussion The HCV Council faculty felt strongly that this statement should be rejected based on the proven benefit in morbidity and mortality for eradicating HCV in patients who are non-cirrhotic; along with the overall cost-effectiveness advantage. Although prioritization of treatment will likely continue to focus on those with advanced disease, the group thought that there is strong evidence to encourage therapy in all patients infected with HCV. the prognostic significance of early viral response and response-guided therapy. The meaning of low-level positive viral load on therapy, though uncommon, is unknown. Given the lack of prognostic significance, the absence of futility rules and the inability to shorten duration in rapid responders, the role of viral load monitoring while on therapy is unclear. This statement investigates the rationale for monitoring HCV viral load while on therapy. ## Summary of evidence Several large multicenter trials show rapid achievement of viral negativity in virtually all subjects, low rates of viral breakthrough (<2%), lack of stopping rules for futility, lack of prognostic significance based on the rate of achieving viral clearance, or rules for response-guided therapy [bib_ref] On treatment HCV RNA as a predictor of virologic response in the..., Welzel [/bib_ref] [bib_ref] Time to viral suppression is not related to achievement of SVR12 in..., Sulkowski [/bib_ref]. SVR rates are over 90% with current first-line therapy and virtually all fail through relapse. As not even the rate of viral clearance predicts relapse, the prognostic or clinical significance of measuring viral load on-treatment is unclear. Ledipasvir/SOF registration trials (ION-1, 2 and 3) enrolled 1950 patients. Only two patients had viral breakthrough (<1%). SVR rates were over 95% in all groups, with 36 (1.8%) failures from relapse [bib_ref] Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection, Afdhal [/bib_ref] [bib_ref] Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without..., Kowdley [/bib_ref]. These findings are not unique to SOF-based therapy. SAPPHIRE-I, II and TURQUOISE II evaluated 3D in cirrhotic and non-cirrhotic genotype 1 patients [bib_ref] ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis, Poordad [/bib_ref] [bib_ref] Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin, Feld [/bib_ref] [bib_ref] Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin, Zeuzem [/bib_ref]. In more than 1100 patients, 1.5% experienced breakthrough, and 2.2% relapsed. This is not likely to change in the future as other investigational therapies report similar results [bib_ref] High efficacy and safety of the all-oral combination regimen, MK-5172/MK-8742 + /-RBV..., Lawitz [/bib_ref]. The lack of prognostic significance of a positive or negative viral load at week 4 questions the utility of monitoring on-treatment viral response. Several potential reasons for assessing on-treatment viral load remain. Firstly, it is believed that a negative HCV RNA is a powerful motivator that reinforces patient adherence. Secondly, a detectable HCV RNA may be a marker for noncompliance or a drug-drug interaction (DDI) and, thus, drug failure. Assessment can easily be incorporated at a time when other labs are drawn. However, one would have to be certain to exclude false-positive results and prevent treatment disruption, as discontinuing treatment could disadvantage many patients who could still achieve SVR [bib_ref] On treatment HCV RNA as a predictor of virologic response in the..., Welzel [/bib_ref] [bib_ref] Time to viral suppression is not related to achievement of SVR12 in..., Sulkowski [/bib_ref]. # Discussion Achieving clearance of HCV RNA by week 4 with highly potent DAA agents is expected in over 95% of patients. The rate of viral breakthrough is <2%, and virtually all failures to achieve SVR will be due to non-compliance or relapse. There are no on-treatment viral predictors of who will relapse, and it is not possible to use on-treatment viral load monitoring to develop either response-guided algorithms or futility rules. Thus, the prognostic significance of HCV-RNA on treatment is low. Nevertheless, the panel felt that it was highly likely that HCV RNA would be measured during treatment in most patients, more as reinforcement of adherence than as a true need to alter the therapeutic regimen. They cautioned against discontinuing treatment in patients with detectable viraemia unless non-adherence could be established. They were strongly against incorporating viral load measurements into algorithms for continuing authorization of treatment by payers, a requirement that has the potential to lead to treatment interruption. ## Rationale and definition of statement The term decompensated cirrhosis implies that the patient has experienced variceal haemorrhage, ascites, spontaneous bacterial peritonitis, encephalopathy or coagulopathy. IFN treatment is compromised by poor tolerability, adverse events and low rates of virological response [bib_ref] A randomized controlled trial of pretransplant antiviral therapy to prevent recurrence of..., Everson [/bib_ref]. IFN-free regimens are the only options available for patients with decompensated cirrhosis. Until data support the use of PIs (NS3/4) in decompensated cirrhosis (Child B/C), this class should also be avoided. ## Summary of evidence Preliminary reports indicate that high rates of SVR can be achieved in patients with decompensated cirrhosis. LDV/SOF/RBV was administered to approximately 100 patients with Child-Turcotte-Pugh (CTP)-B or CTP-C cirrhosis for 12 or 24 weeks [bib_ref] Ledipasvir/sofosbuvir with ribavirin for the treatment of HCV in patients with decompensated..., Flamm [/bib_ref]. SVR rates were 87 and 89% overall, respectively, and did not vary by CTP class [fig_ref] Figure 3: Ledipasvir/sofosbuvir + ribavirin [/fig_ref]. The regimen was well tolerated with few patients discontinuing due to adverse events. Importantly, model for end-stage liver disease (MELD) score decreased in most patients, and serum albumin increased, indicating that improvement in clinical status was also associated with SVR. This same regimen was used to treat patients with post-transplant recurrent hepatitis C and also demonstrated high rates of SVR (96% in CTP-A and 83-85% among CTP-B patients) that was well tolerated. Similar improvement in MELD and albumin were noted. The combination of DCV, SOF and RBV for 12 weeks also demonstrated high efficacy in 60 decompensated cirrhotics in the ALLY-1 trial. Reported SVR12 rates were 92% in Childs A, 94% in Childs B and 56% in Childs C. Benefit from therapy in this fragile population may require more than simply an improvement in biochemical parameters. The English EAP (Early Access Program) Liver International (2016) showed similar results in 467 patients with decompensated cirrhosis treated with 12 weeks of all-oral therapy (SOF/LDV/RBV, SOF/LDV, SOF/DCV/RBV or SOF/ DCV). Overall SVR 12 rates were between 71 and 80%. Hepatic function (reflected by MELD score) improved in 40%; however, the investigators felt that the benefit was primarily gained in subjects younger than 65 with a baseline albumin above 3.5 g/dl. Several additional challenges exist in managing decompensated cirrhosis, even with all-oral regimens. Many patients with decompensated disease have impaired renal function. SOF and RBV are cleared by the kidney, and there are no dose recommendations for patients with estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m 2 or in patients on dialysis. The clearance of other DAA agents may be impaired by altered hepatic metabolism or portal-systemic shunting; for example, simeprevir is not recommended in CTP C cirrhosis due to substantially higher simeprevir exposures. DDIs may alter therapeutic efficacy and increase toxicity [bib_ref] Drug-drug interactions during antiviral therapy for chronic hepatitis C, Kiser [/bib_ref]. # Discussion The panel concurred that all-oral regimens were the treatment of choice for patients with decompensated liver disease, although PIs should be avoided in CTP C cirrhosis. Clearly, SVR can be safely achieved in the majority of patients. However, the major unanswered question is whether SVR in a decompensated patient will obviate the need for liver transplantation with continued improvement in hepatic function or whether it will just provide a temporary respite from progressive liver disease without affecting overall survival. It is expected that long-term follow-up of these patients will help answer this important question and inform whether a pre-transplant or post-transplant antiviral treatment strategy is most effective. Statement 9: patients co-infected with HIV/HCV should no longer be considered a 'special population' ## Rationale and definition of statement In the USA, up to 25% of those infected with the human immunodeficiency virus (HIV) harbour co-infection with HCV [bib_ref] Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: a..., Sherman [/bib_ref]. The burden is thought to range from 250 000 to 300 000 patients with dual infection. Viewed from the opposite direction, approximately 10% of those with chronic HCV infection are also infected with HIV. From a global perspective, these numbers are much larger, with estimates of 4-8 million patients coinfected with HIV/HCV. Historically, unique features of HIV/HCV co-infection led to the designation of this group as a 'special population'. ## Summary of evidence To determine the validity of the proposed statement, the definition of what constitutes a 'special population' and the effect of such a designation requires further scrutiny. Both the FDA and European Medicines Agency (EMA) (USA and European drug regulatory bodies) regard HIV/HCV as a 'special population' group. The designation is designed to ensure that an appropriate number of subjects are entered and treated in clinical trials leading to drug approval so that both patients and healthcare providers have sufficient data on efficacy, safety and unique management considerations. In the FDA Guidance for Industry published in October 2013, the agency specifically notes the need for appropriate DDI studies with commonly used HIV medications and safety data regarding loss of HIV efficacy. They suggest that 300 co-infected patients are needed to complete these assessments. Several unique and relevant biological issues can affect outcomes in HIV/HCV co-infected patients. These include (i) faster rates of fibrotic progression [bib_ref] Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected..., Benhamou [/bib_ref] [bib_ref] Slower fibrosis progression in HIV/HCV-coinfected patients with successful HIV suppression using antiretroviral..., Brau [/bib_ref] ; (ii) increased risk for hepatic decompensation [bib_ref] Hepatic decompensation in antiretroviral-treated patients co-infected with HIV and hepatitis C virus..., Lo Re [/bib_ref] [bib_ref] Effect of antiretroviral therapy on liver-related mortality in patients with HIV and..., Qurishi [/bib_ref] ; c) higher viral loads [bib_ref] Viral kinetics in hepatitis C or hepatitis C/human immunodeficiency virusinfected patients, Sherman [/bib_ref] and (iii) risk of DDIs, particularly between HCV DAA agents and antiretroviral agents [bib_ref] Drug-drug interactions during antiviral therapy for chronic hepatitis C, Kiser [/bib_ref] [bib_ref] Direct-acting antiviral agents for hepatitis C virus infection, Kiser [/bib_ref]. Phase 2 and Phase 3 trial data oppose the need for a 'special population' designation in HIV/HCV co-infected populations, as treatment response rates in coinfected patients are similar to mono-infected subjects with HCV. In the PHOTON-1 trial, treatment-na€ ıve patients with HCV/HIV co-infection were treated with SOF/RBV for 24 weeks if genotype 1 and 12 weeks if genotype 2 or 3. Among those with HCV genotype 1, the SVR12 was 75%. It was 88% in genotype 2 and 67% in genotype 3 [bib_ref] Sofosbuvir plus ribavirin for HCV genotype 1-3 infection in HIV coinfected patients..., Naggie [/bib_ref]. SVR12 data among co-infected patients treated with LDV/SOF for 12 weeks yielded 96% response rates among a cohort of 335 patients, with 95% seen in na€ ıve, 97% in experienced, 96% without cirrhosis and 94% with cirrhosis [bib_ref] Ledipasvir/sofosbuvir for 12 weeks in patients coinfected with HCV and HIV-1, Naggie [/bib_ref]. Other regimens continue to show efficacy comparable to mono-infected subjects. Overall SVR12 rates of 97% were achieved with 12 weeks of DCV/SOF in HIV/ HCV co-infected subjects in ALLY-2. SVR rates were highly independent of race, baseline HCV RNA, advanced fibrosis, and prior treatment exposure [bib_ref] Daclatasvir in combination with sofosbuvir for HIV/HCV coinfection: ALLY-2 study, Wyles [/bib_ref]. This study also included an 8-week duration for treatment-na€ ıve subjects, 10% of whom had cirrhosis. However, relapse rates were higher with an SVR12 of 76%. At this time, shortened treatment duration (8 week) cannot be recommended with this or any other regimen. Of note, antiretroviral regimens were quite limited in some trials. In other DAA studies, alternative dosing regimens were required to adjust for DDIs. In the simeprevir Phase 3 C212 trial, patients were not permitted to use any HIV PIs or efavirenz [bib_ref] Simeprevir (TMC435) with pegylated interferon/ribavirin in patients coinfected with HCV genotype 1..., Dieterich [/bib_ref]. These restrictions do not reflect real-world use of antiretroviral regimens. Future regimens, such as DCV/SOF, will be compatible with a wide range of antiretrovirals. # Discussion The panel agreed that co-infected patients should remain as a 'special population' based on the importance of DDI and monitoring the effects of treatment on HIV disease. However, from an efficacy standpoint, HIV/HCV co-infected patients do as well with potent DAA regimens when treated for 12 weeks as do monoinfected patients. Rationale and definition of statement HCV therapy is now characterized by short courses of safe and well-tolerated, all-oral regimens with SVR rates exceeding 90% [bib_ref] Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection, Afdhal [/bib_ref] [bib_ref] ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis, Poordad [/bib_ref] [bib_ref] Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without..., Kowdley [/bib_ref] [bib_ref] ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV, Ferenci [/bib_ref] [bib_ref] Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin, Feld [/bib_ref]. However, the effect of therapy will be blunted by ongoing deficits in the diagnosis, linkage to care and treatment of chronic HCV infection. Expansion of HCV treatment to nonspecialty providers such as primary care physicians (PCPs) may help address the substantial burden of HCV infection in the USA. ## Summary of evidence Sparse data exist to support or oppose the role of PCPs in the management of HCV. Traditionally, HCV treatment has remained within the realm of specialists. However, with the transition from highly complex regimens to simplified regimens, an opportunity exists to expand the treater pool to non-specialty providers. The need to expand treatment capacity is underscored by profound deficits at each successive step within the HCV care cascade: screening, diagnosis, linkage to care, treatment initiation, treatment completion and achievement of SVR [bib_ref] The new paradigm of hepatitis C therapy: integration of oral therapies into..., Afdhal [/bib_ref] [bib_ref] Awareness of infection, knowledge of hepatitis C, and medical follow-up among individuals..., Denniston [/bib_ref] [bib_ref] Hepatitis C in the United States, Holmberg [/bib_ref]. Among 99 166 veterans with HCV, 60.0% underwent genotype confirmation, [bib_ref] All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C..., Nelson [/bib_ref].9% had no contraindications to HCV treatment, 11.6% received standard HCV treatment (PEG-IFN/RBV), 6.4% completed treatment and a sobering 3.5% achieved SVR [bib_ref] Gaps in the achievement of effectiveness of HCV treatment in national VA..., Kramer [/bib_ref]. A systematic review and meta-analysis of 10 studies addressing the USA, HCV care cascade revealed that only 50% of patients were diagnosed and aware of their infection, 43% had access to outpatient care, 27% had HCV RNA confirmation, 16% were prescribed treatment and 9% achieved SVR [bib_ref] Lo Re V, 3rd. The treatment cascade for chronic hepatitis C virus..., Yehia [/bib_ref]. Although no controversy exists regarding the important role of PCPs in the care cascade, questions remain regarding the level of motivation, knowledge base and capacity of PCPs in treating HCV. Literature suggests significant deficits in both knowledge and current practices of PCPs and trainees regarding the diagnosis and management of HCV. Despite the ability to identify risk factors, few PCPs screen patients for risk factors, test for HCV in patients with risk factors, provide hepatitis A and B vaccinations, or refer infected patients to providers who have experience in antiviral therapy [bib_ref] Hepatitis C knowledge among primary care residents: is our teaching adequate for..., Coppola [/bib_ref] [bib_ref] Family physicians' knowledge and screening of chronic hepatitis and liver cancer, Ferrante [/bib_ref] [bib_ref] Current care of hepatitis C-positive patients by primary care physicians in an..., Nicklin [/bib_ref] [bib_ref] Identification and management of hepatitis C patients in primary care clinics, Shehab [/bib_ref] [bib_ref] Current practice patterns of primary care physicians in the management of patients..., Shehab [/bib_ref] [bib_ref] Management of hepatitis C patients by primary care physicians in the USA:..., Shehab [/bib_ref]. Only a small minority of PCPs is familiar with existing therapies [bib_ref] Management of hepatitis C patients by primary care physicians in the USA:..., Shehab [/bib_ref] , and a recent survey revealed that 56% of PCPs did not believe HCV can be cured. Furthermore, approximately three-quarters of surveyed PCPs were unaware that the FDA had approved oral HCV therapy, and approximately one-third expect to always refer HCV patients to a specialist for management (79). Many reports describe the ability to integrate antiviral therapy within primary care. Unfortunately, most are case reports and demonstration models within specific clinical contexts, such as methadone clinics, community health centers or prison clinics [bib_ref] Developing a modified directly observed therapy intervention for hepatitis C treatment in..., Bruce [/bib_ref] [bib_ref] Clinical trial: a primary-care-based model for the delivery of anti-viral treatment to..., Jack [/bib_ref] [bib_ref] Successful treatment of chronic hepatitis C with pegylated interferon in combination with..., Litwin [/bib_ref]. The most robust support comes from PROJECT ECHO, a prospective observational cohort study in which outcomes of 261 patients managed by PCPs at 21 rural Liver International (2016) satellite clinics were compared to 146 patients managed by the primary university, which supervised HCV case management via telemedicine for the satellite clinics. The SVR outcomes between patients managed by specialty and PCPs were equivalent [bib_ref] Outcomes of treatment for hepatitis C virus infection by primary care providers, Arora [/bib_ref]. Importantly, the ECHO model relies upon formal, structured partnership between the specialty providers with HCV expertise and PCPs [bib_ref] Expanding primary care capacity to treat hepatitis C virus infection through an..., Mitruka [/bib_ref]. Literature suggests that adherence to general Medicare Physician Quality Reporting System (PQRS) HCV quality measures (HCV RNA confirmation, HAV and HBV vaccination) is higher for patients receiving care by both a specialist and PCP than by either a specialist or PCP alone, whereas adherence to treatment-related quality measures (antivirals prescribed, HCV genotype before treatment, HCV RNA at baseline and treatment week 12) was higher for specialists with or without PCP care than was seen in PCP care alone [bib_ref] Quality of care in patients with chronic hepatitis C virus infection: a..., Kanwal [/bib_ref]. Individuals with optimum pretreatment care were more likely to receive antiviral therapy (OR 3.2, 95% CI 2.9-3.5), complete treatment (OR 1.26, 95% CI 1.13-1.43) and achieve SVR (OR 1.3, 95% CI 1.01-1.65) [bib_ref] Process of care for hepatitis C infection is linked to treatment outcome..., Kanwal [/bib_ref]. Patients seen by a specialist are more likely to be prescribed antiviral therapy (OR 9.34, 95% CI 8.03-10.87) (93), although site experience (defined as ≥200 patients treated with antiviral agents), not provider type, was associated with treatment completion (OR 1.87, 95% CI 1.56-2.24) (94). In a large retrospect cohort study of US veterans, only low site experience (defined as <25 treated patients) was associated with SVR (OR 0.71, 95% CI 0.56-0.90); no differences were observed by management (gastroenterology or hepatology, infectious diseases or internal medicine) [bib_ref] Predictors of response of US veterans to treatment for the hepatitis C..., Backus [/bib_ref]. Simple and effective regimens may amplify treatment experience and success rates across all treater groups. # Discussion The HCV Council panel recognizes that the evidence to support or oppose this statement is poor. However, based on expert consensus, the majority argues that HCV treatment should remain within the realm of specialists who have the requisite knowledge, clinical judgment and treatment experience required to provide the best patient care. The current antiviral paradigm remains complex, with the need for an expert clinician to carefully consider multiple factors in guiding patients in treatment decisions, such as HCV genotype and/or subtype, stage of liver fibrosis, prior treatment experience, HIV co-infection and liver disease status (e.g. decompensation, liver cancer, post-transplant). The Council fully anticipates that as treatment transitions to increasingly simple, short and effective regimens which form the basis for 'one size fits all' across genotypes and patient characteristics, the growing role of PCPs in HCV treatment will be welcomed and considered an inevitable and necessary step in our goal of HCV eradication in the USA. # Conclusion All-oral regimens have become the new standard of care for chronic HCV and have already demonstrated remarkable rates of SVR with well-tolerated, convenient dosing across a broad population of patients who previously could not tolerate nor benefit from IFN-based regimens. Despite the rapid accumulation of data and the prompt revisions of treatment recommendations, numerous questions regarding optimal management of certain populations and clinical scenarios remain unanswered. The discussion above provides a summary of evidenced-based expert opinion that may help guide clinicians as additional information is developed. [fig] Figure 1: 3D (paritaprevir/r-ombitasvir + dasabuvir) ± ribavirin (RBV). Ferenci et al. (24). Liver International (2016) [/fig] [fig] Statement 6: due to the high costs of medications, only patients with advanced fibrosis should be offered treatment with all-oral regimens for HCV [/fig] [fig] Statement 7: given the high-efficacy and low-viral breakthrough rates, on-treatment viral load monitoring is no longer requiredRationale and definition of statementDirect-acting antiviral agent studies have reported viral clearance rates of nearly 100% on therapy, eliminating [/fig] [fig] Figure 2: Effects of sustained virological response (SVR) on risk of death. Meta-analysis of 129 studies; RR substantially reduced for all groups with SVR. Adapted from Saleem et al. (49). Liver International (2016) [/fig] [fig] Statement 8: patients with decompensated cirrhosis should be treated with an all-oral regimen for HCV to improve survival [/fig] [fig] Figure 3: Ledipasvir/sofosbuvir + ribavirin (RBV) in patients with decompensated cirrhosis: preliminary result of a prospective, multicenter study. Randomized to sofosbuvir (SOF) + ledipasvir (LDV) (600 mg w/escalation) for 12 or 24 weeks. Patients with G1 or G4 and decompensated cirrhosis. Most patients with MELD > 10 (MELD = 16-20 in 10-46%). Median albumin = 2.6-3.0 g/l; Median platelets = 71-88 K. Flamm et al. (56). [/fig] [table] Table 1: HCV Council statements for evaluation Workshop I: clinical management and treatment strategies: utilizing the new SOC in HCV [/table] [table] Table 2: Council voting schemes [/table] [table] Table 3: Sustained virological response between cirrhotic and non-cirrhotic genotype 1 patients [/table]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/liv.12993	HCV Council 2014, like its predecessor HCV Council 2011, assembled leading clinicians and researchers in the field of hepatitis C to critically evaluate current data regarding best practices for managing patients with chronic hepatitis C virus (HCV).
0357d0cba89ec02d7ff73ad7098f5e981f9acab7	pubmed	Clinical Practice Guidelines From the Association for the Advancement of Blood and Biotherapies (AABB): COVID-19 Convalescent Plasma	Clinical Practice Guidelines From the Association for the Advancement of Blood and Biotherapies (AABB): COVID-19 Convalescent Plasma [bib_ref] The convalescent sera option for containing COVID-19, Casadevall [/bib_ref] [bib_ref] Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment, Luke [/bib_ref] [bib_ref] Deployment of convalescent plasma for the prevention and treatment of COVID-19, Bloch [/bib_ref] [bib_ref] The convalescent sera option for containing COVID-19, Casadevall [/bib_ref] [bib_ref] Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment, Luke [/bib_ref] [bib_ref] Deployment of convalescent plasma for the prevention and treatment of COVID-19, Bloch [/bib_ref] [bib_ref] Deployment of convalescent plasma for the prevention and treatment of COVID-19, Bloch [/bib_ref] [bib_ref] COVID-19 convalescent plasma: interim recommendations from the AABB, Cohn [/bib_ref] ## Editorial comment ## Web-only supplement Annals.org Annals of Internal Medicine © 2022 American College of Physicians 1 ## Annals of internal medicine ## Clinical guideline less than 0.5%. In addition, there have been no reported cases of transfusion-transmitted viral infections or antibody-dependent enhancement in either CCP trials or the U.S. Expanded Access Program. The Association for the Advancement of Blood and Biotherapies (AABB) issued interim recommendations in early 2021 [bib_ref] COVID-19 convalescent plasma: interim recommendations from the AABB, Cohn [/bib_ref]. However, limited data from randomized controlled trials (RCTs) were available at the time, and the recommendations were based on consensus of expert opinion. Many RCTs have subsequently been completed, making it timely to do a more rigorous and formal evaluation. A systematic review was done, and the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method was used to develop these guidelines. # Methods ## Target population These guidelines provide recommendations for clinicians who are treating persons infected with SARS-CoV-2 and who are candidates for CCP transfusion. ## Guideline development process The AABB Board of Directors commissioned a committee of experts to draft clinical practice guidelines. Consistent with previous clinical practice guidelines from the AABB, the committee conducted a formal systematic review and meta-analysis of the data and used the GRADE method to formulate the current recommendations. The committee focused exclusively on randomized trial data to minimize the risk of bias. The guidelines committee comprised experts with understanding of CCP and the GRADE method (Supplement , available at Annals.org). There were 9 current or former members of the AABB clinical transfusion medicine committee (C. , and a patient representative (G.B.). As defined by the AABB conflict of interest policy (10), all committee members were required to disclose financial, professional, intellectual, or personal conflicts, with no substantial conflicts of interest identified. The data were analyzed, and the overall quality of evidence for each outcome was assessed by the 3 nonvoting members of the committee (C.I., N.K., N.S.) who had no involvement with any CCP trials and are authors of the Cochrane Reviews. Five members (L.J.E., A.C., E.M.B., T.W.R., A.A.R.T.) were either principal investigators or helped design a CCP trial. All members voted on each recommendation with the following exceptions: Drs. Tobian, Casadevall, and Bloch were excluded from voting on the recommendations for outpatient and prophylactic use, and Drs. Estcourt and Rice were excluded from voting on the recommendations for inpatient use. A strong recommendation required more than 70% of the committee to vote "strongly for" the recommendation, and a weak recommendation required more than 70% of the committee to vote "for" the recommendation. Disagreements were handled by additional discussion and final voting. ## Evidence review and grading ## Systematic review The guidelines are based on separately published living systematic reviews of the literature on CCP published by Cochrane [bib_ref] Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic..., Piechotta [/bib_ref]. The systematic review was subsequently updated by Cochrane Haematology for these guidelines. This included all RCTs evaluating CCP that were available as either preprint or published articles between 1 January 2019 and 26 January 2022 (Appendix available at Annals.org). The intervention group was CCP from donors who had previously tested positive for SARS-CoV-2. The control groups included persons randomly assigned to nonimmune plasma, normal saline, or standard of care. The trials tested the efficacy of CCP for prophylaxis, patients in the outpatient setting, and hospitalized patients. Subgroup analyses were done to evaluate patients with SARS-CoV-2 antibodies detected at baseline compared with those who did not have antibodies, and a second subgroup analysis included patients with preexisting immunosuppression versus immunocompetent patients. The committee also evaluated the following 2 additional subgroups: patients with severity level 4 COVID-19 according to the World Health Organization (WHO) Clinical Progression Scale (Supplement , available at Annals.org) and duration of symptom onset 7 days or less versus greater than 7 days before receiving CCP; the committee did not vote on these categories (Supplement Methods, available at Annals.org). Before reviewing the data, the committee voted on the most important primary outcomes for the different trial populations. The primary outcomes in the systematic review were SARS-CoV-2 infection status (postexposure prophylaxis trial), hospitalization or all-cause mortality within 28 days (outpatient trials), all-cause mortality within 28 days, and progression or need for invasive mechanical ventilation (WHO stage ≥7) (inpatient trials). Secondary outcomes included transfusion-related reactions, serious adverse events, ventilator-free days, admission to the intensive care unit, and duration of hospitalization. Each clinical trial was assessed for the risk of bias for sequence generation, allocation concealment, blinding, and incomplete outcome data using methods recommended by Cochrane. Additional details are also available in the Supplement (available at Annals. org). Statistical heterogeneity was assessed by both the I 2 and x 2 tests. All analyses were done using Review Manager Web 2022 (Cochrane). For dichotomous outcomes, we calculated the relative risks (RRs) and the corresponding 95% CIs in the intervention group compared with the control group. Meta-analyses were calculated for each comparison and outcome using fixedeffects and random-effects models. ## Clinical guideline convalescent plasma recommendations ## Rating certainty of evidence The committee used the GRADE method to develop the guidelines [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] [bib_ref] GRADE Working Group. Grading quality of evidence and strength of recommendations, Atkins [/bib_ref] [bib_ref] GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and..., Alonso-Coello [/bib_ref]. The evidence profiles were prepared to display data in terms of benefits and harms for the most important outcomes. The profiles provided judgments by the Cochrane group about the rating for risk of bias, consistency, directness, precision, and publication bias. The credibility of subgroup effects was assessed using the ICEMAN (Instrument to assess the Credibility of Effect Modification Analyses) criteria [bib_ref] Development of the Instrument to assess the Credibility of Effect Modification Analyses..., Schandelmaier [/bib_ref]. The panel reviewed the ratings and determined the strength of recommendations during the committee meeting. ## Values and preferences The committee made their recommendations under the assumption that patients would highly value avoiding risks for disease progression, morbidity, and mortality from COVID-19. Thus, when the data suggested that there was limited harm from CCP transfusions and that there was benefit to CCP, the panel was prepared to make recommendations for CCP. ## Guideline use and updates New evidence will be evaluated by the Cochrane living systematic review [bib_ref] Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic..., Piechotta [/bib_ref] and may be used to update these guidelines when substantial new findings are published. Use of CCP will depend on its availability at blood collection centers and hospital policies for treating patients with COVID-19. ## Comments and modification The first, second, and last authors prepared the initial draft guideline document, which was modified and approved by all committee members. Subsequently, the AABB Board of Directors reviewed and approved the guidelines. Before publication, the guidelines were publicly available on the AABB website. # Additional materials Additional resources for the clinical use of CCP are available at the AABB PLasma Antibody Network site (www. aabb.org/get-involved/committees-sections/transfusionmedicine-section/plasma-antibody-network). ## Disclaimer This clinical practice guideline is not intended as an absolute standard and will not apply to all individual decisions on when to transfuse or withhold CCP. ## Recommendations recommendation 1 (outpatient) The AABB suggests CCP transfusion in addition to the usual standard of care for outpatients with COVID-19 who are at high risk for disease progression (weak recommendation, moderate-certainty evidence). [bib_ref] Early outpatient treatment for Covid-19 with convalescent plasma, Sullivan [/bib_ref] [bib_ref] Fundación INFANT-COVID-19 Group. Early high-titer plasma therapy to prevent severe covid-19 in..., Libster [/bib_ref] [bib_ref] Prospective individual patient data meta-analysis of two randomized trials on convalescent plasma..., Millat-Martinez [/bib_ref]. The COnV-ert and CoV-Early trials were published as pooled analyses [bib_ref] Prospective individual patient data meta-analysis of two randomized trials on convalescent plasma..., Millat-Martinez [/bib_ref]. Data were requested, but only mortality data were available for the trial from the CoV-Early investigators (n = 406). The 3 other trials evaluated 1717 participants, including 860 who received 1 unit of high-titer CCP in the intervention group. Two trials compared CCP with a control group of saline placebo (n = 536), and 2 trials compared CCP with standard control plasma (n = 1587) (Supplement , available at Annals.org). All 4 trials required CCP transfusion within 9 days of symptom onset, but there was variability in CCP transfusion timing. The Argentinian trial by Libster and colleagues (21) did not report any adverse events in either the intervention or control group. The COnV-ert trial reported a 5.9% rate of transfusion-related adverse events in the CCP group. The U.S. trial by Sullivan and colleagues [bib_ref] Early outpatient treatment for Covid-19 with convalescent plasma, Sullivan [/bib_ref] reported a 0.2% adverse event rate in the CCP group and a 0.3% adverse event rate in the control plasma group. Most adverse events in all trials were due to mild allergic reactions that are commonly observed with plasma transfusion (Supplement , available at Annals.org). The trial analyses were stratified by the control group. For the outcome "need for either hospitalization requiring oxygenation (WHO ≥5) or death," the trial by Sullivan and colleagues showed a statistically significant reduction (RR, 0.46 [95% CI, 0.23 to 0.90]), as did the trial by Libster and colleagues, but the COnV-ert trial did not show a benefit [fig_ref] Figure 1: CCP transfusion for outpatients with COVID-19 [/fig_ref]. The overall certainty of evidence for the trial by Libster and colleagues and the COnV-ert trial was low and downgraded for serious imprecision, low number of participants, and wide CIs (Supplement , available at Annals.org). The overall certainty of the evidence was moderate for the trial by Sullivan and colleagues (Supplement , available at Annals.org). All 4 trials contributed data to the mortality at 28 days outcome (Supplement [fig_ref] Figure 1: CCP transfusion for outpatients with COVID-19 [/fig_ref] , available at Annals.org). There may be a reduction in mortality, but it was not statistically significant. ## Rationale for recommendation As the primary outcome of interest was preventing hospitalizations that required oxygen and death, and because the overall rate and severity of adverse events was low, the committee voted to suggest CCP for outpatients at high risk for disease progression as defined by the WHO. The trials by Libster and colleagues and Sullivan and colleagues provide very similar efficacy estimates. There was concern that data from the COnV-ert trial was not consistent with data from the trials by Libster and colleagues and Sullivan and colleagues. The COnVert data inconsistency could reflect the use of methylene blue treated CCP given that methylene blue has been ## Convalescent plasma recommendations ## Clinical guideline ## Annals.org Annals of Internal Medicine reported to interfere with immunoglobulin function [bib_ref] Photodynamic action of methylene blue on antipneumococcal serum, Ross [/bib_ref]. Overall, there is biological plausibility for CCP to be used as a passive immunotherapy for outpatients. This is based on early use of CP with other viruses; monoclonal antibody therapy has also been shown to reduce risk for hospitalization for outpatients recently infected with SARS-CoV-2 (24). ## Recommendation 2 (inpatient) The AABB recommends against CCP transfusion for unselected hospitalized persons with moderate or severe disease (strong recommendation, high-certainty evidence). This recommendation does not apply to immunosuppressed patients or those who lack antibodies against SARS-CoV-2. ## Evidence summary There were 28 randomized trials that evaluated CCP in hospitalized patients; 22 trials compared CCP versus placebo or standard of care, 5 trials compared CCP versus standard plasma, and 1 trial compared CCP versus immunoglobulin (Supplement , available at Annals.org) (25-52). Hospitalized patients included those requiring emergency department care, and therefore the study by was included within the inpatient studies. The primary predefined end points included all-cause mortality at 28 days and disease progression defined as the need for invasive mechanical ventilation or death (WHO stage ≥7). The trials were done among hospitalized patients with moderate or severe COVID-19 in North America, South America, Europe, Africa, and Australia and involved 19 625 participants. One to 3 units of CCP were transfused in the intervention group of the trials. Although nearly all trials used high-titer CCP, there was substantial variability in the antibody profiles of CCP provided. There was also variability as to when the CCP was transfused, ranging from the emergency department to more than a week after hospital admission. The transfusion-related adverse events in the intervention group ranged from 0% to 15%. Most of the reported events were minor, transient transfusion reactions. However, 2 trials reported 3 possible deaths each related to CCP (Supplement , available at Annals.org) (25, 29). Among unselected hospitalized patients receiving CCP compared with either placebo or standard of care, CCP did not affect all-cause mortality at 28 days (RR, 0.97 [CI, 0.90 to 1.04]) [fig_ref] Figure 2: CCP transfusion versus standard of care or placebo for hospitalized patients [/fig_ref]. The overall certainty of the evidence was high (Supplement , available at Annals.org). Among unselected hospitalized patients receiving CCP compared with standard plasma, CCP did not affect all-cause mortality at 28 days (RR, 0.73 [CI, 0.45 to 1.19]) (Supplement [fig_ref] Figure 2: CCP transfusion versus standard of care or placebo for hospitalized patients [/fig_ref] , available at Annals.org). The overall certainty in the evidence was low (Supplement ## Outcome Convalescent plasma may have little to no effect on need for hospitalization with at least need for oxygen therapy up to day 28. We did not perform a meta-analysis because of heterogeneity between the studies. Convalescent plasma probably reduces the risk for admission to hospital with need for at least oxygen therapy or death up to day 28. , available at Annals.org). The CCP also had no effect on clinical improvement (that is, weaning or liberation of mechanical ventilation) when compared with placebo or standard of care (RR, 1.05 [CI, 0.96 to 1.14]) or plasma (RR, 5.59 [CI, 0.29 to 108.38]) (Supplement [fig_ref] Figure 3: CCP transfusion versus standard of care or placebo stratified by status of... [/fig_ref] , available at Annals.org). ## Clinical guideline convalescent plasma recommendations ## Rationale for recommendation The CCP seemed to be relatively safe as the vast majority of adverse events were minor, transient reactions despite the very rare possibility of death. However, there was no consistent evidence showing that CCP for unselected hospitalized patients reduces mortality or leads to clinical improvement. These data are consistent with biological plausibility that viral neutralization would have no effect on persons with advanced disease who are in the postviral phase of COVID-19 with systemic inflammation and cytokine storm. ## Recommendation 3 (inpatient) The AABB suggests CCP transfusion in addition to the usual standard of care for hospitalized patients who do not have SARS-CoV-2 antibodies detected at admission (weak recommendation, low-certainty evidence). ## Evidence summary There were 6 randomized trials of hospitalized patients with data on whether SARS-CoV-2 antibodies were present at baseline to assess whether CCP conferred benefit among patients who lacked antibodies compared with those with antibodies (25, 27-30, 52). There were 2 trials that assessed whether CCP was beneficial for this subgroup using a composite outcome of either need for invasive mechanical ventilation or mortality at 28 days (25, 29). These 2 trials had data for 9472 participants. Among those with antibodies, there was no difference in need for mechanical ventilation or mortality [fig_ref] Figure 1: CCP transfusion for outpatients with COVID-19 [/fig_ref] ## + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + ## Twenty of the 22 included studies that compared convalescent plasma versus standard of care or placebo in hospitalized patients reported this outcome. ## A b c d e f The primary outcome was all-cause mortality at day 28. For risk of bias assessment explanation and GRADE assessment, see the Supplement Methods (available at Annals.org). df = degrees of freedom; GRADE = Grading of Recommendations Assessment, Development and Evaluation; M-H = Mantel-Haenszel. ## Convalescent plasma recommendations ## Clinical guideline ## Annals.org Annals of Internal Medicine between those who received CCP and those who received standard of care or placebo [fig_ref] Figure 3: CCP transfusion versus standard of care or placebo stratified by status of... [/fig_ref]. However, among hospitalized patients who lacked SARS-CoV-2 antibodies at baseline, CCP decreased the need for mechanical ventilation or mortality compared with standard of care or placebo (RR, 0.91 [CI, 0.84 to 0.98]). For this subgroup difference, the I 2 was 82.6% with P = 0.020. The overall credibility of the effect modification was moderate. Among the 5 trials that evaluated only mortality, similar direction of effect was seen favoring CCP use for those persons who lacked SARS-CoV-2 antibodies at the time of hospitalization (Supplement [fig_ref] Figure 4: CCP transfusion versus standard of care or placebo stratified by immunosuppression status [/fig_ref] , available at Annals.org). ## Rationale for recommendation Although these subgroup data are in contrast to the overall unselected hospitalized patient data, the committee found that there was moderate certainty of a subgroup difference to suggest that CCP should be transfused to hospitalized patients without SARS-CoV-2 antibodies at baseline. The subgroup difference was seen with both random-and fixed-effects models. Because of the large quantity of data originating from the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial, the certainty of the evidence was high. Evaluating the presence or absence of antibodies was also a prespecified outcome for many of the trials. Finally, there is biological plausibility for CCP being most beneficial for those without antibodies. Besides the recipients initially lacking antibodies, the humoral response is not as effective when it initially begins to develop. The SARS-CoV-2 antibody response improves with time, including increased avidity and isotype switching, that likely leads to improved viral neutralization [bib_ref] SARS-CoV-2 antibody avidity responses in COVID-19 patients and convalescent plasma donors, Benner [/bib_ref]. Throughout history, CP has consistently been most effective when provided early in the course of disease. Observational data have also shown that CCP is most effective when provided earlier to hospitalized patients [fig_ref] Figure 1: CCP transfusion for outpatients with COVID-19 [/fig_ref] ## Likely effect modification use separate effects for each subgroup but note remaining uncertainty The evidence suggests that CP has no beneficial effect on invasive mechanical ventilation/death by day 28 compared with placebo/standard of care in patients with positive results for antibodies at baseline. ## The evidence suggests that cp may reduce the frequency of invasive mechanical ventilation/death by day 28 compared with placebo/standard of care in patients with positive results for antibodies at baseline. § agarwal and colleagues has little effect on the overall effect, 34% of plasma units had no detectable nabs, the maximum nab titer was 1:80, which is below eu and fda recommendation. agarwal and colleagues' study was done in a middle-income country (india) in patients with moderate-severity disease and at the very beginning of the pandemic in 2020. patients received 2 doses (200 ml). no big difference to the recovery collaborative group study (high-income countries receiving hightiter plasma, all hospitalized patients). ## \|\| agarwal and colleagues has little effect on the overall effect, 34% of plasma units had no detectable nabs, the maximum nab titer was 1:80, which is below eu and fda recommendation. agarwal and colleagues' study was done in a middle-income country (india) in patients with moderate-severity disease and at the very beginning of the pandemic in 2020. patients received 2 doses (200 ml). no big difference to the recovery collaborative group study (high-income countries receiving hightiter plasma, all hospitalized patients). ## Notes * the analysis is based on within-trial comparison; effect modification is not similar between trials; however, agarwal and colleagues differed regarding the intervention (low or no nab titer for donor plasma). † number of trials small (both within and between trial). only 2 trials reported the subgroup. ‡ interaction ## Clinical guideline Convalescent Plasma Recommendations [bib_ref] Convalescent plasma antibody levels and the risk of death from Covid-19, Joyner [/bib_ref] [bib_ref] Convalescent plasma associates with reduced mortality and improved clinical trajectory in patients..., Egloff [/bib_ref]. Thus, the committee noted that in immunocompetent patients, the lack of a detectable antibody response could be used as a surrogate for early infection. ## Recommendation 4 (inpatient) The AABB suggests CCP transfusion in addition to the usual standard of care for hospitalized patients with preexisting immunosuppression (weak recommendation, low-certainty evidence). ## Evidence summary There were 3 randomized trials that evaluated whether CCP was efficacious among hospitalized patients with preexisting immunosuppression (cancer, steroids, B-celldepleting therapies, and so forth) [bib_ref] PLACID Trial Collaborators. Convalescent plasma in the management of moderate Covid-19 in..., Bar [/bib_ref] [bib_ref] Effects of potent neutralizing antibodies from convalescent plasma in patients hospitalized for..., Gharbharan [/bib_ref] [bib_ref] Writing Committee for the REMAP-CAP Investigators. Effect of convalescent plasma on organ..., Estcourt [/bib_ref]. The 3 trials had immune status data on 2210 enrolled participants. A forest plot shows there was no difference in mortality at 28 days among immunocompetent persons who received CCP versus the standard of care or placebo [fig_ref] Figure 4: CCP transfusion versus standard of care or placebo stratified by immunosuppression status [/fig_ref]. However, among immunosuppressed hospitalized patients at baseline, CCP decreased mortality compared with standard of care or placebo (RR, 0.71 [CI, 0.51 to 0.98]). For this subgroup difference, the I 2 was 64.5%% with P = 0.090. There was no evidence of effect modification. By ICEMAN criteria, the overall credibility of the subgroup effect was low. This was likely because of the small numbers and wide CIs so there was remaining uncertainty. ## Rationale for recommendation Although the subgroup difference was not statistically significant, the committee suggests with low-certainty evidence that CCP should be provided in addition to the usual standard of care for hospitalized patients with preexisting immunosuppression. Most of the data were derived from the REMAP-CAP (Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia) trial, which had a prespecified outcome of evaluating CCP efficacy in immunosuppressed patients. Patient preferences were considered because this patient population has limited therapeutic options. Patients with preexisting immunosuppression do not respond well to SARS-CoV-2 vaccines and are also at the highest risk for severe complications from COVID-19 [bib_ref] Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant..., Boyarsky [/bib_ref] [bib_ref] Patient trajectories among persons hospitalized for COVID-19. A cohort study, Garibaldi [/bib_ref]. In addition, there is biological plausibility that CCP would be beneficial as CCP provides antibodies to help neutralize the virus among persons who are not able to mount an antibody response. ## Recommendation 5 (prophylaxis) The AABB suggests against prophylactic CCP transfusion for uninfected persons with close contact exposure to a person with COVID-19 (weak recommendation, low-certainty evidence). ## Evidence summary One trial evaluated 168 adults across 19 sites in the United States who had close contact exposure to a person with confirmed COVID-19 in the previous 5 days and a negative SARS-CoV-2 polymerase chain reaction test within the 24 hours before transfusion (Supplement , available at Annals.org) [bib_ref] Transfusing convalescent plasma as post-exposure prophylaxis against SARS-CoV-2 infection: a double-blinded, phase..., Shoham [/bib_ref]. Persons were randomly assigned to 1 unit of high-titer CCP (n = 87) or standard plasma (n = 81). The median time from exposure to transfusion was 2 days (interquartile range, 1 to 4 days). A forest plot [fig_ref] Figure 5: CCP transfusion versus standard plasma as prophylaxis to prevent infection with SARS-CoV-2... [/fig_ref] [fig_ref] Figure 5: CCP transfusion versus standard plasma as prophylaxis to prevent infection with SARS-CoV-2... [/fig_ref] , available at Annals.org). There were 28 adverse events in the CCP group and 58 in the control group (Supplement , available at Annals.org). The overall quality of the RCT evidence for infection within 30 days was low (Supplement , available at Annals.org). The data were downgraded 2 levels for serious imprecision, low number of participants and events, and wide CIs. ## Rationale for recommendation There was no consistent evidence showing that 1 unit of high-titer CCP prevents SARS-CoV-2 infection among highly exposed persons. The CCP data are in contrast to data showing that monoclonal antibodies prevent SARS-CoV-2 infection (59). The differences between CCP and monoclonal antibodies could be due to the quality and/or quantity of antibody present in CCP, different trial populations, and the limited data from only 1 CCP trial. The AABB suggests against prophylactic CCP transfusion because there was no conclusive evidence showing the benefits of CCP in this setting. ## Good clinical practice statement Both observational data [bib_ref] Convalescent plasma antibody levels and the risk of death from Covid-19, Joyner [/bib_ref] [bib_ref] Convalescent plasma associates with reduced mortality and improved clinical trajectory in patients..., Egloff [/bib_ref] [bib_ref] Significantly decreased mortality in a large cohort of coronavirus disease 2019 (COVID-19)..., Salazar [/bib_ref] and randomized trial data showed that CCP is most effective when transfused to infected patients at the earliest possible time and with high neutralizing antibody titers. However, the randomized trial data were difficult to interpret for hospitalized patients with symptoms present less than 7 days or patients with stage 4 COVID-19 severity according to the WHO Clinical Progression Scale (Supplement [fig_ref] Figure 1: CCP transfusion for outpatients with COVID-19 [/fig_ref] , available at Annals.org). For outpatients, it is good practice to transfuse CCP within 5 days of symptom onset, and CCP transfusion continues to be effective up to 9 days after symptom onset [bib_ref] Early outpatient treatment for Covid-19 with convalescent plasma, Sullivan [/bib_ref]. In addition to the timing, high-titer CCP units are the most effective [bib_ref] Fundación INFANT-COVID-19 Group. Early high-titer plasma therapy to prevent severe covid-19 in..., Libster [/bib_ref] [bib_ref] Convalescent plasma antibody levels and the risk of death from Covid-19, Joyner [/bib_ref] , and high-titer CCP can now be obtained from persons who have had a primary infection and vaccination. # Discussion During the initial waves of the pandemic, CCP became one of the most commonly used therapies despite limited data on its efficacy. Now that data are available, the AABB suggests high-titer CCP transfusion for infected patients who are outpatients with risk for progression, those without detectable SARS-CoV-2 antibodies, and those who are immunosuppressed. The AABB recommends against CCP transfusion for those patients with later-stage COVID-19. The beneficial effects of CCP are primarily associated with its neutralizing antibodies, which target SARS-CoV-2 and assist in viral clearance [bib_ref] Coronavirus disease 2019 convalescent plasma and the severe acute respiratory syndrome coronavirus..., Bloch [/bib_ref] [bib_ref] Sex, age, and hospitalization drive antibody responses in a COVID-19 convalescent plasma..., Klein [/bib_ref]. Thus, persons who benefit the most from CCP are those treated early and who have not yet developed their own neutralizing antibodies. As SAR-CoV-2 antibody detection is easily available at most hospitals and also by point-of-care assays, the recommendations could be easily implemented. In addition to neutralization, CCP antibodies provide additional benefits, as they can also stimulate phagocytosis, complement activation and antibody dependent cellular cytotoxicity against SARS-CoV-2 [bib_ref] Markers of polyfunctional SARS-CoV-2 antibodies in convalescent plasma, Natarajan [/bib_ref]. Overall, the efficacy is likely related to antibody avidity, the inflammatory environment, and multiple functions of the antibodies in CCP [bib_ref] SARS-CoV-2 antibody avidity responses in COVID-19 patients and convalescent plasma donors, Benner [/bib_ref] [bib_ref] Markers of polyfunctional SARS-CoV-2 antibodies in convalescent plasma, Natarajan [/bib_ref] [bib_ref] Cytokine and chemokine levels in coronavirus disease 2019 convalescent plasma, Bonny [/bib_ref]. There are several advantages of CCP, especially as SARS-CoV-2 evolves and new variants of concern (VOCs) emerge. In vitro data suggest that high-titer CCP continues to be effective against the Omicron VOC (66, 67), which has many mutations in the spike glycoprotein. However, data indicate that the Omicron VOC and 2. Also, CCP can be collected from persons who have been both infected with SARS-CoV-2 and vaccinated, thus ensuring very high titers of neutralizing antibodies. Finally, CCP is relatively easy to collect, making it a less expensive therapeutic option than other passive antibody therapies. There are limitations to these guidelines. Although the committee waited until most of the RCT data were available, there are still ongoing trials, and the evidence base remains incomplete. There is substantial variability in the quantity of neutralizing antibodies present in CCP units [bib_ref] Sex, age, and hospitalization drive antibody responses in a COVID-19 convalescent plasma..., Klein [/bib_ref] , and it is difficult to compare antibody titers across all trials because different assays were used to quantify the presence of antibodies. In addition, the ideal quantity of CCP needed is unknown. Fortunately, the FDA's emergency use authorization has now set minimum standards for titers permitted for CCP to be used, and these levels are higher than most of the CCP used in the trials. Many of the trials were initiated near the beginning of the pandemic, which led to confounding factors that have affected the trial results; these include changes in therapies and availability of highly effective vaccines. In addition, there was duplication of RCT results for late stages of disease and limited data available for early disease when CCP is most effective. Limited data are available on the role of CCP in the vaccinated population. The applicability of these guidelines may also vary depending on the disease severity of each VOC. However, CCP likely has the most potential with the current VOCs for persons with preexisting immunosuppression who do not respond well to vaccination. In comparison with other CCP guidelines, the recommendations and authorizations from other societies and government agencies vary often by the timing of their most recent evaluation. In December 2021, the WHO issued 2 strong recommendations against CCP use for either patients with nonsevere COVID-19 or patients with severe COVID-19 (69). The WHO only recommends CCP use in the context of clinical trials. In April 2022, the National Institutes of Health COVID-19 Treatment Guidelines Panel recommended against CCP for immunocompetent hospitalized patients and stated that there is insufficient evidence to recommend either for or against CCP for outpatients or immunosuppressed hospitalized patients (70). In March 2022, the Infectious Diseases Society of America issued a strong recommendation against CCP for hospitalized patients with COVID-19. However, the Infectious Diseases Society of America has a conditional recommendation to transfuse CCP for ambulatory patients with mild to moderate COVID-19 who are at high risk for progression and without other treatment options. In December 2021, the FDA revised the emergency use authorization to limit the use of high-titer CCP for patients with COVID-19 who are immunosuppressed. The AABB recommendations for those without antibodies or who are immunosuppressed are consistent with the FDA but may differ from the other societies because AABB specifically focused on targeted hospital patient populations who could receive CCP rather than unselected groups, many later in their disease course. The AABB's recommendations for CCP use in outpatients at high risk for disease progression and against CCP use in unselected hospitalized patients with severe disease are consistent with other organizations. There are several areas of uncertainty that would benefit from additional clinical trials. Although the AABB suggests that CCP should be provided for immunosuppressed patients with COVID-19, the committee strongly encourages additional research in this area. Additional data are also needed about the role of CCP in combination with other antiviral therapies. In addition, there are limited data on the safety and efficacy of CCP in pediatric patients and pregnant women. In conclusion, the data about optimal use of CCP has dramatically advanced in the past 2 years. Similar to the historical data for use of CP in other viral outbreaks (1-4), randomized trial data have shown that CCP is most beneficial when the units contain high levels of neutralizing antibodies and are transfused early after infection. The AABB's recommendations are biologically consistent in supporting CCP transfusion for patients without antibodies. Coronavirus disease 2019 CP is relatively easy to obtain and often one of the first therapeutics available for emerging infections. These key principles will be important to incorporate during the current evolving pandemic and future epidemics. [fig] Figure 1: CCP transfusion for outpatients with COVID-19. [/fig] [fig] : Information provided directly by study authors. † Downgraded 2 levels for serious imprecision, low number of participants/events, and wide CIs. ‡ Downgraded 1 level for serious imprecision, low number of participants/events, and wide Cls. Only 1 of the 2 studies that assessed this comparison reported this outcome.The top panel compares CCP to standard of care or placebo with the outcome of need for hospitalization with need of at least oxygen by mask or nasal prongs or death. The bottom panel compares CCP to standard plasma with the outcome of need for hospitalization with need of at least oxygen by mask or nasal prongs or death. For risk of bias assessment explanation and GRADE assessment, see the Supplement Methods (available at Annals.org). For WHO grading, see SupplementTable 8(available at Annals.org). COnV-ert = Convalescent Methylene Blue Treated (MBT) Plasma for Early Treatment in Non-hospitalised Mild or Moderate COVID-19 Patients: a Randomized Double Blind Study; GRADE = Grading of Recommendations Assessment, Development and Evaluation; M-H = Mantel-Haenszel; WHO = World Health Organization. [/fig] [fig] Figure 2: CCP transfusion versus standard of care or placebo for hospitalized patients. tau 2 = 0.00; F 2 = 6.26, df = 7 (P = 0.51); I 2 = 0% Test for overall effect: Z = 0.58 (P = 0.56) Heterogeneity: tau 2 = 0.10; F 2 = 5.80, df = 3 (P = 0.12); I 2 = 48% Test for overall effect: Z = 1.09 (P = 0.27) Heterogeneity: tau 2 = 0.00; F 2 = 7.63, df = 7 (P = 0.37); I 2 = 8% Test for overall effect: Z = 0.49 (P = 0.62) Heterogeneity: tau 2 = 0.00; F 2 = 19.92, df = 19 (P = 0.40); I 2 = 5% Test for overall effect: Z = 0.89 (P = 0.39) Test for subgroup differences: F 2 = 1.02, df = 2 (P = 0.60); I [/fig] [fig] Figure 3: CCP transfusion versus standard of care or placebo stratified by status of SARS-CoV-2 antibodies at baseline. Study or Subgroup, Year (Reference) Antibodies detected at baseline Agarwal et al, 2020 (29) RECOVERY Collaborative Group, 2021 (25) Subtotal (95% CI) Total events Heterogeneity: F 2 = 0.24, df = 1 (P = 0.63); I 2 = 0% Test for overall effect: Z = 1.19 (P = 0.23) No antibodies detected at baseline Agarwal et al, 2020 (29) RECOVERY Collaborative Group, 2021 (25) Subtotal (95% CI) Total events Heterogeneity: F 2 = 0.52, df = 1 (P = 0.47); I 2 = 0% Test for overall effect: Z = 2.33 (P = 0. [/fig] [fig] Figure 4: CCP transfusion versus standard of care or placebo stratified by immunosuppression status. Study or Subgroup, Year (Reference) Bar et al, 2021 (28) Estcourt et al, 2021 (52) Gharbharan et al, 2021 (46) Subtotal (95% CI) Total events Heterogeneity: F 2 = 1.46, df = 2 (P = 0.48); I 2 = 0% Test for overall effect: Z = 2.06 (P = 0.04) Bar et al, 2021 (28) Estcourt et al, 2021 (52) Gharbharan et al, 2021 (46) Subtotal (95% CI) Total events Heterogeneity: F 2 = 9.58, df = 2 (P = 0.008); I 2 = 79% Test for overall effect: Z = 0.75 (subgroup differences: F 2 = 2.82, df = 1 (P = 0.09); effect modification-use overall effect for each subgroup but note remaining uncertainty Only 1 within-study comparison. † Number of trials small (both within and between trial). ‡ Interaction P > 0.05 for the random-effects model; difference between random effects and fixed effects. Notes Three studies reported immunosuppression at baseline subgroup data for this outcome. All studies in high-income countries. Studies by Estcourt and colleagues and Bar and colleagues in persons with severe disease. The primary outcome was all-cause mortality at 28 days in hospitalized patients. For risk of bias assessment explanation and GRADE assessment, see the Supplement Methods (available at Annals.org). df = degrees of freedom; GRADE = Grading of Recommendations Assessment, Development and Evaluation; ICEMAN = Instrument to assess the Credibility of Effect Modification Analyses; M-H = Mantel-Haenszel. [/fig] [fig] Figure 5: CCP transfusion versus standard plasma as prophylaxis to prevent infection with SARS-CoV-2 within 30 days. [/fig]	None	None	The Association for the Advancement of Blood and Biotherapies developed clinical practice guidelines for the appropriate use of COVID-19 convalescent plasma. This article describes the evidence and rationale for recommendations for inpatient and outpatient treatment and prophylaxis.
9a97fec57df4ebbd92d56b7cab6a2d498880e55a	pubmed	Recommendations for treatment of childhood non-severe pneumonia	Recommendations for treatment of childhood non-severe pneumonia WHO recommendations for early antimicrobial treatment of childhood pneumonia have been eff ective in reducing childhood mortality, but the last major revision was over 10 years ago. The emergence of antimicrobial resistance, new pneumonia pathogens, and new drugs have prompted WHO to assemble an international panel to review the literature on childhood pneumonia and to develop evidence-based recommendations for the empirical treatment of non-severe pneumonia among children managed by fi rst-level health providers. Treatment should target the bacterial causes most likely to lead to severe disease, including Streptoccocus pneumoniae and Haemophilus infl uenzae. The best fi rst-line agent is amoxicillin, given twice daily for 3-5 days, although co-trimoxazole may be an alternative in some settings. Treatment failure should be defi ned in a child who develops signs warranting immediate referral or who does not have a decrease in respiratory rate after 48-72 h of therapy. If failure occurs, and no indication for immediate referral exists, possible explanations for failure should be systematically determined, including non-adherence to therapy and alternative diagnoses. If failure of the fi rst-line agent remains a possible explanation, suitable secondline agents include high-dose amoxicillin-clavulanic acid with or without an aff ordable macrolide for children over 3 years of age. # Introduction Each year, clinical pneumonia occurs in an estimated 156 million children aged under 5 years, 1 and causes approximately a fi fth of all deaths among such children, most of whom are in low-income nations. 2 To reduce the morbidity and mortality of pneumonia in children, guidelines currently known as the Integrated Management of Childhood Illness (IMCI) have been developed by WHO and partners for fi rst-level health systems. IMCI has been implemented by many organisations and reduces mortality eff ectively, 3,4 although implementation can be improved. 5,6 These guidelines include recommendations for the case management of acute respiratory illness. They indicate when referral is needed and specify appropriate antimicrobial agents when referral is not needed. WHO recommendations for the treatment of pneumonia have provided critical guidance to fi rst-level health-care workers worldwide, but the last major revision is more than 10 years old. The fi rst WHO recommendations for respiratory disease case management were published in a 1981 WHO memorandum. The memorandum was aimed at encouraging a systematic approach to the management of children with possible pneumonia in resource-poor settings, based on simple algorithms and empirical treatment. Recommended agents included drugs available at the time of publication, with both intramuscular and oral drugs listed, such as procaine penicillin, ampicillin, erythromycin, co-trimoxazole, and sulfamethoxypyridazine, and noted that there was as yet little experience with co-trimoxazole. Second-line agents for use in children still ill after 48 h included chloramphenicol or oxacillin. WHO published a revised document in 1991, after much experience had been gained with the case-management approach and empirical treatment. For treatment of non-severe pneumonia at the fi rst-level health facility, this document recommended oral co-trimoxazole as the preferred agent, with injectable procaine penicillin and oral amoxicillin as alternatives. A 2005 technical update of the WHO IMCI guidelines recommended oral amoxicillin (50 mg/kg per dose, in two divided doses) or co-trimoxazole (8 mg/kg trimethoprim per dose, in two divided doses) for the treatment of non-severe pneumonia; 9 if antimicrobial resistance to co-trimoxazole was high, oral amoxicillin was preferred. During the past decade, various organisations have issued recommendations for paediatric pneumonia treatment. 10-14 These recommendations are primarily intended for high-income to middle-income nations. New information on antimicrobial resistance, the changing epidemiology of pneumonia, and the availability of a broader range of fi rst-line and second-line antimicrobial agents provides the impetus for updated recommendations for antimicrobial treatment of nonsevere pneumonia among children assessed by fi rst-level health providers, often with basic health training. The WHO Department of Child and Adolescent Health and Development selected and assembled this panel to review the current literature on childhood pneumonia and to defi ne further the most appropriate antimicrobial agents for treatment of non-severe pneumonia. Specifi cally, we were asked to defi ne the appropriate fi rstline antimicrobial agent, treatment failure, when to change therapy, and appropriate second-line antimicrobial agents. # Methods The international panel consisted of nine clinicians and researchers with experience in defi ning and treating Review pneumonia among children in various settings. We communicated by regular conference calls and by email. After reviewing the available evidence, we discussed issues such as interpretation of aetiological study results and antimicrobial resistance data. The initial focus was to identify appropriate fi rst-line and second-line antimicrobial agents for the empirical treatment of nonsevere pneumonia in children by fi rst-level health-care workers. However, we determined that to address secondline therapy, a defi nition of treatment failure and determination of when to change therapy were required (panel). ## Search strategy A literature search was done to generate a foundation for recommendations. The results for appropriate fi rst-line and second-line antimicrobial agents (webtable) were similar those obtained by a Cochrane review. Evidence was collected with a focus on publications from January, 1991 (the date of the last recommendations) through September, 2008, by searches of PubMed, EMBASE, and the Cochrane Central Registrar of Controlled Trials, in addition to bibliographies of relevant articles and the author's records. Search terms were "pneumonia", "child", "childhood", "pediatric", "paediatric", "antibiotic", "trial", and "cohort", and was limited to available articles in English or an English abstract that included children with pneumonia under age 5 years in the study. For the selection of antimicrobial agents, 36 articles that assessed more than one antimicrobial agent and the seven articles that assessed diff erent durations or doses of antimicrobial agents by use of a randomised controlled trial were included in the review. Articles were excluded if no treatment failure data were available as an outcome or if they exclusively enrolled children with very severe pneumonia. If an article presented results of children with a spectrum of diagnosis (eg, sinusitis, otitis media, and pneumonia) only results for children with pneumonia were included, if possible. These articles provide the basis, along with the panel's experience, for the recommendations. ## Development of recommendations Initial recommendations were drafted and then circulated to a broader group of reviewers for comment. The broader group included experts with experience in the treatment and epidemiology of pneumonia, as well as representatives from the WHO regional offi ces. [fig_ref] Table 1: Outline of recommendations [/fig_ref] outlines the recommendations developed, with strength of each major recommendation and the quality of supporting evidence based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The GRADE quality of evidence categories include high, intermediate, low, and very low, and was determined by the panel's review of the literature. The studies available for this review, with few exceptions, were observational in nature rather than blinded randomised trials, and therefore, the GRADE quality of evidence was rarely higher than intermediate. After the review by the broader group, the strength of each recommendation was determined by the panel members. ## Recommendation 1 Amoxicillin is the preferred initial antimicrobial agent for the treatment of non-severe pneumonia. The dose of amoxicillin is 50 mg/kg per day in two divided doses for a 3-day treatment course in areas with low HIV prevalence, and 5 days in areas of high HIV prevalence. In some situations, such as where local evidence clearly indicates infrequent resistance, co-trimoxazole (8 mg/kg trimethoprim in two divided doses) may be an acceptable alternative. ## Rationale and evidence summary Pneumonia is, strictly speaking, a pathological diagnosis, determined by clinical means. Radiological consolidation is commonly used as a surrogate, but is often not feasible at fi rst-level health facilities. Review validated to identify children with specifi c treatment needs, 7 such as those needing antimicrobial therapy or referral to higher levels of care. Non-severe pneumonia is diagnosed in a child with cough or diffi culty breathing accompanied by tachypnoea, defi ned as a respiratory rate of at least 40 breaths per min in a child aged 12-59 months, or at least 50 breaths per min in an infant aged 2-11 months. Use of these criteria identifi es 80% of children with pneumonia who need antimicrobial therapy. 7 Children aged 2-59 months require immediate referral if they have signs of severe or very severe pneumonia (lower chest indrawing or central cyanosis), stridor when calm, or IMCI-defi ned danger signs (inability to drink or breastfeed, convulsions, persistent vomiting, lethargy, or unconsciousness). Children aged less than 2 months with pneumonia have, by defi nition, severe pneumonia due to their higher risk for mortality, and thus require referral. Identifi cation or prediction of the likely organisms that cause pneumonia is the most important step in determining appropriate antimicrobial therapy. Despite the importance of understanding the aetiology of pneumonia, few recent studies have been done in resource-poor settings, [bib_ref] Antimicrobial susceptibility patterns of Haemophilus isolates from children in eleven developing nations, Weinberg [/bib_ref] [bib_ref] The epidemiology of acute respiratory tract infection in young children: comparison of..., Selwyn [/bib_ref] or in areas with high HIV prevalence. [bib_ref] A trial of a 9-valent pneumococcal conjugate vaccine in children with and..., Klugman [/bib_ref] [bib_ref] Failure of standard antimicrobial therapy in children aged 3-59 months with mild..., Jeena [/bib_ref] The most useful studies that have been done generally use one of two approaches: vaccine probe methods or comprehensive diagnostic testing protocols. Vaccine probe studies may provide the best possible estimates of pathogen-specifi c pneumonia burden because they are not limited by insensitive diagnostic testing practices. [bib_ref] Bacterial pneumonia vaccines and childhood pneumonia: are we winning, refi ning, or..., Obaro [/bib_ref] However, these studies are extremely costly and generally estimate only the role of vaccine-type strains of the pathogen and often focus on severe or hospitalised pneumonia cases. By contrast, studies that incorporate a wide range of diagnostic tests off er the possibility of detecting many pathogens. The diagnostic tests used, however, are often insensitive and sometimes not specifi c, which limits data quality. [bib_ref] Pneumonia research to reduce childhood mortality in the developing world, Scott [/bib_ref] Directly obtaining specimens from the site of infection by lung aspiration before antimicrobial administration, potentially a gold-standard approach in children, produces positive results in 62% of appropriately selected cases, according to a review of 13 studies. [bib_ref] Etiology of severe pneumonia in children in developing countries, Shann [/bib_ref] Although this approach produces a relatively high yield, it is limited to peripheral lobar pneumonias that may selectively decrease the yield of several pathogens and therefore may not be representative of all severe pneumonia. The results of aetiological studies require cautious interpretation because estimates of the proportion of pneumonia caused by the diff erent pathogens do vary. The sensitivity of culture-based techniques for identifying bacteria is compromised by previous antimicrobial administration, which is often not assessed. If antimicrobial exposure before culture is common, the measured results in culture-based studies may signifi cantly underestimate those organisms that are sensitive to commonly prescribed antimicrobial agents, such as Streptococcus pneumoniae and Haemophilus infl uenzae, and overestimate organisms such as Staphylococcus aureus. Although the limitations listed above are numerous, successful treatment ultimately depends on targeting the causative agents. Therefore, despite these limitations, Estimates based on proportion of radiographically confi rmed pneumonia prevented by vaccination with 7-valent and 9-valent vaccine (vaccine probe studies), [bib_ref] A trial of a 9-valent pneumococcal conjugate vaccine in children with and..., Klugman [/bib_ref] [bib_ref] Effi cacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal..., Cutts [/bib_ref] [bib_ref] The impact of a 9-valent pneumococcal conjugate vaccine on the public health..., Madhi [/bib_ref] and supported by lung aspiration studies [bib_ref] Etiology of severe pneumonia in children in developing countries, Shann [/bib_ref] Haemophilus infl uenzae 0-31% Increasing use of highly effi cacious vaccine against disease by H infl uenzae type b may decrease its role as a pathogen Non-type b may play a greater role in non-severe pneumonia than type b [bib_ref] Haemophilus infl uenzae pneumonia: type b or non-type b?, Shann [/bib_ref] Found to be a signifi cant cause of pneumonia in all vaccine probe studies, 29-31 except one, [bib_ref] Incidences of vaccine-preventable Haemophilus infl uenzae type b pneumonia and meningitis in..., Gessner [/bib_ref] and in lung aspiration studies [bib_ref] Etiology of severe pneumonia in children in developing countries, Shann [/bib_ref] Staphylococcus aureus 1-33% Presents clinically as a severe, necrotising pneumonia with rapid progression [bib_ref] Etiology of severe pneumonia in children in developing countries, Shann [/bib_ref] Non-typhoidal salmonellae 0-28% Bacteraemia may present with features consistent with a clinical diagnosis of pneumonia [bib_ref] Use of clinical syndromes to target antibiotic prescribing in seriously ill children..., Berkley [/bib_ref] [bib_ref] Nontyphoidal Salmonella infections of children in tropical Africa, Graham [/bib_ref] [bib_ref] Importance of enteric bacteria as a cause of pneumonia, meningitis and septicemia..., O'dempsey [/bib_ref] Estimates are based on studies from tropical Africa [bib_ref] Use of clinical syndromes to target antibiotic prescribing in seriously ill children..., Berkley [/bib_ref] [bib_ref] Improvements in nutritional management as a determinant of reduced mortality from community-acquired..., Bahwere [/bib_ref] Associated with non-severe pneumonia in some malaria-endemic regions of Africa 34 Mycoplasma pneumoniae 5% Limited diagnostic capacities in low-income countries [bib_ref] Etiology and treatment of community-acquired pneumonia in ambulatory children, Wubbel [/bib_ref] [bib_ref] Etiology of childhood pneumonia: serologic results of a prospective, population-based study, Heiskanen-Kosma [/bib_ref] [bib_ref] The role of Chlamydia pneumoniae in acute respiratory tract infections in young..., Weber [/bib_ref] [bib_ref] Agacfi dan A. Role of Mycoplasma pneumoniae and Chlamydia pneumoniae in children..., Somer [/bib_ref] Proportion of pneumonia associated with infection increases with age, the greatest burden is in children aged >3 years [bib_ref] Epidemiology of severe pneumonia caused by Legionella longbeachae, Mycoplasma pneumoniae, and Chlamydia..., Phares [/bib_ref] Assumption that infections do not cause signifi cant morbidity or mortality lacks evidence to be either validated or invalidated [bib_ref] Pneumonia associated with infection with pneumocystis, respiratory syncytial virus, chlamydia, mycoplasma, and..., Shann [/bib_ref] [bib_ref] Chlamydial pneumonia in children requiring hospitalization: eff ect of mixed infection on..., Tsai [/bib_ref] Chlamydophila pneumoniae 3-10% Limited diagnostic capacities in low-income countries [bib_ref] Etiology and treatment of community-acquired pneumonia in ambulatory children, Wubbel [/bib_ref] [bib_ref] Etiology of childhood pneumonia: serologic results of a prospective, population-based study, Heiskanen-Kosma [/bib_ref] [bib_ref] The role of Chlamydia pneumoniae in acute respiratory tract infections in young..., Weber [/bib_ref] Proportion of pneumonia associated with infection increases with age, the greatest burden is in children aged >3 years [bib_ref] Epidemiology of severe pneumonia caused by Legionella longbeachae, Mycoplasma pneumoniae, and Chlamydia..., Phares [/bib_ref] Poor quality serological data for very young children [bib_ref] Antibody response to Chlamydia pneumoniae infection in children with respiratory illness, Kutlin [/bib_ref] Moraxella catarrhalis 0-9% Often not the focus of pneumonia microbiological studies [bib_ref] Reappraisal of lung tap: review of an old method for better etiologic..., Vuori-Holopainen [/bib_ref] Klebsiella pneumoniae 0-4% One study noted a higher proportion of 14% in children with previous antimicrobial use [bib_ref] Reappraisal of lung tap: review of an old method for better etiologic..., Vuori-Holopainen [/bib_ref] Rare exception in malnourished children 46 ## Viral (9-64%) Respiratory syncytial virus 1-39% Particularly important in young infants [bib_ref] Respiratory syncytial virus infection in tropical and developing countries, Weber [/bib_ref] Infl uenza viruses 0-22% Important cause throughout age range [bib_ref] Respiratory syncytial virus infection in tropical and developing countries, Weber [/bib_ref] Increasingly documented in the tropics [bib_ref] Global patterns in seasonal activity of infl uenza A/H3N2, A/H1N1, and B..., Finkelman [/bib_ref] Adenoviruses 0-54% Limited diagnostic testing and use of poor or insensitive tests [bib_ref] Respiratory syncytial virus infection in tropical and developing countries, Weber [/bib_ref] Parainfl uenza viruses 0-46% Occurrence in alternating years means that single-year studies have limited value [bib_ref] Seasonal trends of human parainfl uenza viral infections: United States, Fry [/bib_ref] Human metapneumovirus 2-8% Recent but well-documented cause of pneumonia [bib_ref] Human metapneumovirus as a cause of community-acquired respiratory illness, Stockton [/bib_ref] [bib_ref] Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and..., Williams [/bib_ref] [bib_ref] Human metapneumovirus-associated lower respiratory tract infections among hospitalized human immunodefi ciency virus..., Madhi [/bib_ref] [bib_ref] Human metapneumovirus infection in the United States: clinical manifestations associated with a..., Esper [/bib_ref] Others (including bocavirus, coronaviruses, and rhinoviruses) ## 4-30% Recent PCR-based studies more consistently identify new viruses, but their signifi cance remains to be defi ned [bib_ref] Detection and typing by molecular techniques of respiratory viruses in children hospitalized..., Pierangeli [/bib_ref] [bib_ref] Human coronavirus infections in rural Thailand: a comprehensive study using real-time reverse-transcription..., Dare [/bib_ref] [bib_ref] Human bocavirus: a novel parvovirus epidemiologically associated with pneumonia requiring hospitalization in..., Fry [/bib_ref] These estimates of aetiological burden have wide ranges. Variation may be real, due to increased proportions of aetiologies due to high HIV prevalence, as well as seasonal (eg, infl uenza) and geographical (eg, Salmonella) variability. However, the primary source of variability may be due to measurement, either enrolment criteria (hospitalised versus outpatient enrolment), inadequate diagnostic testing of blood cultures with low yield (eg, blood culture), or misclassifi cation (eg, urine antigen testing). Previous antimicrobial administration also may result in underestimation of some agents, and poor laboratory quality can also play an important part. [bib_ref] Microbial surveillance for Streptococcus pneumoniae in rural Thailand: lessons learned, laboratory capacity,..., Fischer [/bib_ref] Zero percentages (except in the case of Klebsiella) are often due to lack of diagnostic testing and the use of poor or insensitive tests, which are the important reasons for failure to consistently identify these pathogens, although in some cases true seasonal or geographical variations may contribute. Review estimates of the common pathogens that cause pneumonia in children are required to determine appropriate empirical antimicrobial therapy. Whereas these recommendations are for non-severe pneumonia, it is important to remember that aetiological studies usually enrol hospital inpatients with severe pneumonia. The common bacterial and viral causes of pneumonia pathogens are shown in table 2. Estimates include rather broad ranges of the plausible aetiological fractions. Most studies lack comprehensive investigation of viral causes of pneumonia, but in the studies that do provide such estimates, approximately 25% (range 9-64%) of pneumonia acquired in the community has a positive viral diagnostic test. [bib_ref] Human metapneumovirus as a cause of community-acquired respiratory illness, Stockton [/bib_ref] [bib_ref] Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and..., Williams [/bib_ref] [bib_ref] Human metapneumovirus-associated lower respiratory tract infections among hospitalized human immunodefi ciency virus..., Madhi [/bib_ref] [bib_ref] Human metapneumovirus infection in the United States: clinical manifestations associated with a..., Esper [/bib_ref] Identifi cation of a virus does not necessarily imply that the pneumonia is exclusively caused by that virus, because viral and bacterial agents may coexist, making the role of each pathogen uncertain. [bib_ref] Etiology of acute lower respiratory tract infections in Gambian children: I. Acute..., Forgie [/bib_ref] [bib_ref] Diagnoses of acute lower respiratory tract infections in children in Rawalpindi and..., Ghafoor [/bib_ref] [bib_ref] Etiology of acute lower respiratory tract infection in children from Alabang, Metro..., Tupasi [/bib_ref] [bib_ref] A role for Streptococcus pneumoniae in virus-associated pneumonia, Madhi [/bib_ref] These recommendations for non-severe pneumonia are limited by the lack of data on the causes of pneumonia among children treated outside hospital, as described above. However, an important goal of treatment for non-severe pneumonia is to prevent the progression to severe pneumonia. Therefore, directing antimicrobial therapy for non-severe pneumonia towards the pathogens known to cause severe pneumonia is believed to be appropriate. Pathogens such as S pneumoniae and H infl uenzae are prominent treatable causes of severe pneumonia, and fi rst-line antimicrobial therapy has historically been directed primarily at these pathogens. An approach that targets these two aetiological agents has been repeatedly shown to be eff ective at reducing pneumonia morbidity and overall mortality through studies and clinical experience during the past 15 years. 3 Altering empirical fi rst-line treatment to better cover atypical agents, S aureus, non-typhoidal salmonellae, or others, might be considered on theoretical grounds based on the abovereferenced studies, but such an approach lacks evidence that it would reduce morbidity or mortality. Many studies have compared the effi cacy of diff erent antimicrobial agents for treating pneumonia in children (webtable). However, despite the large number of studies, most are limited by small sample sizes, and lack the power to conclusively show non-inferiority. These studies are also hampered by the inability to accurately and consistently defi ne treatment failure, largely due to the limited resources available in the fi eld. Interpretation is also limited by the so-called "Pollyanna phenomenon". In settings where an antimicrobial agent is compared with a standard agent, the potentially dangerous subset of bacterial cases that are the intended target of study are diluted by the inclusion of milder, selflimited, viral disease, which results in poor antimicrobial agents seeming to be more effi cacious, and superior antimicrobial agents seeming less effi cacious against the standard agent, as noted by Marchant and colleagues 62 in the setting of otitis media. The lack of bacterial endpoints complicate our understanding of the clinical relevance of antimicrobial resistant for the management of pneumonia in the community. Our perceptions of the clinical relevance of amoxicillin, macrolide, and co-trimoxazole resistance for oral outpatient management of pneumonia are all based on the failure of these oral agents to eradicate resistant S pneumoniae from the middle ear. [bib_ref] Measuring the comparative effi cacy of antibacterial agents for acute otitis media:..., Marchant [/bib_ref] Although Straus and colleagues [bib_ref] Antimicrobial resistance and clinical eff ectiveness of co-trimoxazole versus amoxycillin for pneumonia..., Straus [/bib_ref] suggest that co-trimoxazole has a higher failure rate in severe pneumonia treatment than amoxicillin, the role of resistance was unclear, even though resistance has been the most frequently proposed explanation. A sub-analysis did not show a signifi cant increase in failure among co-trimoxazole-resistant S pneumoniae or H infl uenzae treated with co-trimoxazole. [bib_ref] Antimicrobial resistance and clinical eff ectiveness of co-trimoxazole versus amoxycillin for pneumonia..., Straus [/bib_ref] Few pneumonia studies have described the clinical impact of co-trimoxazole resistance on the treatment of pneumonia. [bib_ref] Response to cotrimoxazole in the management of childhood pneumonia in fi rst-level..., Noorani [/bib_ref] In-vitro resistance to co-trimoxazole correlates with poor clinical outcome in the treatment of these pathogens in acute otitis media. Trials of treatment for acute otitis media have measured bacteriological failures by use of tympanocentesis, comparing middle-ear fl uid cultures before and after therapy to show bacterial eradication with treatment. In one tympanocentesis study, [bib_ref] Bacteriologic and clinical effi cacy of trimethoprim-sulfamethoxazole for treatment of acute otitis..., Leiberman [/bib_ref] co-trimoxazole resistance resulted in higher rates of bacteriological failures for H infl uenzae and S pneumoniae. A caveat is that middle-ear fl uid concentrations of many drugs are substantially lower than comparable lung concentrations, and therefore antimicrobial agents used in therapy for acute otitis media may perform more poorly against strains with decreased susceptibility than antimicrobials used in pneumonia therapy. With this caveat, the available data suggest that in vitro co-trimoxazole resistance is meaningful in some clinical circumstances. This conclusion, if relevant for pneumonia, has important implications for countries where co-trimoxazole resistance is common. First-line antimicrobial agents should be eff ective, reliable, widely available, and aff ordable in resource-poor settings. The 2005 technical update of the WHO IMCI guide lines recommended oral amoxicillin or co-trimoxazole as fi rst-line treatment for non-severe pneumonia because of their low cost and wide spectrum of coverage. Historically, co-trimoxazole and amoxicillin have been evaluated for the treatment of non-severe pneumonia. Two studies, both done in Pakistan, have compared amoxicillin to co-trimoxazole in children aged under 5 years. [bib_ref] Antimicrobial resistance and clinical eff ectiveness of co-trimoxazole versus amoxycillin for pneumonia..., Straus [/bib_ref] [bib_ref] Clinical effi cacy of co-trimoxazole versus amoxicillin twice daily for treatment of..., Catchup Study Group [/bib_ref] The absolute diff erence in treatment failure between children with treatment failure after taking co-trimoxazole relative to amoxicillin is illustrated in fi gure 1. The study by Straus and colleagues 63 included children with both severe and non-severe pneumonia, whereas the study by the CATCHUP (Co-trimoxazole Amoxicillin Trial in CHildren Under 5 years for Pneumonia) study group [bib_ref] Clinical effi cacy of co-trimoxazole versus amoxicillin twice daily for treatment of..., Catchup Study Group [/bib_ref] included only children with non-severe pneumonia. The duration and dosage of amoxicillin therapy has been assessed and summarised in a WHO 2003 consultative meeting report.Two clinical trials in India and Pakistan examined 3-day (short) versus 5-day (standard) amoxicillin treatment courses for pneumonia and showed equal eff ectiveness of the two durations. [bib_ref] Clinical effi cacy of 3 days versus 5 days of oral amoxicillin..., Pakistan Multicentre Amoxycillin [/bib_ref] [bib_ref] Three day versus fi ve day treatment with amoxicillin for non-severe pneumonia..., Agarwal [/bib_ref] Shortened courses have not been as well studied in areas of high HIV prevalence, where a substantially greater burden of severe bacterial pneumonia among HIVinfected persons exists. Prudence indicates that shortening treatment to a 3-day course should be studied before being implemented in such settings. Variations of amoxicillin dose have not been well studied for the treatment of childhood pneumonia. One study of 836 children compared 3 days of amoxicillin in 45 mg/kg versus 90 mg/kg doses and did not show a signifi cant diff erence in treatment failure 5 days after initiation of therapy. 70 ## Recommendation 2 Treatment failure is defi ned as the development of lower chest-wall indrawing, central cyanosis, stridor while calm, or IMCI-defi ned danger signs at any time during a child's illness or a persistently raised respiratory rate at 72 h (48 h in an area of high HIV prevalence). ## Rationale and evidence summary Treatment failure was previously vaguely defi ned as "the same" (ie, a respiratory rate persistently above the ageappropriate IMCI cut-off ) or deterioration after 2 or 3 days of therapy. 8 Deterioration is development of chest indrawing, central cyanosis, stridor when calm or IMCI-defi ned danger signs. If the child does not deteriorate, these signs and symptoms are traditionally assessed at a scheduled follow-up visit 48 h after the initiation of therapy. However, on the basis of results of a study in Pakistan, 72 h may be acceptable in countries with low HIV prevalence. [bib_ref] Can WHO therapy failure criteria for non-severe pneumonia be improved in children..., Hazir [/bib_ref] These results should be replicated in other low-income countries, particularly those with high HIV prevalence. We believe that children who have a persistently raised respiratory rate and no indication for immediate referral should undergo a brief but systematic assessment to determine whether second-line therapy would be benefi cial. ## Recommendation 3 A brief but systematic assessment should be used for children who have failed therapy for non-severe Hospital assessment Common agents may be responsible for at least a third of outpatient pneumonia treatment failures; uncommon agents may be responsible for a minor fraction; rare agents are probably responsible for only occasional treatment failures; globally uncommon agents may be common in certain geographic areas, although they are uncommon as causes for pneumonia treatment failure globally. Based on data from Heff elfi nger et al [bib_ref] Evaluation of children with recurrent pneumonia diagnosed by World Health Organization criteria, Heff Elfi Nger [/bib_ref] and discussions of the panel based on their clinical experience. †Note that referral to the next level facility instead of a hospital may occasionally be appropriate, depending on the resources at the facility and the suspected condition. ## Rationale and evidence summary The literature does not describe when treatment failure should prompt a change of therapy. Treatment failure may occur for many reasons, only one of which is use of a drug to which the infecting agent is not susceptible. Many of these reasons are described in table 3, and most require assessment in hospital and specifi c therapies. If a child develops signs indicative of the need for immediate referral, before or after treatment is initiated, they should be referred immediately. 7,9 We believe that children who fail to improve but do not require immediate referral should be systematically assessed before changing antimicrobial agents. This assessment can begin with the fi rst-level health worker determining whether failure is due to inability or unwillingness to take the medicine appropriately. If the health worker believes that the child has taken the antimicrobial agent correctly, other conditions resulting in treatment failure should be considered. If an initial assessment by the health worker indicates that these considerations are unlikely and referral is not warranted, a second-line agent should expand coverage. This assessment by the fi rst-level health worker may be guided by an algorithm. The effi cacy of algorithms has been shown in the assessments of initial case management by acute respiratory illness guidelines. 3,4,7 However, we are not aware of any studies that show the effi cacy of an algorithm that systematically assesses a child who does not improve after therapy. [fig_ref] Figure 2: Example algorithm of how to systematically assess children aged >2 months and... [/fig_ref] shows an example of an algorithm developed by us, which aims to be simple for health workers to use accurately and consistently. It addresses the major causes of treatment failure, but is not a validated tool, and is off ered here purely as an example. ## Recommendation 4 In the setting of fi rst-level health providers, children initially treated with amoxicillin who have a persistently raised respiratory rate and no indication for referral should receive high-dose amoxicillin with clavulanic acid (80-90 mg/kg per day amoxicillin) for second-line therapy to provide coverage for the major pathogens likely to cause severe disease. A 5-day treatment course should be prescribed for the second-line antimicrobial agents. For children over 3 years of age, an aff ordable macrolide or azalide (eg, 50 mg/kg erythromycin in four divided doses for 7 days) may be added to the existing regimen for a 5-day or 7-day treatment course. For children failing fi rst-line treatment with co-trimoxazole, the recommendation is to switch to a 5-day course of amoxicillin (50 mg/kg). ## Rationale and evidence summary We defi ne second-line antimicrobial agents as those that are used in the setting of treatment failure when no indication for immediate referral is present (ie, IMCI danger signs, lower chest indrawing, stridor, or central cyanosis) and other reasons for treatment failure have been excluded. No studies were identifi ed that assessed second-line antimicrobial agents; therefore, second-line antimicrobial agents should logically be selected to treat organisms that fail fi rst-line therapy. Whereas a substantial proportion of failures of fi rst-line agents may be due to mild and self-limited viral infections, the second-line agent should ensure coverage of resistant organisms and cover a broader range of organisms that would not be treated with typical fi rst-line agents; in some settings, coverage may be extended to include S aureus or non-typhoidal salmonellae. A second-line antimicrobial agent should broaden or enhance coverage in the setting of treatment failure. Our recommendations on the best second-line anti microbial If Integrated Management of Childhood Illness guidelines have been followed, the child should have been assessed for malnutrition and HIV in settings with high prevalence. This fi gure is off ered only as an example of such an algorithm that can be developed. *yyy=multiple trials with strong trial evidence, yy=some trials with good evidence, y=minimal trials and evidence. †Pharmacokinetic/pharmacodynamic (PK/PD) properties are used to help determine the susceptibility breakpoints of antimicrobial agents and therefore the agent's likely effi cacy. PK/PD properties for drug classes are as follows: aminopenicillins, penicillins, and cephalosporins=time above minimum inhibitory concentration (MIC) 40%; macrolides and fl uoroquinolones=area under the curve/MIC above 30. ‡Costs for non-oral medications do not include administration, syringe, or needle costs. §Treatment course was 5 days and dose was based on a 10 kg child, except intramuscular penicillin and ceftriaxone, for which cost includes only the drug cost and does not include needles and administration. Although drug cost may be a critically important consideration, it may be acceptable for a second-line antimicrobial agent to be more expensive than fi rst-line agents. Treatment course prices of US$0·50, $1, and $2 were used as cut-off s to assess agent's acceptability [fig_ref] Table 4: Antimicrobial agents used for treatment of community-acquired pneumonia [/fig_ref]. Appropriate second-line agents must enhance coverage not already provided by the fi rst-line agent. Parenteral antimicrobial agents are often used in hospital settings, but are rarely used in outpatient clinics in low-income countries. The perception by some patients and providers that parenteral agents are always more eff ective than oral agents can be diffi cult to correct. Therefore, introduction of a parenteral antimicrobial agent such as ceftriaxone to peripheral settings may be impractical for these and other reasons in most situations. ## Review If a child was initially taking co-trimoxazole at the correct pneumonia treatment dose, the preferred secondline agent would be oral amoxicillin at 50 mg/kg in two divided doses for 5 days. If the fi rst-line agent was amoxicillin, the second antimicrobial agent choice should expand the spectrum or enhance coverage. Use of highdose amoxicillin-clavulanic acid (80-90 mg/kg daily of divided doses of amoxicillin with a maximum of 6·4 mg/kg clavulanic acid daily) is another possibility to enhance activity against beta-lactamase-producing H infl uenzae and resistant S pneumoniae, but would not cover atypical bacteria. Most oral second-generation and third-generation cephalosporin antimicrobial agents are more expensive, but have improved coverage against beta-lactamaseproducing H infl uenzae. Cefuroxime and cefi xime are reasonably priced, although they are not as active as highdose amoxicillin-clavulanic acid against S pneumoniae. [bib_ref] Antimicrobial resistance among pediatric respiratory tract infections: clinical challenges, Jacobs [/bib_ref] In addition, these agents do not provide coverage for M pneumoniae or C pneumoniae. Oral chloramphenicol palmitate is a less desirable second-line agent for non-severe pneumonia. This antimicrobial agent is bacteriostatic against a wide range of potential pathogens and bactericidal against most S pneumoniae and H infl uenzae, although there is some resistance to chloramphenicol. Bone-marrow toxicity includes reversible, dose-dependent suppression, as well as aplastic anaemia, the latter occurring in approximately one in 24 500 to 40 000 courses. [bib_ref] Chloramphenicol: a review of its use in clinical practice, Feder [/bib_ref] [bib_ref] Prescribing practices and attitudes toward giving children antibiotics, Paluck [/bib_ref] Although chloramphenicol is active against a wide range of causal agents and is inexpensive, the potential for bone-marrow toxicity limits its use as a fi rst-line agent and as a universal second-line agent. Some panel members expressed reservations about this agent because of safety concerns with its use as an oral agent for mild disease in the outpatient setting. Also important are concerns about driving resistance in settings where parenteral chloramphenicol may be the sole agent to treat meningococcal meningitis. Oral chloramphenicol may be useful in children if intramuscular antimicrobial agents are not available and immediate transportation to a higher level of care, such as a hospital, is not possible. Although tetracycline is the appropriate drug for the treatment of some paediatric infections, the small risk of associated side-eff ects outweigh the potential advantages of widespread use of the drug for non-severe pneumonia treatment. Similarly, the respiratory fl uoroquinolones are not optimum second-line drugs for outpatient pneumonia because of the theoretical risk of toxic eff ects in young children, as well as the measurable risk of promoting resistance to this valuable class of antimicrobial agents. Azithromycin, clarithromycin, and erythromycin are reasonably priced, but the role of these agents is limited to extending the antimicrobial spectrum to atypical organisms, because these agents are relatively inactive against H infl uenzae and there is increasing resistance among S pneumoniae. [bib_ref] Antimicrobial resistance among pediatric respiratory tract infections: clinical challenges, Jacobs [/bib_ref] Therefore, an aff ordable macrolide or azalide may be considered for a child who is not better but not worsening at time of re-assessment and is over 3 years of age, when these atypical infections are more likely. Erythromycin may be used in three or four divided doses for a 5-day treatment course at a daily dose of 40 mg/kg. [bib_ref] Etiology and treatment of community-acquired pneumonia in ambulatory children, Wubbel [/bib_ref] Advantages of erythromycin over azithromycin or clarithromycin include low-cost and wide availability and disadvantages include gastrointestinal disturbance and frequent dosing. Macrolides or azalides are also indicated for those who have a documented allergy to penicillin or other beta-lactam agents. Co-trimoxazole was not considered as a secondline agent because co-trimoxazole resistance in S pneumoniae often co-exists with penicillin resistance, and, if the fi rst-line agent used was amoxicillin, the addition of co-trimoxazole would probably not be of benefi t. These general recommendations may need to be modifi ed for children living in areas where HIV or malaria are common, or if referral is not possible. ## Review Countries introducing algorithms for empirical use by fi rst-level health workers should identify such areas and consider modifi cation of the recommendations. ## Areas with a high prevalence of hiv Special attention is required in regions where HIV prevalence has consistently exceeded 5% in at least one defi ned subpopulation, as is the case in much of eastern, central, and southern Africa, and certain regions of Asia and Latin America. In these high prevalence areas, HIV counselling and testing is recommended for all children aged under 10 years seen in paediatric health services.The burden of HIVassociated pneumonia in such regions is substantial. One study in an area with an HIV-positive prevalence of 5% among children aged under 5 years reported that 45% of hospitalised pneumonia and 85% of pneumonia deaths occurred among HIV-positive children. [bib_ref] Increased burden of respiratory viral associated severe lower respiratory tract infections in..., Madhi [/bib_ref] Prophylactic co-trimoxazole has been shown to improve survival and to reduce pneumonia-related deaths in HIV-infected children and should therefore be administered. [bib_ref] Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): a..., Chintu [/bib_ref] Children presenting with pneumonia should be assessed for symptomatic HIV infection in areas where HIV is a public-health problem and should be tested if indicated by use of methods such as that described by Horwood and colleagues. [bib_ref] Diagnosis of paediatric HIV infection in a primary health care setting with..., Horwood [/bib_ref] For children living in areas of high HIV prevalence, or who have clinical suspicion or a diagnosis of HIV infection, and who present with nonsevere pneumonia, the recommended treatment is amoxicillin, irrespective of co-trimoxazole prophylaxis status. Pneumocystis jirovecii is known to be a cause of severe, progressive pneumonia, especially among children aged 2-6 months, 84 but its role in non-severe pneumonia in HIV-infected children was not evaluated as part of this review. If such a child fails fi rst-line therapy for non-severe pneumonia, the child should be referred to hospital for management by WHO guidelines,including HIV testing and broad-spectrum parenteral antimicrobial agents. Finally, children in high prevalence areas without clinical suspicion or a diagnosis of HIV infection who fail to improve on fi rst-line therapy should be treated according to the standard recommendations outlined in this review. ## Malaria-endemic areas The clinical overlap between malaria and pneumonia in children is well recognised. [bib_ref] Usefulness of clinical case-defi nitions in guiding therapy for African children with..., Redd [/bib_ref] Symptomatic malaria may have clinical features consistent with a diagnosis of pneumonia, whereas children with pneumonia may have co-incidental malaria parasitaemia. [bib_ref] Overlap in the clinical features of pneumonia and malaria in African children, O'dempsey [/bib_ref] Co-trimoxazole therapy for non-severe pneumonia was recommended in some countries where malaria diagnosis was unavailable at fi rst-level facilities, in part because co-trimoxazole has some activity against both malaria and common bacterial causes of pneumonia in children. [bib_ref] Co-trimoxazole for childhood febrile illness in malaria-endemic regions, Bloland [/bib_ref] [bib_ref] Effi cacy of trimethoprim-sulfamethoxazole compared with sulfadoxine-pyrimethamine plus erythromycin for the treatment..., Hamel [/bib_ref] However, co-trimoxazole is not a fi rst-line anti-malaria drug, and amoxicillin, which does not have anti-malarial activity, is now preferred to co-trimoxazole as fi rst-line therapy for non-severe pneumonia. Therefore, if a child has clinical features of non-severe pneumonia but malaria cannot be excluded, the recommended fi rstline therapies for malaria and pneumonia should both be prescribed. Caution should be exercised in the use of erythromycin as a second-line agent if mefl oquine or halofantrine are prescribed for malaria, due to the increased the risk of arrhythmia. A complication of malaria is severe anaemia that, like pneumonia, can cause rapid breathing. In malariaendemic regions, children presenting with rapid breathing should be assessed for severe anaemia. If laboratory assessment is not available, marked pallor may be assessed by examining the palms of the hands, nail beds, and conjunctivae. Any child with a clinical diagnosis of pneumonia who also has severe anaemia should be referred to hospital for assessment. ## Areas where referral is not possible A child who fails treatment and meets criteria for referral should be transported to and assessed at a centre that can provide more intensive therapy. However, referral is impossible in some areas. In these situations, the child should receive treatment with agents that provide broader coverage and high activity against pathogens that cause severe pneumonia. These antimicrobial agents include injectable antimicrobial agents such as ceftriaxone, penicillin/gentamicin, or chloramphenicol. # Conclusions The WHO-recommended systematic case-management approach has greatly reduced the mortality of children with pneumonia. These updated recommendations, now identifying amoxicillin as the preferred fi rst-line agent and specifying the approach to changing to an appropriate second-line agent in the event of treatment failure (table 1), aim to improve treatment protocols for fi rstlevel health providers for children with non-severe pneumonia. These recommendations were developed by use of the available evidence for the treatment of children with pneumonia in low-income countries. The evidence basis for some of the recommendations was limited, and more research is needed in several areas. These areas include an improved understanding of the aetiology of pneumonia in children, both severe and non-severe, using optimum diagnostic testing, a better understanding of the reasons for treatment failure, and the determination of the best systematic method for the assessment of treatment failure by fi rst-level health workers. In the meantime, adaptation of these general recommendations to fi t country-specifi c treatment algorithms should help to resolve some of the uncertainty surrounding the appropriate management of young children with nonsevere pneumonia. ## Search strategy and selection criteria These are described in detail in the Methods section. ## Review ## Confl icts of interest We declare that we have no confl icts of interest. [fig] Figure 1: Absolute percentage diff erence in treatment failure among children with pneumonia treated with co-trimoxazole versus amoxicillin Analysis of two studies done in Pakistan and their pooled results given with 95% CIs. Straus et al 63 showed a signifi cant diff erence in the proportion of children with severe pneumonia who were treatment failures from 33% failing co-trimoxazole to 18% failing amoxicillin. The CATCHUP group 66 showed 19% of children failing co-trimoxazole and 16% failing amoxicillin. [/fig] [fig] Figure 2: Example algorithm of how to systematically assess children aged >2 months and <5 years, initially diagnosed and treated with non-severe pneumonia and who returned for follow-up, in low HIV prevalence settings, based on the experience and recommendations of the panel This assessment is intended to supplement and not to replace the clinical judgment of the fi rst-level health worker. [/fig] [table] Table 1: Outline of recommendations [/table] [table] Table 2: Common pathogens that cause pneumonia in otherwise healthy children aged 2-59 months [/table] [table] Table 3: Potential reasons for treatment failure for WHO-defi ned pneumonia at 72 h and possible solutions [/table] [table] Table 4: Antimicrobial agents used for treatment of community-acquired pneumonia [/table]	None	http://www.thelancet.com/article/S1473309909700441/pdf	None
782fb2e0b95a11e06536a78d4e42884e088abc92	pubmed	Italian Association of Clinical Endocrinologists (AME) and Italian Chapter of the American Association of Clinical Endocrinologists (AACE) Position Statement: Clinical Management of Vitamin D Deficiency in Adults	Italian Association of Clinical Endocrinologists (AME) and Italian Chapter of the American Association of Clinical Endocrinologists (AACE) Position Statement: Clinical Management of Vitamin D Deficiency in Adults Vitamin D deficiency is very common and prescriptions of both assay and supplementation are increasing more and more. Health expenditure is exponentially increasing, thus it is timely and appropriate to establish rules. The Italian Association of Clinical Endocrinologists appointed a task force to review literature about vitamin D deficiency in adults. Four topics were identified as worthy for the practicing clinicians. For each topic recommendations based on scientific evidence and clinical practice were issued according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) System. (1) What cut-off defines vitamin D deficiency: even though 20 ng/mL (50 nmol/L) can be considered appropriate in the general population, we recommend to maintain levels above 30 ng/mL (75 nmol/L) in categories at risk. (2) Whom, when, and how to perform screening for vitamin D deficiency: categories at risk (patients with bone, liver, kidney diseases, obesity, malabsorption, during pregnancy and lactation, some elderly) but not healthy people should be screened by the 25-hydroxy-vitamin D assay. (3) Whom and how to treat vitamin D deficiency: beyond healthy lifestyle (mostly sun exposure), we recommend oral vitamin D (vitamin D2 or vitamin D3) supplementation in patients treated with bone active drugs and in those with demonstrated deficiency. Dosages, molecules and modalities of administration can be profitably individually tailored. (4) How to monitor the efficacy of treatment with vitamin D: no routine monitoring is suggested during vitamin D treatment due to its large therapeutic index. In particular conditions, 25-hydroxy-vitamin D can be assayed after at least a 6-month treatment. We are confident that this document will help practicing clinicians in their daily clinical practice. # Introduction Vitamin D3 (cholecalciferol) is produced in the skin from 7-dehydrocholesterol by ultraviolet (UV) radiations at levels of sunlight exposure that do not induce skin burns (UV 290-315 nm) and is subsequently removed after its binding to vitamin D-binding protein (VDBP). Liver and other body tissues metabolize vitamin D3 synthesized in the skin and the orally ingested vitamin D2 (ergocalciferol) and D3 to 25-hydroxy-vitamin D [25(OH)D], the main circulating form, by means of 25-hydroxylase activity; 25(OH)D is then further metabolized in the kidneys to 1,25-dihydroxyvitamin D [1.25(OH) 2 D] by the enzyme CYP27B1 to regulate calcium, phosphate and bone metabolism. In addition, a wide variety of non-calcemic tissues and cells, including macrophages, also convert 25(OH)D to [bib_ref] Grading quality of evidence and strength of recommendations, Atkins [/bib_ref] D] for the purpose of regulating a variety of biologic functions in an autocrine/paracrine manner; 1.25(OH) 2 D is the major hormonal form of vitamin D and is responsible for most of its biologic actions. The tightly controlled production of 1.25(OH) 2 D in the kidneys is stimulated by the parathyroid hormone (PTH) and is inhibited by calcium, phosphate and fibroblast growth factor (FGF)-23 [bib_ref] Vitamin D: Production, metabolism, and mechanisms of action, Bikle [/bib_ref]. Vitamin D metabolites are transported in the blood bound to VDBP and albumin, produced by liver, and only a minority circulates as a free form. The receptors for 1.25(OH) 2 D (vitamin D receptor, VDR) are widely distributed transcription factors that regulate the expression of the genes, which mediate its biologic activity [bib_ref] Vitamin D: Production, metabolism, and mechanisms of action, Bikle [/bib_ref]. The classic target tissues-bone, gut, and kidney-are involved with calcium homeostasis, mainly through the regulation of transcellular calcium transport; 1.25(OH) 2 D stimulates calcium absorption in the intestine and calcium reabsorption in the distal tubule of the kidney; 1.25(OH) 2 D regulates both the formation and resorption of bone by promoting the differentiation of osteoblasts and regulating the production of proteins such as collagen, alkaline phosphatase (ALP), osteocalcin and Receptor Activator of Nuclear Factor-Kappa B Ligand (RANKL) [bib_ref] Vitamin D: Production, metabolism, and mechanisms of action, Bikle [/bib_ref]. Subclinical deficiency of vitamin D is a highly prevalent condition in the general population and, in recent years, an increasing number of subjects are treated with different formulations of vitamin D, thus increasing costs linked to vitamin D assays and preparations. Presently, physicians involved in the prescription of vitamin D demonstrate a variable clinical approach to the screening of its deficiency, the modalities of treatment and the monitoring of therapy over time. In order to overcome these shortcomings, the Italian Association of Clinical Endocrinologists (AME) appointed, in 2016, a panel of experts for the definition of the optimal management of vitamin deficiency in clinical practice. During a preliminary symposium, 200 physicians with specific expertise discussed the relevant items and identified the main hot topics in vitamin D deficiency. Subsequently, the expert panel reviewed the pertinent literature data and achieved a consensus on the recommendations. Whenever evidence was contrasting or equivocal, a majority of 2/3 was required to provide conclusions that were based on the panelists' clinical experience. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system was adopted for the present Position Statement [bib_ref] Grading quality of evidence and strength of recommendations, Atkins [/bib_ref] [bib_ref] A case for clarity, consistency, and helpfulness: State-of-the-art clinical practice guidelines in..., Swiglo [/bib_ref] [bib_ref] Grade Working Group. GRADE: An emerging consensus on rating quality of evidence..., Guyatt [/bib_ref]. According to GRADE, evidence is categorized into four quality levels (high, moderate, low, or very low), while recommendations are classified as strong ("recommendations") or weak ("suggestions"), on the basis of the quality of supporting evidence and level of agreement between the panel members [bib_ref] A case for clarity, consistency, and helpfulness: State-of-the-art clinical practice guidelines in..., Swiglo [/bib_ref]. Whenever possible, the level of evidence (LoE) has been reported beside each quotation using the following symbols: very low (⊗ ), low (⊗⊗ ), moderate (⊗⊗⊗ ) and high (⊗⊗⊗⊗) quality. Briefly, "very low quality" evidence is derived from unsystematic clinical observations (case report, case series) or very indirect evidence (i.e., surrogate end-points); "low quality" evidence is from observational studies or randomized controlled trials (RCT) with major limits; "moderate quality evidence" derives from RCTs with important limitations or from rigorous observational studies; "high quality evidence" are well performed RCTs and, exceptionally, strong evidence from unbiased observational studies [bib_ref] A case for clarity, consistency, and helpfulness: State-of-the-art clinical practice guidelines in..., Swiglo [/bib_ref]. As recently underlined [bib_ref] Clinical Management of Low Vitamin D: A Scoping Review of Physicians, Rockwell [/bib_ref] , further research is needed to inform better clinical guidelines in this area, and to assess implementation practices that will encourage evidence-based management practices for vitamin D insufficiency in adult populations. Moreover, greater understanding of physician management of uncertainty in clinical practice may help to avoid overutilization and inconsistent practice in similar clinical situations. ## Clinical issues ## What is the cut-off that defines vitamin d deficiency? As the plasma 25(OH)D levels are regarded as the most reliable indicator of vitamin D storage in the human body [bib_ref] Vitamin D: Production, metabolism, and mechanisms of action, Bikle [/bib_ref] [bib_ref] Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical..., Holick [/bib_ref] , the diagnosis of vitamin D deficiency is based on the determination of total plasma 25(OH)D concentrations. At present, there is no agreement on "normal levels" of 25(OH)D. Throughout the years, the cut-off was progressively increased from 12 to 20 and, finally, to 30 ng/mL [bib_ref] Unsal, I. Analysis of changes in parathyroid hormone and 25 (OH) vitamin..., Serdar [/bib_ref] [bib_ref] Simultaneous quantification of vitamin D 3 , 25-hydroxyvitamin D 3 and 24,25-dihydroxyvitamin..., Burild [/bib_ref] nmol/L, respectively), mainly because of the confusion of the normal with the desirable levels [bib_ref] Vitamin D deficiency. Is there really a pandemic?, Manson [/bib_ref]. Normal levels are defined as those between ±2 standard deviation (SD) from the mean values in normal population, while desirable levels are set by regulatory agencies for the prevention of diseases on the basis of observational studies. Currently, there is consensus that 25(OH)D levels lower than 20 ng/mL (50 nmol/L) are associated in adults with: - Secondary hyperparathyroidism, osteomalacia or osteoporosis [bib_ref] Effects of age and serum 25-OH-vitamin D on serum parathyroid hormone levels, Valcour [/bib_ref] [bib_ref] Screening for vitamin D deficiency: A systematic review for the U.S. Preventive..., Leblanc [/bib_ref] ; - Proximal limb muscle weakness, ataxia, and increased risk of falls [bib_ref] Interventions for preventing falls in older people living in the community, Gillespie [/bib_ref] [bib_ref] Vitamin D: Musculoskeletal health, Bhattoa [/bib_ref] ; - Increased risk of fractures [bib_ref] Vitamin D and vitamin D analogues for preventing fractures associated with involutional..., Avenell [/bib_ref] ; - Hampered effect of drugs used for osteoporosis [bib_ref] The 25(OH)D level needed to maintain a favorable bisphosphonate response is ≥33..., Carmel [/bib_ref]. In 2010, the Institute of Medicine (IOM), due to the lack of evidence for a benefit derived from increase in the normal threshold of vitamin D, defined deficiency, insufficiency and sufficiency of 25(OH)D as a serum value <12 ng/mL (30 nmol/L), 12-20 ng/mL (30-50 nmol/L) and 20-30 ng/mL (50-75 nmol/L), respectively [bib_ref] The 2011 report on dietary reference intakes for calcium and vitamin D..., Ross [/bib_ref]. In 2011 the USA Endocrine Society together with other Scientific Societies upgraded these three thresholds to <20 ng/mL (50 nmol/L), 20-30 ng/mL (50-75 nmol/L), and 30-100 ng/mL (75-250 nmol/L), respectively [bib_ref] Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical..., Holick [/bib_ref]. The upgrading was based on the demonstration (even if with a low quality evidence) of an increased intestinal calcium absorption [bib_ref] Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D, Heaney [/bib_ref] and a decreased level of circulating PTH (reviewed in 6) when 25(OH)D values were >30 ng/mL (75 nmol/L). These higher cut-offs were also based on the variability of the available 25(OH)D assay results and on the results of an autopsy study on subjects dead after traffic accidents [bib_ref] Bone mineralization defects and vitamin D deficiency: Histomorphometric analysis of iliac crest..., Priemel [/bib_ref]. Histomorphometric evaluation showed large osteoid areas (allegedly corresponding to vitamin D deficiency) mostly in presence of 25(OH)D levels < 20 ng/mL (50 nmol/L) or, less frequently (namely 21%) between 20 and 30 ng/mL (50 and 75 nmol/L). That study of course did not employ the gold standard method of double tetracycline labeling and is further biased by the lack of data about renal function, calcium levels and intake, physical activity, and so on. Notably, seasonal variations in vitamin D plasma levels are well established, with values that are higher in Summer and Autumn than in Winter and Spring [bib_ref] Environmental factors that influence the cutaneous production of vitamin D, Holick [/bib_ref]. The latitude (northern vs. southern), skin color (black vs. white), sex (females vs. males), and body mass index (BMI) (higher vs. lower) contribute to the variability of serum vitamin D [bib_ref] Influence of season and latitude on the cutaneous synthesis of vitamin D3:..., Webb [/bib_ref] [bib_ref] A population-based model to consider the effect of seasonal variation on serum..., Vuistiner [/bib_ref] , as well. An extensive revision of the data regarding the 25(OH)D target levels for the different outcomes is not the aim of the present position statement. For cancer prevention, however, serum 25(OH)D levels between 36 and 48 ng/mL are reportedly associated with favorable outcomes. For the improvement of endpoints such as bone mineral density (BMD), lower extremity function, dental health, incident falls, fractures, hypertension and admission to nursing home, the most appropriate serum 25(OH)D level is described as greater than 30 ng/mL (75 nmol/L) [bib_ref] Optimal Serum 25-Hydroxyvitamin D Levels for Multiple Health Outcomes, Bischoff-Ferrari [/bib_ref]. These cut-offs, however, are not supported by high quality evidence. Literature data are thus univocal for the indication to vitamin D treatment in all subjects with serum 25(OH)D levels < 20 ng/mL (50 nmol/L) but are controversial for values between 20 and 30 ng/mL (50 and 75 nmol/L). The revision of the major meta-analyses of the RCTs on vitamin D supplementation was not, similarly to cancer prevention, one of the aims of this position statement. However, the experts' panel agreed that, even if available data are not consistent, a serum 25(OH)D level of at least 30 ng/mL (75 nmol/L) should be the target for the prevention of fracture risk and muscle function deterioration in older adults [bib_ref] Optimal Serum 25-Hydroxyvitamin D Levels for Multiple Health Outcomes, Bischoff-Ferrari [/bib_ref]. So, when 25(OH)D values are between 20 and 30 ng/mL (50 and 75 nmol/L), particularly if they are measured in Summer/Autumn, the measurement of serum PTH may be used for the confirmation of an actual vitamin D deficiency [bib_ref] Temporal relationship between vitamin D status and parathyroid hormone in the United..., Kroll [/bib_ref]. The relationship between 25(OH)D and PTH values, however, is not linear, it depends even on calcium intake [bib_ref] Scientific opinion on Dietary Reference Values for vitamin D, Efsa Nda Panel [/bib_ref] , the threshold for plateau is not clearly defined [bib_ref] Effects of age and serum 25-OH-vitamin D on serum parathyroid hormone levels, Valcour [/bib_ref] [bib_ref] The 2011 report on dietary reference intakes for calcium and vitamin D..., Ross [/bib_ref] [bib_ref] Vitamin D measurement standardization: The way out of the chaos, Binkley [/bib_ref] , and secondary hyperparathyroidism reportedly occurred only in a third of patients of a large series with 25(OH)D values ≤ 12 ng/mL (30 nmol/L) [bib_ref] Serum 25-Hydroxyvitamin D insufficiency in search of a bone disease, Shah [/bib_ref]. We recommend to maintain 25(OH)D levels above 30 ng/mL (75 nmol/L) in subjects: ## - With osteopenia, osteoporosis or fragility fractures; - On treatment for osteoporosis; - Who belong to at risk categories (see Section 3.1). We suggest to consider serum PTH measurement when vitamin D values are lower than 30 ng/mL (75 nmol/L), particularly if tested in Summer and Autumn. ## What is the scope of the problem? The estimated prevalence of vitamin D deficiency in adult population depends on its cut-off definition (specifically, <20 vs. <30 ng/mL) [bib_ref] Screening for vitamin D deficiency: A systematic review for the U.S. Preventive..., Leblanc [/bib_ref]. The National Health and Nutrition Examination Survey showed that 25% of population was at risk for insufficiency, as defined by serum 25(OH)D levels of 12 to 20 ng/mL, and that 8% had very low 25(OH)D levels (<12 ng/mL) [bib_ref] Demographic differences and trends of vitamin D insufficiency in the US population, Ginde [/bib_ref]. In NHANES, mean 25(OH)D levels appeared lower in the years 2000-2004 than in 1988-1994, but these changes are due to assay changes rather than to an actual decline. In an adult subgroup from NHANES, however, changes in BMI, milk intake, and sun protection appeared to contribute to a small but real decline in vitamin D status [bib_ref] Demographic differences and trends of vitamin D insufficiency in the US population, Ginde [/bib_ref]. If the 25(OH)D cut-off value for the definition of vitamin D deficiency is raised to 30 ng/mL, its prevalence obviously increases. According to NHANES data (2001 to 2006), 42% of subjects showed 25(OH)D levels between 20 and 30 ng/mL [bib_ref] Demographic differences and trends of vitamin D insufficiency in the US population, Ginde [/bib_ref] and were classified as affected by vitamin D insufficiency according to Endocrine Society guidelines [bib_ref] Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical..., Holick [/bib_ref]. In a study on Swedish healthy people, approximately 75% of the subjects had serum 25(OH)D values < 30 ng/mL (<75 nmol/L) during 75% of the year and 50% had serum 25(OH)D < 20 ng/mL (<50 nmol/L) during 50% of the year [bib_ref] Seasonal variations in serum 25-hydroxy vitamin D levels in a Swedish cohort, Klingberg [/bib_ref]. In Switzerland, the prevalence of vitamin D insufficiency (serum 25(OH)D levels between 20 ng/mL and 30 ng/mL, 50 nmol/L and 75 nmol/L) and deficiency (<20 ng/mL, <50 nmol/L) was 36% and 38%, respectively [bib_ref] Vitamin D deficiency, Holick [/bib_ref]. In spite of the much lower latitude, a study from Turkey reported serum 25(OH)D values lower than 30 ng/mL (75 nmol/L) in 75% of the cases [bib_ref] Unsal, I. Analysis of changes in parathyroid hormone and 25 (OH) vitamin..., Serdar [/bib_ref]. As for Italy, several studies on vitamin D status have been performed over the past 20 years in populations that embrace different age ranges and living conditions. Isaia et al. reported 25(OH)D circulating levels less than 12 ng/mL (30 nmol/L) in 76% of Italian women over 70 years of age, in late Winter [bib_ref] Prevalence of hypovitaminosis D in elderly women in Italy: Clinical consequences and..., Isaia [/bib_ref]. In subjects institutionalized or with underlying diseases, the percentage of subjects with hypovitaminosis D was even more. Moreover, in 608 young and healthy women, 30% resulted to be deficient (cut-off of serum 25(OH)D < 20 ng/mL, 50 nmol/L). In younger subjects also, the levels of vitamin D were lower in women and in Winter [bib_ref] Longitudinal evaluation of vitamin D status in healthy subjects from southern Italy:..., Carnevale [/bib_ref]. The InChianti studio, that from 1998 studies the aging processes on 1107 participants and collects information about diet, sun exposure, disability, kidney function, levels of 25(OH)D and PTH, revealed values of serum vitamin D, on average, higher than 20 ng/mL (50 nmol/L) in healthy adults, but significantly reduced in males ≥ 60 years and females ≥ 50 years [bib_ref] 25(OH)D Serum levels decline with age earlier in women than in men..., Maggio [/bib_ref] [bib_ref] Serum 25-Hydroxyvitamin D, Plasma Klotho, and Lower-Extremity Physical Performance Among Older Adults:..., Shardell [/bib_ref]. In the study by Houston et al., 64% of subjects > 65 years (average 75 years) had values < 20 ng/mL (50 nmol/L), and deficiency of vitamin D was found in approximately 30% of women and 14% of males and insufficiency was in 75% of women and 51% of males [bib_ref] Association between vitamin D status and physical performance: The InCHIANTI study, Houston [/bib_ref]. Another Italian study on 974 patients, ≥75 years of age, with femoral fracture from 4 large provincial hospitals, located in Central-Northern Italy, showed 25(OH)D circulating mean levels of 12.2 ± 9.4 ng/mL (30.5 ± 23.5 nmol/L) with >50% having <12 ng/mL (30 nmol/L) and only 16% > 20 ng/mL (50 nmol/L) [bib_ref] Vitamin D supplementation is required to normalize serum level of 25OH-vitamin D..., Lauretani [/bib_ref]. A recent observational study on serum vitamin D levels in Italian pediatric populations/young adults demonstrated 25(OH)D levels not significantly reduced in the young and healthy young adults. In 113 normal weight and 444 obese children (prepubertal and pubertal), approximately 70% of normal weight children had 25(OH)D levels > 30 ng/mL (75 nmol/L) and 30% < 30 ng/mL, and approximately 55% of obese children had 25(OH)D levels > 30 ng/mL and 45% < 30 ng/mL [bib_ref] Vitamin D levels in a paediatric population of normal weight and obese..., Bellone [/bib_ref]. Another pediatric Italian study revealed 50% of teenagers with 25(OH)D levels >30 ng/mL (75 nmol/L). Logistic regression analysis showed the following odd ratios (OR) in these specific dichotomous categories: overweight (OR 5.02) and obese (OR 5.36) versus subjects with normal BMI, lack of sun exposure (OR 8.64) versus optimal, regular use of "sunscreens" (OR 7.06) versus non-regular users. Moreover, significant higher relative risk for hypovitaminosis D was observed in Winter (OR 27.20), Spring (OR 26.44), Fall (OR 8.27) versus Summer [bib_ref] Prevalence of hypovitaminosis D and predictors of vitamin D status in Italian..., Vierucci [/bib_ref]. So, the available data in Italy confirm unequivocally high prevalence of vitamin D deficiency in the elderly, especially in certain subgroups at greater risk and therefore, different strategies, according to the age groups in which no deficiency is generalized (strategies of "case finding"), and elderly population in which an overall situation of deficiency is expected, are necessary. ## Vitamin d deficiency and damage to organs beyond bone Several reports show an association of vitamin D deficiency with increased risk of mortality [bib_ref] Vitamin D and mortality: Individual participant data meta-analysis of standardized 25 hydroxyvitamin..., Gaksch [/bib_ref] , cancer (particularly colon, prostate, and breast cancer) [bib_ref] Vitamin D, cancer risk, and mortality, Tagliabue [/bib_ref] , cardiovascular disease [bib_ref] Vitamin D and cardiovascular disease: Controversy unresolved, Mheid [/bib_ref] , type 1 and type 2 diabetes [bib_ref] Vitamin D deficiency and diabetes, Berridge [/bib_ref] , autoimmune diseases [bib_ref] Does vitamin D play a role in autoimmune endocrine disorders? A proof..., Altieri [/bib_ref] , and decreased fertility [bib_ref] Association of vitamin D intake and serum levels with fertility: Results from..., Fung [/bib_ref]. Even though the topic is beyond the scope of our statement, we did not find evidence-based data demonstrating the efficacy of vitamin D for decreasing the risk of these chronic diseases [bib_ref] Effect of vitamin D supplementation on non-skeletal disorders: A systematic review of..., Autier [/bib_ref]. Accordingly, we believe that vitamin D determination and substitution treatment are not yet warranted to prevent or treat clinical disorders that are different from bone diseases. ## Diagnostic issues ## When to order a vitamin d assay? Individuals at risk should always be screened for vitamin D deficiency [fig_ref] Table 1: Categories of patients that should be screened for vitamin D deficiency [/fig_ref]. As in these subjects vitamin D treatment is expected to produce a rapid favorable effect, vitamin D determination is definitely cost-effective [bib_ref] Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical..., Holick [/bib_ref] [bib_ref] Vitamin D deficiency, Holick [/bib_ref] [bib_ref] Vitamin D status: Measurement, interpretation and clinical application, Holick [/bib_ref] [bib_ref] Benefit-risk assessment of vitamin D supplementation, Bischoff-Ferrari [/bib_ref]. Even though many authors found low vitamin D plasma levels in healthy people worldwide, no evidence exists as for a benefit of vitamin D deficiency screening and/or treatment at a general population level [bib_ref] Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical..., Holick [/bib_ref]. We recommend screening for vitamin D deficiency in at risk populations. We recommend against screening for vitamin D deficiency in healthy people. ## Which molecular forms of vitamin d are assayed by laboratories? The vast majority of clinical laboratories measure circulating serum 25(OH)D that is the sum of 25(OH) vitamin D2 plus 25(OH) vitamin D3 [bib_ref] Simultaneous quantification of vitamin D 3 , 25-hydroxyvitamin D 3 and 24,25-dihydroxyvitamin..., Burild [/bib_ref]. Total serum 25(OH)D is the best available indicator of cutaneous synthesis (sunlight, skin) and total intake (food, supplements). Due to the widespread use of both vitamin D2 and vitamin D3 supplements, assays should always measure both 25(OH)D2 and 25(OH)D3, which is not the case for some immunoassays. To accurately measure total vitamin D, it must be dissociated from VDBP: in automated methods, details of this process are generally proprietary to the assay platform, and not known. Other possible explanations for different results by various immunoassays are: ## - Cross reactivity with metabolites (such as 3-epi 25OH-D) that is variable in different kits. ## - Presence of eterophilic antibodies. - Lack of assay standardization. To minimize these drawbacks, the standardization of 25(OH)D values by immunoassay methods to liquid chromatography (LC)-Tandem mass spectrometry (MS/MS) equivalent values or direct measurement by LC-MS/MS will provide valid conclusions about the actual health implications of vitamin D deficiency or insufficiency [bib_ref] Measuring 25-hydroxyvitamin D in a clinical environment: Challenges and needs, Hollis [/bib_ref] [bib_ref] Clinical utility of simultaneous quantitation of 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D by..., Kaufmann [/bib_ref]. We suggest to employ the same method for serial measurements of vitamin D in any patient (panel agreed on the recommendation and downgraded it to suggestion due to feasibility reasons). ## 1,25-(oh) 2 -vitamin d assay: friend or foe? Serum levels of 1.25(OH) 2 D have little or no relationship to vitamin D stores. They are primarily regulated by PTH and FGF-23 levels, which, in turn, are regulated by calcium, vitamin D and phosphates [bib_ref] Vitamin D status: Measurement, interpretation and clinical application, Holick [/bib_ref] [bib_ref] Relative value of 25(OH)D and 1,25(OH) 2 D measurements, Lips [/bib_ref]. So, in vitamin D deficiency 1.25(OH) 2 D levels increase and confusion may arise if its blood concentration is assumed as a measure of vitamin D storage [bib_ref] Assessment of circulating 25(OH)D and 1,25(OH) 2 D: Emergence as clinically important..., Hollis [/bib_ref]. 1.25(OH) 2 D determination may be useful in a few clinical conditions [bib_ref] New horizons for assessment of vitamin D status in man, Lensmeyer [/bib_ref] [bib_ref] Bone and mineral metabolism, Fraser [/bib_ref] : - When an elevated calcemia is associated with a low PTH level, as in granulomatous diseases (tuberculosis, sarcoidosis) and in some lymphomas. ## - In some patients with end-stage kidney disease. ## - In hereditary or acquired disorders of vitamin D and phosphate metabolism. We recommend against routine 1,25-(OH) 2 -vitamin D assessment. ## Which additional parameters may be useful in an incidental finding of vitamin d deficiency? In case of an incidental finding of very low 25(OH)D levels, serum calcium, phosphate, ALP, PTH, magnesium, and creatinine should be evaluated [bib_ref] Proton pump inhibitors and hypomagnesemia in the general population: A population based..., Kieboom [/bib_ref] [bib_ref] Essential nutrient interactions: Does low or suboptimal magnesium status interact with vitamin..., Rosanoff [/bib_ref] [bib_ref] Magnesium Supplementation in Vitamin D Deficiency, Reddy [/bib_ref]. These data better define the repletion of body stores and may suggest the screening for potentially concomitant low vitamin D-associated diseases (see [fig_ref] Table 1: Categories of patients that should be screened for vitamin D deficiency [/fig_ref] for possible differential diagnoses). We suggest the evaluation of the above-mentioned laboratory parameters in selected cases, specifically for the screening of potentially concomitant low vitamin D-associated diseases. ## Should a severe vitamin d deficiency lead to dual energy x-ray absorptiometry (dxa) evaluation? Vitamin D deficiency may cause osteomalacia and increase the risk of low bone mass and fragility fractures [bib_ref] Vitamin D and vitamin D analogues for preventing fractures associated with involutional..., Avenell [/bib_ref]. It is appropriate to perform a densitometric evaluation by DXA at spine and hip in any subject whose risk of fractures is increased. Briefly, BMD testing is indicated in women aged 65 and in men aged 70 and older, in post-menopausal women younger than 65 and men < 70 years with low body weight, with prior fractures, who take drugs associated with bone loss, or with diseases or conditions associated with bone loss. All patients considered for a pharmacologic therapy for osteoporosis should first receive BMD testing [bib_ref] Executive summary of the 2015 ISCD position development conference on advanced measures..., Shepherd [/bib_ref]. The presence of asymptomatic fractures should be ruled out, also considering the familiarity for fragility fractures. We suggest to perform DXA examination whenever the fracture risk is increased. ## Vitamin d should be checked after a fragility fracture? As vitamin D insufficiency/deficiency may impair the response to the bone-active drugs [bib_ref] The 25(OH)D level needed to maintain a favorable bisphosphonate response is ≥33..., Carmel [/bib_ref] , it appears reasonable to test vitamin D levels previously to the treatment with any bone-active drug, and, if necessary, to assure adequate supplementation. We suggest to check 25(OH)D levels in any patient with established osteoporosis before starting the treatment. ## How to manage the persistence of severe vitamin d deficiency after loading doses and chronic replacement therapy? Instead of further increasing vitamin D dosage, it is appropriate to rule out secondary causes of vitamin D deficiency by lab assays as depicted at Section 3.4. Other procedures may be considered according to clinical context [bib_ref] Preventive Services Task Force. Screening for vitamin D deficiency in adults: U.S...., Lefevre [/bib_ref]. We recommend to rule out secondary causes of vitamin D deficiency whenever serum 25(OH)D levels are not normalized as expected after treatment. The major dietary source of vitamin D is cod liver oil, but also fishes, such as mackerel, carp, eel, salmon, smoked sturgeon, trout, swordfish and tuna provide a satisfactory vitamin D intake. Egg yolk, a few mushrooms and breakfast grains provide only a small intake of vitamin D that is nearly absent in meat and cheese. ## Therapeutic issues Diet can be an important determinant of vitamin D status, and is influenced by the cultural nutritional practice and national policy [bib_ref] A systematic literature review for the 5th edition of the Nordic Nutrition..., Lamberg-Allardt [/bib_ref]. Plasma 25(OH)D concentrations were lower in vegetarians and vegans than in meat and fish eaters in a UK study [bib_ref] Plasma concentrations of 25-hydroxyvitamin D in meat eaters, fish eaters, vegetarians and..., Crowe [/bib_ref]. Consistently, the Hoorn Study in The Netherlands reported that the main determinants of vitamin D status were the time spent outdoors, the higher BMI, the consumption of oil-rich fish and fortified fat (fortified with 3 IU/g) and the use of vitamin D supplements [bib_ref] Potentially modifiable determinants of vitamin D status in an older population in..., Van Dam [/bib_ref]. In US, vitamin D is mainly ingested through fortified foods: milk and yogurt are the main contributors but other foods, such as breakfast grains, margarine, orange juice, and soy drinks, are also fortified. A report from NHANES showed that 100% of the population after two years of age had a vitamin D intake below the estimated average requirement and that this figure decreased by 7% with fortified foods and by 30% with additional supplements [bib_ref] Foods, fortificants, and supplements: Where do Americans get their nutrients?, Fulgoni [/bib_ref]. The dietary contribution to the desirable plasma levels of 25(OH)D is considerably lower in Italy than in US, due to the composition of diet (with less animal fats) and to the lack of appropriate fortification and supplementation of foods. In Italy, diet provides approximately 300 IU/day, so in Winter, when sun exposure is virtually absent, supplements for 1200-2000 IU/day must be guaranteed [bib_ref] Italian Society for Osteoporosis; et al. Guidelines on prevention and treatment of..., Adami [/bib_ref]. We suggest not to consider the dietary sources as adequate for the achievement of an optimal vitamin D status in Italy. ## What about the sun exposure for the treatment of vitamin d deficiency? The main source of vitamin D for human body is the action of sunlight. Data about sun exposure and vitamin D synthesis are inconsistent, as sunlight accounts for 30% according to IOMand for 80% according to Holick [bib_ref] Vitamin D deficiency, Holick [/bib_ref]. The skin synthesis of vitamin D is self-limited by the production of inactive metabolites that prevents the risk of vitamin D intoxication even after excessive sun exposure. Notably, the efficiency of skin production of vitamin D was adaptively increased by depigmentation when dark skinned people migrated from Africa to northern latitudes. Presently it was reported that a dark skin could produce up to six-times less vitamin D than a pale skin under the same UV exposure [bib_ref] Factors that influence the cutaneous synthesis and dietary sources of vitamin D, Chen [/bib_ref] [bib_ref] Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D..., Luxwolda [/bib_ref]. Italian epidemiologic studies reported that 25(OH)D levels differed by near 40% between subjects with either a low or an average sun exposure, suggesting a 60-90% contribution of the sun exposure to vitamin D synthesis [bib_ref] Italian Society for Osteoporosis; et al. Guidelines on prevention and treatment of..., Adami [/bib_ref]. Aging is associated with a decrease in the time of sun exposure, in the area of the exposed surface, and in the efficiency of the skin production of vitamin D [bib_ref] Aging decreases the capacity of human skin to produce vitamin D3, Maclaughlin [/bib_ref]. Furthermore, from November to March the intensity of UVB rays is insufficient for the conversion of 7-dehydro-cholesterol into cholecalciferol, right above and below the 33th parallel (including also Mediterranean Europe) [bib_ref] Vitamin D: An overview of vitamin D status and intake in Europe, Spiro [/bib_ref]. In young adults, a Summer sun exposure (without sunscreen) of about 25% of body surface (face and arms) for 15 min twice or thrice a week is equivalent to an oral dose of 25 µg (1000 IU) of vitamin D [bib_ref] Modelling the seasonal variation of vitamin D due to sun exposure, Diffey [/bib_ref]. So, Summer vacation at sea plus 30 min daily in open space can be considered as sufficient for an adequate production and do not require a screening for vitamin D deficiency. Workers without adequate sun exposure, such as indoor workers and rotating shift-workers mainly with night shift (included health professionals), should be added to the population traditionally considered at risk for vitamin D deficiency (see Section 3.1). We suggest not to consider sun exposure as adequate for the achievement of an optimal vitamin D status in Italy. ## How to supply vitamin d? Vitamin D is absorbed through passive diffusion and an incompletely known process involving membrane carriers, especially cholesterol transporters. Concomitant fat ingestion may improve vitamin D absorption [bib_ref] Intestinal absorption of vitamin D: A systematic review, Silva [/bib_ref] , but vitamin D can be absorbed also without fat or oily vehicles. Factors that modify cholesterol absorption diminish vitamin D absorption as well. There are conflicting data as to whether vitamin D2 and vitamin D3 are equally effective in increasing and maintaining serum concentrations of 25OH-D, particularly when a low dose treatment is performed. Several studies suggest that vitamin D3 should be preferentially used to optimize vitamin D status in the general population [bib_ref] Short and long-term variations in serum calciotropic hormones after a single very..., Romagnoli [/bib_ref] [bib_ref] Evaluation of ergocalciferol or cholecalciferol dosing, 1600 IU daily or 50,000 IU..., Binkley [/bib_ref] [bib_ref] Daily supplementation with 15 µg vitamin D 2 compared with vitamin D..., Tripkovic [/bib_ref] , in particular for the maintenance of adequate plasma 25(OH)D levels in the long term [bib_ref] Long-term vitamin D 3 supplementation is more effective than vitamin D 2..., Logan [/bib_ref] [bib_ref] Vitamin D 3 seems more appropriate than D 2 to sustain adequate..., Olivieri [/bib_ref]. Notably, the oral assumption of vitamin D, either D2 or D3, appears more effective for increasing serum 25(OH)D than the equivalent dose given by injection both in the short and long-term assumption [bib_ref] Effect of a single oral dose of 600,000 IU of cholecalciferol on..., Cipriani [/bib_ref] [bib_ref] Long-term bioavailability after a single oral or intramuscular administration of 600,000 IU..., Cipriani [/bib_ref]. So, cholecalciferol, currently the most used therapy for the treatment of osteopenia/osteoporosis, should be used as first line therapy [bib_ref] Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical..., Holick [/bib_ref]. However, some vegan people may prefer the use of ergocalciferol that is not of animal origin [bib_ref] Treatment with 50,000 IU vitamin D 2 every other week and effect..., Demetriou [/bib_ref]. Cholecalciferol is commercially available as drops (10,000 units/mL) and as vials with different potency (25,000 U, 50,000 U, 100,000 U, and 300,000 U) to be administered either orally or parenterally. No tablets are available in Italy. We recommend treatment with cholecalciferol by mouth as the first line therapy in most patients. ## What is the appropriate dosage of vitamin d supplementation? Vitamin D dosage and schedule depend on different factors: severity of deficiency, body weight, age of the patient, and need of rapid normalization of blood levels. It is usually appropriate to achieve target levels within 2-3 months [bib_ref] Italian Society for Osteoporosis; et al. Guidelines on prevention and treatment of..., Adami [/bib_ref] [bib_ref] Guidelines for the diagnosis, prevention and management of osteoporosis, Rossini [/bib_ref] and, when the intestinal absorption is normal and baseline 25(OH)D levels are very low, in a healthy adult subject it has been estimated an average 0.7-1.0 ng/mL (1.7-2.5 nmol/L) rise for every 100 IU of daily ingested vitamin D [bib_ref] Italian Society for Osteoporosis; et al. Guidelines on prevention and treatment of..., Adami [/bib_ref]. Subsequently, the increase slows as the 25(OH)D levels rise. When malabsorption is suspected, after performing what suggested at Section 3.4, the use of hydroxylated metabolites or injectable formulations of vitamin D may be considered. The role of vitamin D supplementation in the prevention of falls is still controversial. A recent RCT [bib_ref] Monthly high-dose vitamin D treatment for the prevention of functional decline. A..., Bischoff-Ferrari [/bib_ref] evaluated 200 elderly women, selected on the basis of a prior fall, divided into three groups on the basis of different monthly vitamin D3 dosage: 24,000 IU/monthly (control group), 60,000 IU/monthly or 24,000 IU/monthly plus 300 µg calcifediol. Although higher doses of supplements were more effective in reaching target levels of 25OH-D, the risk of falls was significantly increased. The study showed a 5.5 times greater risk of falling in patients reaching the highest quartile of 25(OH)D level (44.7-98.9 ng/mL) compared with those reaching the lowest quartile (21.3-30.3 ng/mL), suggesting an U-shaped (rather than a J-shaped) curve of the effect of vitamin D status on prevention of falls. A second RCT confirmed these data [bib_ref] Medium doses of daily vitamin D decrease falls and higher doses of..., Smith [/bib_ref] but the association of the risk of falls and fractures with vitamin D status may be influenced by factors, such as assay standardization, lifestyle, or hypovitaminosis D-related disease masked by self-supplementation started before baseline vitamin D status assessment. Finally, a RCT on community-dwelling old women showed a correlation between the annual oral administration of a large dose of cholecalciferol (500,000 IU) for 3-5 years and an increased the risk of falls [bib_ref] Annual high-dose oral vitamin D and falls and fractures in older women:..., Sanders [/bib_ref]. A meta-analysis of 32 studies [bib_ref] Meta-analysis of all-cause mortality according to serum 25-hydroxyvitamin D, Garland [/bib_ref] revealed no association of serum 25(OH)D levels with all-cause mortality, while serum 25(OH)D levels were inversely associated with a lower all-cause mortality rates for values up to 70 ng/mL (175 nmol/L). A recent study showed that, after the standardization of the different assays for 25(OH)D levels, the risk of death from all causes increased with decreasing 25(OH)D levels < 16 ng/mL (40 nmol/L). No association was present for values between 16 ng/mL (40 nmol/L) and 48 ng/mL (120 nmol/L) [bib_ref] The reverse J-shaped association between serum total 25-hydroxyvitamin D concentration and all-cause..., Durazo-Arvizu [/bib_ref]. Vitamin D deficiency and insufficiency are rapidly corrected by 50,000 IU of vitamin D once a week for 8 weeks [bib_ref] Redefining vitamin D insufficiency, Malabanan [/bib_ref] [bib_ref] Letter: Vitamin D 2 Treatment for Vitamin D Deficiency and Insufficiency for..., Pietras [/bib_ref]. A daily dose of 5000 IU of vitamin D for 8 weeks is an alternative approach [bib_ref] Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol, Heaney [/bib_ref]. Finally, to maintain vitamin D sufficiency, a simple strategy is the administration of 50,000 IU twice a month [bib_ref] Treatment with 50,000 IU vitamin D 2 every other week and effect..., Demetriou [/bib_ref] , or, alternatively, a daily dose of 1500-2000 IU [bib_ref] Photobiology of vitamin D in mushrooms and its bioavailability in humans, Keegan [/bib_ref]. The achievement of target 25(OH)D levels is not changed by different timing of vitamin D administration in controlled settings [bib_ref] Evaluation of ergocalciferol or cholecalciferol dosing, 1600 IU daily or 50,000 IU..., Binkley [/bib_ref] [bib_ref] A randomized controlled trial of vitamin D dosing strategies after acute hip..., Papaioannou [/bib_ref] , while the adherence to treatment may be variable according to the vitamin D schedule (daily, weekly or monthly intervals). A deferred administration of dietary supplements may be useful to obtain adherence to the therapy and more stable 25(OH)D blood levels. We suggest the following schedules for vitamin D supplementation: - Deficiency and insufficiency: 50,000 IU once a week for 8 weeks; alternatively, a daily dose of 5000 IU for 8 weeks; - Maintenance of sufficiency: 50,000 IU twice a month; alternatively, a daily dose of 1500-2000 IU. We suggest an individually tailored approach for vitamin D administration, involving the patient's opinion about the schedule (daily, weekly or monthly) that may offer the best adherence. ## When hydroxylated metabolites of vitamin d should be prescribed? Calcifediol has been reported to restore normal circulating levels of vitamin D more rapidly than cholecalciferol [bib_ref] Relative effectiveness of oral 25-hydroxyvitamin D 3 and vitamin D 3 in..., Cashman [/bib_ref] [bib_ref] Effects of cholecalciferol vs calcifediol on total and free 25-hydroxyvitamin D and..., Shieh [/bib_ref] [bib_ref] Correction of vitamin D status by calcidiol: Pharmacokinetic profile, safety, and biochemical..., Minisola [/bib_ref]. Reliable comparative evaluations of hydroxylated vitamin D metabolites vs. vitamin D-equivalent doses are lacking. Calcifediol can be used in the general population and has an elective indication in congenital abnormalities of hepatic 25-hydroxylase activity [bib_ref] Vitamin D-dependent rickets type 1B (25-hydroxylase deficiency): A rare condition or a..., Molin [/bib_ref] , intestinal malabsorption and, sometimes, obesity [bib_ref] Impaired release of vitamin D in dysfunctional adipose tissue: New cues on..., Di Nisio [/bib_ref]. Calcifediol is available in drops (0.15 mg/mL, where 1 drop contains 5 µg). Due to its potency, 3-4 drops/day or 20-30 drops/week of calcifediol are generally adequate to restore normal 25(OH)D plasma levels [bib_ref] Relative effectiveness of oral 25-hydroxyvitamin D 3 and vitamin D 3 in..., Cashman [/bib_ref] [bib_ref] Effects of cholecalciferol vs calcifediol on total and free 25-hydroxyvitamin D and..., Shieh [/bib_ref]. Alpha-calcidiol and 1.25(OH) 2 D (that is the mono-and di-hydroxylated vitamin D metabolites) should not be used for the routine treatment of vitamin D deficiency due to the risk of hypercalcemia and/or hypercalciuria and the unfeasibility of a reliable monitoring with plasma 25(OH)D levels [bib_ref] Systematic review of the benefits and harms of calcitriol and alfacalcidiol for..., O'donnell [/bib_ref]. On the other hand, in patients with chronic renal failure (CRF) the 1α-hydroxylation of vitamin D precursors is compromised. So, the prevention of hypocalcemia, of secondary hyperparathyroidism, and of renal osteodystrophy requires the use of the active metabolite of vitamin D. The treatment of these patients is traditionally based on the administration of 1.25(OH) 2 D but in subjects with CRF is also present a 25(OH)D deficiency, due to nutritional factors, poor exposure to sunlight, and inhibition of liver 25-hydroxylation by uremic toxins. Thus, the administration of cholecalciferol in post-dialytic phase contributes to the reduction of PTH levels [bib_ref] Hypovitaminosis D in chronic kidney disease patients: Prevalence and treatment, Cuppari [/bib_ref]. The "Kidney Disease: Improving Global Outcomes" (KDIGO) guidelinesuggests the measurement of 25(OH)D levels in patients with CRF and their correction according to the criteria used for the general population, in addition to appropriate changes in calcium and phosphate intake [bib_ref] National Osteoporosis Society Vitamin D Guideline Summary, Aspray [/bib_ref] [bib_ref] Canadian Society of Nephrology Commentary on the KDIGO Clinical Practice Guideline for..., Akbari [/bib_ref]. As PTH stimulates the renal 1-hydroxylation of 25(OH)D [bib_ref] Vitamin D: Production, metabolism, and mechanisms of action, Bikle [/bib_ref] , in patients with hypoparathyroidism the activation of vitamin D is impaired. Thus, the treatment of hypoparathyroidism should be based on the use of the active form of vitamin D, i.e., 1.25(OH) 2 D [bib_ref] Management of hypoparathyroidism: Summary statement and guidelines, Brandi [/bib_ref]. Cholecalciferol has no direct action on bones, but patients with CRF [bib_ref] 25-Hydroxyvitamin D testing and supplementation in CKD: An NKF-KDOQI controversies report, Kramer [/bib_ref] [bib_ref] Effects of vitamin D or its analogues on the mortality of patients..., Lu [/bib_ref] or hypoparathyroidism [bib_ref] Management of hypoparathyroidism: Summary statement and guidelines, Brandi [/bib_ref] with demonstrated vitamin D deficiency should be supplemented with cholecalciferol to warrant the "non-classical" effects of this vitamin. 1.25(OH) 2 D is commercially available as tablets (0.25 µg and 0.50 µg) and vials (1 µg/mL). Alpha-calcidiol is commercially available as tablets (0.25 µg and 1 µg) and drops (2 µg/mL, where 1 drop contains 0.05 µg). We suggest the use of calcifediol in case of: Calcium supplements in subjects with normal food intake are reported to increase the risk of nephrolithiasis and cardio-and cerebrovascular events [bib_ref] Vascular events in healthy older women receiving calcium supplementation: Randomised controlled trial, Bolland [/bib_ref] [bib_ref] Effect of calcium supplements on risk of myocardial infarction and cardiovascular events:..., Bolland [/bib_ref] [bib_ref] Concordance of results from randomized and observational analyses within the same study:..., Bolland [/bib_ref]. As these data are still controversial [bib_ref] Calcium supplementation and the risks of atherosclerotic vascular disease in older women:..., Lewis [/bib_ref] [bib_ref] The effects of calcium supplementation on verified coronary heart disease hospitalization and..., Lewis [/bib_ref] [bib_ref] Calcium intake and cardiovascular disease risk: An updated systematic review and meta-analysis, Chung [/bib_ref] , calcium supplements (at the dosage recommended for the different periods of life) should be prescribed only in case of documented nutritional deficiency [bib_ref] The calcium and vitamin D controversy, Abrahamsen [/bib_ref]. We recommend calcium plus vitamin D supplements in patients with insufficient calcium intake, particularly if osteoporotic and taking bone active drugs. ## Vitamin d overtreatment: myth or reality? The USA Endocrine Society guidelines recommend an upper threshold for daily vitamin D intake of 10,000 IU [bib_ref] Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical..., Holick [/bib_ref] , while the IOM committee recommends an upper daily intake of 4000 IU [bib_ref] The 2011 report on dietary reference intakes for calcium and vitamin D..., Ross [/bib_ref]. However, clinical vitamin D toxicity is rare and blood concentrations of 25(OH)D associated with doubtless toxicity are rarely found [bib_ref] Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical..., Holick [/bib_ref]. No harm has been reported with a daily intake of 10,000 IU (250 µg) of vitamin D [bib_ref] Vitamin D: Production, metabolism, and mechanisms of action, Bikle [/bib_ref] , while long-term studies on the effects of a daily intake greater than 10,000 IU or the maintenance of serum 25(OH)D levels above 100 ng/mL (250 nmol/L) are lacking. So, symptoms of vitamin D toxicity are unusual with a daily intake up to 10,000 IU, while toxicity may be associated with a daily intake > 10,000 IU [bib_ref] Italian Society for Osteoporosis; et al. Guidelines on prevention and treatment of..., Adami [/bib_ref]. Acute vitamin D toxicity, characterized by hypercalcemia and its associated symptoms, is generally reported in presence of serum 25(OH)D values > 140 ng/mL (350 nmol/L) [bib_ref] Vitamin D metabolism in patients intoxicated with ergocalciferol, Mawer [/bib_ref] [bib_ref] Overview of the conference "Vitamin D and Health in the 21st Century:..., Brannon [/bib_ref] [bib_ref] Changing incidence of serum 25-hydroxyvitamin D values above 50 ng/mL: A 10-year..., Dudenkov [/bib_ref]. We recommend a dosage of vitamin D up to a maximum of 4000 IU/day. We recommend against doses above 10,000 IU/day. We suggest a careful surveillance of any possible intake, because patients might inadvertently assume products containing additional amounts of vitamin D. ## Treatment monitoring ## Vitamin d assessment during supplementation: when and how? Vitamin D pharmacokinetics is complex and serum 25(OH)D level is influenced not only by vitamin D supplement but also by dietary vitamin D intake and exposure to sunlight [bib_ref] Italian Society for Osteoporosis; et al. Guidelines on prevention and treatment of..., Adami [/bib_ref]. Monitoring of serum 25(OH)D during supplementation is generally unnecessary but is appropriate in patients with symptomatic vitamin D deficiency, malabsorption conditions, and when poor compliance is suspected. In patients at risk of persistent 25(OH)D level below 30 ng/mL (75 nmol/L), retesting after 8-12 weeks may be appropriate. In the other patients, retesting should not be performed before 6 months of vitamin D supplementation [bib_ref] The 25(OH)D level needed to maintain a favorable bisphosphonate response is ≥33..., Carmel [/bib_ref] [bib_ref] Vitamin D status and response to treatment in post-menopausal osteoporosis, Adami [/bib_ref] [bib_ref] Effect of parathyroid hormone (1-34) on fractures and bone mineral density in..., Neer [/bib_ref] [bib_ref] Osteoporosis, teriparatide, and dosing of calcium and vitamin D, Licata [/bib_ref]. We recommend against routine serum 25(OH)D testing during vitamin D supplementation. We suggest the assessment of vitamin D levels after at least 6 months of therapy, also if combined with bone active drugs, in patients: ## - With previous severe hypovitaminosis D or persistent risk of severe hypovitaminosis because of renal or liver failure, metabolic bone diseases, malabsorption, severe obesity, hypogonadism, glucocorticoid treatment; - At risk for hypercalcemia due to underlying diseases (i.e., granulomatosis and lymphoproliferative tumors) where 1.25(OH) 2 D assay is appropriate for monitoring; - Who assume high doses of vitamin D and present with symptoms of vitamin D toxicity. ## Vitamin d and drugs interactions: what we need to know The 25-hydroxylase CYP3A4 enzyme, which converts ergo-and cholecalciferol to 25(OH)D, is a phase I biotransformation enzyme for many drugs. Several drugs are metabolized by CYP3A4, while other medications may inhibit or induce CYP3A4 activity [bib_ref] Drug-vitamin D interactions: A systematic review of the literature, Robien [/bib_ref]. Further interfering mechanisms include: - Altered absorption of the fat-soluble vitamin D with drugs that inhibit the absorption or enhance the elimination of dietary fat. - Increased risk of hypercalcemia when vitamin D intake is associated with calcium-sparing medications. [fig_ref] Table 2: Vitamin D and drugs interaction [/fig_ref] reports the drugs that may more frequently interfere with the absorption and metabolism of vitamin D. We suggest the evaluation of concomitant medical treatments for a potential interference with vitamin D absorption and metabolism. We suggest the correction of vitamin D deficiency even in patients on teriparatide. ## Special contexts ## Vitamin d and pregnancy Many pregnant women are at risk of vitamin D deficiency [bib_ref] Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical..., Holick [/bib_ref] , a condition associated with increased risk of pregnancy complications, mainly pre-eclampsia and cesarean section [bib_ref] Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical..., Holick [/bib_ref]. A correlation between maternal vitamin D deficiency (<20 ng/mL, <50 nmol/L) and gestational diabetes, small for gestational age (SGA) newborns, preterm delivery, and pediatric asthma is reported [bib_ref] Vitamin D supplementation during pregnancy: Improvements in birth outcomes and complications through..., Hollis [/bib_ref] [bib_ref] Vitamin D administration during pregnancy as prevention for pregnancy, neonatal and postnatal..., Wagner [/bib_ref]. Accordingly, these complications appear less frequent in pregnant women whose 25(OH)D levels are above 40 ng/mL (100 nmol/L) [bib_ref] Vitamin D supplementation during pregnancy: Improvements in birth outcomes and complications through..., Hollis [/bib_ref] [bib_ref] Vitamin D supplementation for women during pregnancy, De-Regil [/bib_ref]. Vitamin D supplementation in pregnancy is safe up to 4000 IU/day [bib_ref] Vitamin D administration during pregnancy as prevention for pregnancy, neonatal and postnatal..., Wagner [/bib_ref]. A systematic review of RCTs demonstrated that prenatal vitamin D supplementation is associated with increased mean birth weight, reduced risk of SGA, reduced risk of wheeze in offspring, and increased infant length at one year of age, with no effect on preterm birth [bib_ref] Vitamin D supplementation during pregnancy: State of the evidence from a systematic..., Roth [/bib_ref]. Supplementation should be individually tailored due to the variable response to treatment due to the different body weight and sun exposure [bib_ref] Determinants of maternal 25-hydroxyvitamin D response to vitamin D supplementation during pregnancy, Moon [/bib_ref]. We suggest to assay 25(OH)D levels in pregnancy to screen for its deficiency. We suggest the supplementation of pregnant women with cholecalciferol, aiming at a serum 25(OH)D level > 40 ng/mL (100 nmol/L). ## Bmi and vitamin d treatment: does it matter? Obesity and vitamin D deficiency represent an important health problem worldwide, at least in western countries [bib_ref] Dietary surveys indicate vitamin intakes below recommendations are common in representative Western..., Troesch [/bib_ref]. The relationship of serum 25(OH)D levels with BMI is controversial because both a negative and a positive correlation between these parameters, or its absence, were reported [bib_ref] Serum 25-hydroxy vitamin D levels in relation to body mass index: A..., Saneei [/bib_ref]. This variability may be explained by the cross-sectional design of most studies, but other variables may be relevant: latitude, season, gender (especially different adiposity between men and women with the same BMI) [bib_ref] Serum 25-hydroxyvitamin D 3 and body composition in an elderly cohort from..., Jungert [/bib_ref] , dress customs [bib_ref] Vitamin D deficiency and sun avoidance among university students at Abu Dhabi, Anouti [/bib_ref] , public health intervention on vitamin D supplementation [bib_ref] Sunlight exposure or vitamin D supplementation for vitamin D-deficient non-Western immigrants: A..., Wicherts [/bib_ref] , and living in developed or developing countries [bib_ref] Socioeconomic status and obesity, Mclaren [/bib_ref]. A well-conducted meta-analysis of 34 cross-sectional studies with adequate quality [bib_ref] Serum 25-hydroxy vitamin D levels in relation to body mass index: A..., Saneei [/bib_ref] demonstrated a weak, negative correlation between serum 25(OH)D levels and BMI in healthy adults, males and females, living in developed countries. The same correlation was evident also for men living in developing countries, but not for women. The strength of the meta-analyses, however, was low due to the high heterogeneity of the studies (I 2 = 82.2%). Finally, a randomized study in obese subjects demonstrated that the 25(OH)D response to vitamin D3 supplementation is directly related to the dose and body size, with ≈2.5 IU/kg required for every unit (ng/mL) increment in 25(OH)D level [bib_ref] 25-Hydroxyvitamin D response to graded vitamin D3 supplementation among obese adults, Drincic [/bib_ref]. In conclusion, a weak inverse correlation between serum vitamin D and BMI is demonstrated. Obese patients (BMI > 30 kg/m 2 ) might require 2-3 times more vitamin D to both treat and prevent vitamin D deficiency and insufficiency [bib_ref] The importance of body weight for the dose response relationship of oral..., Ekwaru [/bib_ref]. Due to its pharmacokinetic profile, calcifediol might represent an alternative option [bib_ref] Impaired release of vitamin D in dysfunctional adipose tissue: New cues on..., Di Nisio [/bib_ref] [bib_ref] Calcidiol [25(OH)D3]: From diagnostic marker to therapeutical agent, Brandi [/bib_ref] [bib_ref] The clinical use of vitamin D metabolites and their potential developments: A..., Cianferotti [/bib_ref]. We suggest to consider obese patients at high risk for vitamin D deficiency. We suggest a duplicated, or triplicated, dose of vitamin D in obese patients and the use of calcifediol instead of vitamin D in this setting. Author Contributions: Roberto Cesareo proposed the idea to write this document and coordinated the task force. Topics were subdivided among all authors, which revised literature data and wrote a paragraph draft. All authors discussed the whole draft by e-mail and during two meetings. Roberto Attanasio coordinated the writing committee. Michele Zini attributed levels of evidence to references. ## Conflicts of interest: The authors declare no conflict of interest. ## Abbreviations [fig] 4. 1: Fortified Food for Treating Vitamin D Deficiency: What Is Their Role? The Dietary Guidelines for Americans identified vitamin D among the four foods of interest for public health [63]. [/fig] [table] Table 1: Categories of patients that should be screened for vitamin D deficiency. Drug interfering with vitamin D metabolism (anti-seizure medications, glucocorticoids, AIDS medications, anti-fungals, cholestyramine) • Granulomatous disorders and some lymphomas (in these cases, also 1.25(OH) 2 D should be tested) [/table] [table] Table 2: Vitamin D and drugs interaction.Drug-vitamin D interactions that may induce side effects Thiazides [/table]	None	https://www.mdpi.com/2072-6643/10/5/546/pdf	Vitamin D deficiency is very common and prescriptions of both assay and supplementation are increasing more and more. Health expenditure is exponentially increasing, thus it is timely and appropriate to establish rules. The Italian Association of Clinical Endocrinologists appointed a task force to review literature about vitamin D deficiency in adults. Four topics were identified as worthy for the practicing clinicians. For each topic recommendations based on scientific evidence and clinical practice were issued according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) System. (1) What cut-off defines vitamin D deficiency: even though 20 ng/mL (50 nmol/L) can be considered appropriate in the general population, we recommend to maintain levels above 30 ng/mL (75 nmol/L) in categories at risk. (2) Whom, when, and how to perform screening for vitamin D deficiency: categories at risk (patients with bone, liver, kidney diseases, obesity, malabsorption, during pregnancy and lactation, some elderly) but not healthy people should be screened by the 25-hydroxy-vitamin D assay. (3) Whom and how to treat vitamin D deficiency: beyond healthy lifestyle (mostly sun exposure), we recommend oral vitamin D (vitamin D2 or vitamin D3) supplementation in patients treated with bone active drugs and in those with demonstrated deficiency. Dosages, molecules and modalities of administration can be profitably individually tailored. (4) How to monitor the efficacy of treatment with vitamin D: no routine monitoring is suggested during vitamin D treatment due to its large therapeutic index. In particular conditions, 25-hydroxy-vitamin D can be assayed after at least a 6-month treatment. We are confident that this document will help practicing clinicians in their daily clinical practice.
57179679d3d4938327b1eb1d9ac5652085d5f185	pubmed	COVID-19 and ART: the view of the Italian Society of Fertility and Sterility and Reproductive Medicine	COVID-19 and ART: the view of the Italian Society of Fertility and Sterility and Reproductive Medicine publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.755RBMO VOLUME 40 ISSUE 6 2020On behalf of the Italian Society of Fertility and Sterility and Reproductive Medicine (SIFES-MR)ABSTRACTThe COVID-19 pandemic is an unprecedented global situation. As assisted reproductive technology (ART) specialists, we should be cautious, carefully monitoring the situation while contributing by sharing novel evidence to counsel our patients, both pregnant women and would-be mothers. Time to egg collection and drop-out rates are critical parameters for scheduling treatments once the curve of infections has peaked and plateaued in each country. In order to reduce the values for these two parameters, infertile patients now require even more support from their IVF team: urgent oocyte collection for oncology patients must be guaranteed, and oocyte retrievals for women of advanced maternal age and/or reduced ovarian reserve cannot be postponed indefinitely. This document represents the position of the Italian Society of Fertility and Sterility and Reproductive Medicine (SIFES-MR) in outlining ART priorities during and after this emergency. T hirteen years ago, Cheng and colleagues reported in Clinical Microbiology Reviews that: Coronaviruses are well known to undergo genetic recombination, which may lead to new genotypes and outbreaks. The presence of a large reservoir of SARS-CoV-like viruses in the horseshoe bats, together with the culture of eating exotic mammals in southern China, is a time bomb. [bib_ref] Severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging..., Cheng [/bib_ref] At the start of January 2020, China announced a new major epidemic focus of coronavirus disease 2019 , now rapidly expanding worldwide. Despite contrasting theories regarding the origin of this virus, its natural development has recently been demonstrated [bib_ref] The proximal origin of SARS-CoV-2, Andersen [/bib_ref]. On 11 March 2020, the General Director of the World Health Organization (WHO) declared the disease COVID-19 to be a pandemic (https://www.who.int/docs/defaultsource/coronaviruse/transcripts/whoaudio-emergencies-coronavirus-pressconference-full-and-final-11mar2020. pdf?sfvrsn=cb432bb3_2). In this regard, many countries are using a combination of containment and mitigation activities with the intention of delaying major peaks of patients to manage the limited number of hospital beds and facilities demanded [bib_ref] COVID-19: towards controlling of a pandemic, Bedford [/bib_ref]. Following China, Italy was the country that had the highest number of cases (on 30 March 2020, 101,739 cases, with 3981 patients currently in intensive care units and 11,591 deaths). During the first 10 days of March 2020, data from Italy showed that 9-11% of patients actively infected with COVID-19 were requiring intensive care [bib_ref] COVID-19 and Italy: what next?, Remuzzi [/bib_ref]. Lisa Rosenbaum recently stated in the New England Journal of Medicine: Though Italy's health system is highly regarded …, it has been impossible to meet the needs of so many critically ill patients simultaneously. Elective surgeries have been cancelled, semielective procedures postponed, and operating rooms turned into makeshift ICUs. With all beds occupied, corridors and administrative areas are lined with patients, some of them receiving noninvasive ventilation. [bib_ref] Facing Covid-19 in Italy -Ethics, Logistics, and Therapeutics on the Epidemic's Front..., Rosenbaum [/bib_ref] The author further elegantly stated 'the tragedy in Italy reinforces the wisdom of many public health experts: the best outcome of this pandemic would be being accused of having overprepared' and we, as the Italian Society of Fertility and Sterility and Reproductive Medicine (SIFES-MR), undoubtedly share her stance and have thus drafted this report for assisted reproductive technology (ART) specialists worldwide. The aim of this manuscript is to propose a strategy to recalibrate the approach of ART specialists who must deal with this potentially long-lasting COVID-19 emergency. ## Covid-19 emergency and pregnancy Although the impact of this infection on babies is low , newborns or children might be asymptomatic carriers of the infection, which might go undetected while being spread to the wider population. Moreover, confirmation of infection at present consists mainly of PCR for acute illness, and although many serological tests to identify antibodies are being developed, they require validation with well-characterized sera before being considered reliable. The current scenario is fluid, especially when dealing with the impact of COVID-19 on gestation. To date, Fan and colleagues have postulated a lack of vertical transmission of SARS-CoV-2, virus not being reported in any screened products of conception or in newborns (two of whom had an infected mother) . Evidence published in The Lancet by Chen and co-workers confirmed these results in nine late pregnancies [bib_ref] Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine..., Chen [/bib_ref]. Clearly, infected mothers (and those suspected to have the infection) must avoid close contact with their newborn, especially avoiding breastfeeding, as highlighted by Qiao in their comment on Chen's report [bib_ref] What are the risks of COVID-19 infection in pregnant women?, Qiao [/bib_ref]. In general, all this evidence must be confirmed in larger studies, especially because equally underpowered and possibly biased reports of adverse gestational/neonatal outcomes have been also reported . In relation to the first or second trimester of gestation, the latest updates from the Centers for Disease Control and Prevention (CDC) have not reported any issue to date (https://www.cdc. gov/coronavirus/2019-ncov/prepare/ pregnancy-breastfeeding.html?CDC_ AA_refVal=https://www.cdc.gov/ coronavirus/2019-ncov/specific-groups/ pregnancy-faq.html), but conclusive information on the risks from the virus are clearly absent [bib_ref] Novel corona virus disease (COVID-19) in pregnancy: What clinical recommendations to follow?, Liang [/bib_ref]. Of note, the drugs and treatments required in case of gestational issues are strongly contraindicated in the first and second trimesters. However, no scientific society has yet, to our knowledge, issued recommendations to discourage fertile couples from conceiving spontaneously during the COVID-19 emergency. ## Covid-19 emergency: the position of italian and international scientific societies in the field of art The authority for ART in Italy, the Superior Institute of Health (ISS) and the National Center of Transplants (CNT), delivered their 'Prevention measures of transmission of new Coronavirus infection (SARS-CoV-2) in Italy for reproductive cells and treatments of ART' on 17 March 2020 (Prot.605/ CNT2020; 2020 http://www.trapianti. salute.gov.it/imgs/C_17_cntAvvisi_233_0_ file.pdf). They recommended the following: (i) avoidance of non-urgent gamete donation programmes; (ii) suspension of IVF programmes and office activity for couples who have not yet started ovarian stimulation, unless the treatment is urgent because of cancer or advanced maternal age; and (iii) starting new treatments only if no symptoms of infection are reported. La Marca and colleagues summarized these recommendations in a comprehensive comment published in Fertility and Sterility , and SIFES-MR together with PMA Italia issued their own preliminary recommendations for Italian IVF centres (http://www. pma-italia.it/IT/news.xhtml/news/258comunicazione-congiunta-fondazionepma-italia-e-sifes), as did other Italian scientific societies in the ART field. Internationally, on 19 March 2020 the European Society for Human Reproduction and Embryology (ESHRE) suggested preventing the establishment of new pregnancies through deferred embryo transfer, preventing patients from travelling for fertility treatment and avoiding additional stress on healthcare systems. On 23 March, ESHRE's annual meeting was cancelled, and 2 days later a 'COVID-19 working group to monitor scientific reports relevant to reproductive medicine' was formed (https://www.eshre.eu/Home/ COVID19WG). The American Society for Reproductive Medicine (ASRM) Task Force released an official document on 17 March 2020 (https://www.asrm. org/news-and-publications/covid-19/), then updated on 30 March (https:// www.asrm.org/globalassets/asrm/asrmcontent/news-and-publications/covid-19/ covidtaskforceupdate1.pdf), suggesting that all new treatments should be suspended, embryo transfers suspended, treatment for patients already in the cycle or requiring urgent stimulation and cryopreservation continued, and elective surgery and non-urgent diagnostic procedures suspended, thus minimizing interperson interaction, with an increase in adoption of telemedicine. The aim of these national and international documents is to safeguard the health of ART operators, of couples undergoing ART and of newborns, who must all deal with this COVID-19 emergency. These precautionary measures are based on the principles of responsibility and solidarity, and are aimed at preventing the contagion, avoiding overload of the healthcare system, as well as establishing a pregnancy in this situation. ## Infertility in italy: a constant decreasing trend in the number of live births and the key role of art The Italian population (60.7 million) decreases by 0.2% every year and has a life expectancy of 82.5 years. It is among the oldest-aged populations in the world and is facing difficulties in financing pensions due to a lack of younger taxpayers. There are 1.35 births per woman versus 1.96 in France and 1.8 in the USA. In Italy, as well as in the majority of other countries, infertility occurs in approximately 20% of the population, with many women undergoing ART when they are over 37 years old, and 35.2% of the total number of candidates being older than 40. There are more than 300 IVF centres in Italy, which overall performed 71,686 cycles in 2017 and resulted in 2.5% of the live births of country's live births (2.9% of IVF-derived live births being through gamete donation programme) (https://www.epicentro.iss.it/focus/pma/ aggiornamenti). Clearly, ART has a key role in Italy, a fact that cannot be overlooked in the current emergency. ## Covid-19 emergency: putative strategy to schedule art treatments after the peak of infections A precautionary approach is strongly recommended until reliable data are produced [bib_ref] Potential Maternal and Infant Outcomes from (Wuhan) Coronavirus 2019-nCoV Infecting Pregnant Women:..., Schwartz [/bib_ref]. SIFES-MR suggests that all patients who have already started ovarian stimulation should consider deferring embryo transfer via oocyte/ embryo cryopreservation. It is preferable to postpone pregnancy until reliable evidence is produced on the relationship between COVID-19 and gestation. In terms of oocyte retrieval, it is our opinion that the recommendation of scientific societies like the ASRM to continue 'urgent [infertility] treatments which are time-sensitive' should not be limited to patients scheduled for 'gonadotoxic therapy or extirpative reproductive surgery', but should include other categories of time-sensitive patients. In this regard, infertility is 'a disease', according to the International Committee for Monitoring Assisted Reproductive Technologies (ICMART)-WHO glossary of infertility , for which the impact of the 'time' variable is critical, especially in populations of women who are of advanced maternal age or have a reduced ovarian reserve, whose chances sharply decrease over time. In these women further postponement of ovarian stimulation and increasing the time to oocyte retrieval for an indefinite period will certainly affect their chance of achieving a live birth. Therefore, SIFES-MR suggests scheduling oocyte/embryo cryopreservation in these patients first, soon after the peak of COVID-19 infection has been passed in each country, while always guaranteeing oocyte retrieval for oncology patients. During this pandemic, some important aspects become essential: (i) the careful identification of infertile women who fall into these time-sensitive categories; (ii) the efficient personalization of the stimulation based on maternal age and ovarian reserve; and (iii) prevention of the ART-related risks (ovarian hyperstimulation syndrome , complications associated with the oocyte retrieval, and multiple gestations). It is implicit that the only ART clinics that should be allowed to perform oocyte retrieval in this emergency are those which have high expertise in the management of potentially infectious specimens, are equipped to cope with putative complications, are competent in vitrification and warming procedures, and are following the recommendations of scientific societies of embryologists such as the Italian Society of Embryology, Reproduction and Research (SIERR; https://www.sierr.it/comunicazioni-newsembriologia-ricerca/emergenza-covid-19raccomandazioni-sierr-per-il-laboratoriodi-pma.html; De [bib_ref] COVID-19: the perspective of Italian embryologists managing the IVF laboratory in pandemic..., De Santis [/bib_ref]. Given these prerequisites, all ART clinics are also tissue centres that are inherently characterized by a protected setting and environment that constantly safeguards both patients and operators. Of note, infected patients/operators, those suspected to be infected and those who have been in contacted with infected individuals (or those suspected to have the infection) should undergo quarantine as a duty towards the community, and must be restricted from entering clinics. ## Prevention of ohss The first choice of action for women undergoing ART during this emergency period is tailoring the gonadotrophin dose with a fixed gonadotrophin-releasing hormone (GnRH) antagonist protocol, GnRH agonist triggering and freeze-all of oocytes or embryos. This protocol will almost completely eradicate the risk of OHSS [bib_ref] An OHSS-Free Clinic by segmentation of IVF treatment, Devroey [/bib_ref]. Moreover, in Italy embryo cryopreservation is allowed only to protect the safety of women and their newborns, so a freeze-all approach in this COVID-19 emergency respects the current regulation, in view of the absence of evidence of SARS-CoV2 effect on gestation . # Art-related complications The risk of multiple gestations and putative gestational issues does not exist if transfer procedures are not performed. As oocyte retrieval would be done instead, the putative surgical complications could be managed in the clinic; if not, this procedure must not be allowed during this emergency period. Nevertheless, the true prevalence of oocyte retrieval-related complications is negligible and does not justify a suspension of ovarian stimulations so as to not overload hospitals: the prevalence of haemoperitoneum is reported to be 0.2%, that of infection or abscess 0.04% (only 60% of patients requiring hospitalization), and that of anaesthesiadependent issues (e.g. hypotension, pneumothorax, pulmonary oedema and malignant hyperthermia) also 0.04% [bib_ref] Appraisal of clinical complications after 23,827 oocyte retrievals in a large assisted..., Levi-Setti [/bib_ref]. ## Summary of sifes-mr recommendations To guarantee the execution of ART treatments and reduce both the time to oocyte retrieval and risk of drop outs in time-sensitive patients, we suggest the following: -Using telehealth (consultations via telephone or videoconferencing) where appropriate for new and returning patients. Where face-toface consultations are required, it is advisable to minimize the number of people attending, limiting the number of people in the waiting room, ensuring at least 1 m distance between them, scheduling the appointments and texting patients when they are ready to be seen, and wearing face masks, gloves and overshoes. Generally, consider reducing the number of non-essential monitoring visits. -Prioritizing access to new ART treatments as follows: oncology patients always to be guaranteed treatment, with treatment then for women with advanced maternal age or reduced ovarian reserve women soon after the peak of infection in each country. -Screening patients for putative symptoms of infection both via a telephone interview before they attend any clinical space and in person on their arrival (chaperones should also be screened). -Avoiding treatment of patients at higher risk of COVID-19 infection due to pre-existing clinical conditions, for example renal disease, diabetes mellitus, hypertension, liver disease, heart problems and all diseases leading to immunocompromise, such as AIDS, cancer or malnutrition. -Intensifying the cleaning and disinfection of common spaces in fertility clinics according to the authorities' relevant recommendations. -Avoiding procedures such as ovulation induction for timed sexual intercourse and intrauterine insemination as these procedures are more frequent with younger women, for whom the 'time' variable is less important. -Adopting personalized ovarian stimulation protocols based on anti-Müllerian hormone concentration and antral follicle count with a fixed dose of gonadotrophin and a fixed antagonist protocol, agonist trigger for oocyte maturation, and freeze-all approach. These actions aim to minimize the need for ultrasound monitoring and the risk of OHSS, and will avoid embryo transfer procedures. -Emergency plans should be in place for the management of potential staffing shortages, supply shortages and unintended exposure of staff members to the risk of COVID-19 infection. In particular, the whole IVF team (clinicians, embryologists, nurses, technicians and secretariats) should be organized into groups of persons always working together, in order to guarantee the quality and safety levels of the procedures and the continuity of care in case of quarantine. -Supporting couples via honest counselling regarding the still unknown effects of COVID-19 on a putative gestation. -Advising clinical and psychological support for infertile patients seeking a pregnancy, to avoid them having a feeling of uncertainty (depending on or additional to this pandemic scenario) that might negatively affect their future reproductive choices, thereby resulting in an increased prevalence of treatment drop-out [bib_ref] Why do patients discontinue fertility treatment? A systematic review of reasons and..., Gameiro [/bib_ref]. # Conclusions COVID-19 disease is an unprecedented global situation that is drastically changing our daily life and perspective. ART specialists should be precautious, carefully following the situation while contributing by sharing novel evidence to counsel our patients, both pregnant women and would-be mothers. All recommendations issued during this emergency are clearly subject to future updates. In this scenario, time to egg collection and drop-out rates are critical for scheduling future treatments once the curve of infection has peaked and finally plateaued in each country. In order to reduce both time to egg collection and drop-out rate, infertile patients now more than ever require the support of their clinicians and of the whole IVF team; urgent oocyte collections for oncology patients must be always guaranteed, and oocyte retrievals for women who have advanced maternal age or reduced ovarian reserve cannot be postponed indefinitely. This is our duty towards our patients, as infertility is increasing over time, simultaneously in countries such as Italy with a constant decline in the live birth rate. Finally, we consider it ethically correct to allow infertile couples to maintain a viable chance of a future pregnancy throughout this pandemic. These patients would otherwise be discriminated against in relation to fertile couples who can still autonomously choose to conceive during this possibly long-lasting global emergency.	None	http://www.rbmojournal.com/article/S1472648320301826/pdf	None
e281f5940520f8472fcb0ab8e59e4cbbd12b4514	pubmed	Vision and Eye Health in Children 36 to <72 Months: Proposed Data System	Vision and Eye Health in Children 36 to <72 Months: Proposed Data System Guidance is provided regarding specific elements to be included, as well as the characteristics and architecture of such a data system. Vision screening for preschool-aged children is endorsed by many organizations concerned with children's health issues. Currently, there is a lack of data on the proportion of children screened and no effective system to ensure that children who fail screenings access appropriate comprehensive eye examinations and follow-up care.Results. The expansion of currently existing, or developing integrated health information systems, which would include child-level vision screening data, as well as referral records and follow-up diagnosis and treatment, is consistent with the proposed national approach to an integrated health information system (National Health Information Infrastructure). Development of an integrated vision data system will enhance eye health for young children at three different levels: (1) the child level, (2) the health care provider level, and (3) an epidemiological level. Conclusions. It is critical that the end users, the professionals who screen children and the professionals who provide eye care, be involved in the development and implementation of the proposed integrated data systems. As essential stakeholders invested in ensuring quality eye care for children, this community of professionals should find increasing need and opportunities at local, state, and national levels to contribute to cooperative guidance for data system development. (Optom Vis Sci 2015;92:24Y30) T he Maternal and Child Health Bureau established the National Center for Children's Vision and Eye Health (NCCVEH) to recommend methods that would increase rates of vision screening and eye examinations in children aged 36 to younger than 72 months. The NCCVEH facilitated an independent expert panel of professionals in eye care, pediatrics, and related fields; this panel established guidelines, recommendations for data collection, and performance measures to track national goals related to children's visual health. The rationale and process used to develop the recommendations are fully described in the Appendix, available online at http://links.lww.com/OPX/A191. The United States Preventive Services Task Force recommends vision screening for all children at least once between the ages of 3 and 5 years to detect the presence of amblyopia or its risk factors.At the present time, the United States lacks reliable data on the proportion of children in the population that receive this recommended preventive service. Existing national estimates suggest a rate of vision screening between 30 and 64%. [bib_ref] Compliance with vision-screening guidelines among a national sample of pediatricians, Wall [/bib_ref] [bib_ref] Preschool vision testing by health providers in the United States: findings from..., Kemper [/bib_ref] Other literature states that rates may be as low as 2 to 6%. [bib_ref] Quantitative pediatric vision screening in primary care settings in Alabama, Marsh-Tootle [/bib_ref] The disparity in these rates appears to be related to the manner in which the data are collected. The higher estimates (30 to 64%) are seen in data from Medicaid administrative claims, whereas direct observation yields significantly lower rates (2 to 6%). As part of Healthy People 2020, national targets have been set to increase the rate of vision screening of children younger than 5 years to a modest goal of 44%.Vision screening alone will not lead to the earlier diagnosis and treatment of amblyopia and other vision problems. Screening is important to identify who is at risk for a vision problem; a comprehensive eye examination is imperative to diagnose and make the appropriate treatment recommendations. An integrated data system is recommended to help ensure that pediatricians and others who conduct and/or monitor vision screening can view the results of the screening and make the necessary referral to an optometrist or ophthalmologist for appropriate diagnostic testing and treatment. There are few data on the proportion of children who have failed a vision screening and subsequently accessed comprehensive eye care, and even fewer data on outcomes of vision screening at a population level. [bib_ref] Project Universal Preschool Vision Screening: a demonstration project, Hartmann [/bib_ref] Currently, there is no uniform approach to documentation of vision screening results. Many vision screening data records are paper based, whereas other data reside on individual software programs that have been developed for internal reporting based on the needs of specific local programs or providers. Such software programs typically do not offer standardization of the type of information collected, nor have they been developed to be compatible with school health or electronic medical records. Finally, there is little, if any, monitoring of subjects who fail screenings to verify that follow-up care with an ophthalmologist or optometrist for diagnosis and treatment has been completed. Providers of vision screening services may be unaware of previous attempts to screen an individual child, the results of those screenings, or whether the child accessed appropriate diagnostic and treatment services, which leads to poor coordination of services for these children. This lack of communication can generate both duplication and omission of vision screening efforts. An integrated data system could provide standardized data collection and reporting formats, as well as a tracking mechanism to ensure that eye care diagnosis and treatment are completed for children who fail a vision screening. Better data systems will work toward improving communication, reducing duplication of health services, and enhancing receipt of appropriate eye care. This article discusses the considerations for the development of such a system. ## Inclusion of vision screening data in an integrated health information system The panel considered possible approaches to the development of data systems for monitoring vision screening and follow-up eye care services and ultimately favored a model that merged vision screening data with an integrated health information system at the state level. 7 Such a system allows for the combination of health data from various sources that can be used to derive information about health status, health care provision, use of services, and impact on health.The National Committee for Vital and Health Statistics was chartered to advise the Secretary for Health and Human Services on health data, statistics, privacy, and national health information issues. The National Committee for Vital and Health Statistics has proposed national guidelines, the National Health Information Infrastructure (NHII), that would lead to uniformity in integrated health information systems. They outlined the important role that a uniform approach to integrated health information will serveVallowing information to be used on three distinct levels:personal level: to support subjects in their own wellness and health care decision making; (2) health care provider level: to ensure access to comprehensive and accurate patient data that will aid in clinical decision making; and (3) epidemiological level: for improved surveillance, monitoring changes, and development of interventions including public health awareness and education.With a truly integrated system, state-level vision screening data would be entered in a uniform manner, following NHII guidelines, and using established data validity and reliability protocols. This system would incorporate vision screening data from screenings administered at various sites such as in the educational-, community-, or public healthYbased settings. The data could be uploaded into the integrated system individually per child or via a digital file generated off-line at the time of the screening. Appropriate identifying information would allow data to be assigned at the child level and reduce duplication of record entry via an established data algorithm. The system would allow direct online entry from vision screenings administered in the medical home, as well as limited eye examination data from an optometrist or ophthalmologist. The primary care provider, or community vision screening program, would be able to review the data (according to data security access levels) to determine if the child had already received a vision screening, and the results of that screening. If the child had not been screened, the provider or community screener would conduct the screening as recommended.If the child had been referred for a comprehensive eye examination, the provider would have an opportunity to review the limited outcome data from the eye examination. If the eye examination had not yet taken place, the provider could reinforce the importance of and/or facilitate scheduling an appointment with an ophthalmologist or optometrist. Similarly, the community vision screener would have information that a vision screening had already been performed during the period when the child was 36 to younger than 72 months old. In most instances, community screeners cannot be expected to assume responsibility for monitoring medical care; however, they should take the opportunity to reinforce the need for the parents to follow through with recommendations for additional care. The introduction of vision examinations for children as an essential health care benefit, as part of the Patient Protection and Affordable Care Act, suggests that information from optometrists and ophthalmologists be integrated into a general electronic health record (EHR) for the child. One expectation of the NHII guidelines is that communication across a variety of EHRs will ultimately be possible and practical. It is anticipated that eye doctors would share information regarding diagnosis and treatment for an individual child that would be accessible to the primary care provider and the school health care provider through a Health Information Exchange. Access to this information would improve communication among patient families, schools, community programs, primary health care providers, and optometrists and ophthalmologists, thereby empowering all individuals involved in a child's vision health. The integrated database proposed here for vision screening would be the beginning of such a monitoring system. As EHRs become better integrated into the anticipated Health Information Exchange, such a system would provide quality surveillance data that can be used to document the prevalence of eye disorders, determine the accessibility of intervention services from optometrists and ophthalmologists, and ultimately allow monitoring of vision and eye health performance measures to facilitate the reduction of health care disparities.Integration of Vision Data with other Child Health Data at the State Level The panel recommends that efforts to integrate vision care data with other child health data should build on existing state-level approaches to data integration following national guidelines for uniform data collection. A targeted protocol would include expansion of the statewide immunization information systems to incorporate information on vision screenings and eye care. These systems already have the appropriate security measures to safeguard privacy of information. This approach would allow monitoring of vision care services provided by different types of health care professionals, including tracking of receipt of follow-up care and outcome measures. Although ophthalmology and optometry currently do not use these systems, it is recommended that they be allowed to review existing data and to add limited clinical results and treatment recommendations from their comprehensive eye examinations. At least four states (Michigan, Minnesota, Ohio, and Rhode Island) have developed integrated immunization systems during the last 5 to 10 years. The state of Ohio provides a specific successful example for vision: Ohio's immunization registry, Impact Statewide Immunization Information System (Impact SIIS), is a secure, Web-based immunization information system housed at the Ohio Department of Health that provides an accurate, efficient way to ensure that children and Ohioans of all ages receive the appropriate vaccinations. As of December 2011, Impact SIIS was expanded to include data from vision and hearing screening programs, allowing screening data from multiple types of providers to be entered into the system. 12 ## Characteristics of an effective child vision health data system A robust data system must be user-friendly with regard to data entry, monitoring, and retrieval of information. Data entry should be accepted from educational, community, or public health settings, as well as primary careY or eye careYbased screenings. This approach to data integration will require systematic data collection, including child-specific identifiers to ensure that the data are accurately linked to the correct child. ## Data flow Vision screening data would be input by a variety of vision screening programs. Primary care providers, school nurses, and educational settings would continue to have access to this integrated database while respecting applicable privacy laws (the Health Insurance Portability and Accountability Act and the Family Educational Rights and Privacy Act). Optometrists and ophthalmologists would be able to access information related to vision screening outcomes as well as share results from comprehensive eye examinations and additional follow-up services. This proposed design would ideally enhance the interchange of information concerning specific children among ophthalmologists, optometrists, primary care providers, and community programs, any of whom would be able to inspect the successful completion of vision screening, screening referral, and limited follow-up plan for an individual child. Furthermore, this system should be designed so that the family is able to review medical information contained within the system, albeit without the ability to modify any data. ## Demographic information required for a robust system Demographic information must be included in the vision screening record to ensure that the data entered are linked to the correct child and to prevent unnecessary duplication of individual children in the database. The US Centers for Disease Control and Prevention (CDC) has defined a set of ''core data items'' for this purpose [fig_ref] TABLE 1: Data items for unique identification of each child 10 Patient ID [/fig_ref].These data items have been adopted by the American Immunization Registry Association and the CDC in order to standardize the Immunization Information System (IIS) across states. The standards were developed by the Immunization Information Systems Support Branch, CDC/National Center for Immunization and Respiratory Diseases (NCIRD), through a consensus process involving input from a variety of IIS managers and technical experts from across the United States. These data elements are considered critical for electronic data exchange and are intended as Functional Standards for all IISs from 2013 to 2017. It is possible that a smaller set of identifiers could be used in specific circumstances if the other data items can be autopopulated. However, this must be determined for each screening site through consultation with appropriate state offices. ## Specific vision care data elements to be included The panel considered the vision-related data elements that should be included in any state data system. [fig_ref] FIGURE 1: FIGURE 1. [/fig_ref] shows the minimum data components to be included in an integrated vision data system. The ''Vision Screening Process'' column lists data that will verify that a valid vision screening process has been completed. The ''NOT Screened'' column details fields that should be reported when a vision screening is not completed, and finally the ''Screening Outcome'' column details data fields that should be captured after a completed screening. These data components align with the recommendations presented in the manuscript from the expert panel on Vision Screening for Children Aged 36 to Younger than 72 Months: Recommended Practices. [bib_ref] for the National Expert Panel to the National Center for Children's Vision..., Cotter [/bib_ref] Individual states may choose to collect additional data points such as visual acuity for each eye that can allow for increased surveillance of screening program quality. Additionally, the system needs a standard method of delivering vision screening results and a referral plan to the parents or guardian of the child being screened. The system should have a mechanism to provide feedback to the educational-, community-, or public healthYbased vision screening programs that the primary care provider or medical home has accessed the information from the vision screening. Finally, the integrated vision data system should contain a component that would capture the results summarizing outcome and treatment recommendations from a comprehensive eye examination. Vision screening data elements. **It may not be possible for community screening programs to determine these diagnoses; however, automatic referral from a medical home screening would be expected to include these categories. The minimal information that should be entered would allow the effectiveness of the screening program to be evaluated at least with regard to the accuracy of children who fail the screening and are referred for a comprehensive eye examination. Specific items are detailed in [fig_ref] TABLE 2: Data from eye care provider Data from initial eye examination Date of... [/fig_ref] and include the following: provider's ID code, refractive error measured for each eye, if glasses were prescribed and the correction prescribed for each eye, yes/no questions concerning specific diagnoses, timeline for next visit to the eye doctor, and if an additional referral was required. ## Operating characteristics of integrated vision care data system The panel provided the following recommendations for the data system operation: 1. User-friendly data entry that can be accomplished through online Web-based entry or uploading of a digital file that was generated off-line at the time of vision screening. 2. Data security mechanisms to safeguard privacy of health and education records, in accordance with guidelines from the Health Insurance Portability and Accountability Act and the Family Educational Rights and Privacy Act. Patient confidentiality procedures should include informed consent for access to health data by authorized individuals. Parents of children being screened should authorize and be made aware of such disclosures. 3. Use of the screening data should be evaluated periodically to ensure that the system is of high quality, is accessible to those who need the information, and demonstrates appropriate use by stakeholders. ## Follow-up considerations It is expected that this data system will include a surveillance component to track both individual vision screening results and receipt of follow-up care provided by an optometrist or ophthalmologist. At a minimum, these data can be used on a population level to measure the proportion of children who are screened, the proportion who are referred from the screening, and the proportion of those who receive eye care. Explicit performance metrics were also developed by this panel (see Marsh-Tootle et al. 14 in this issue). ## Considerations for successful integration There are significant concerns that use of electronic data systems for vision screening and eye examination results may increase patient care documentation time. [bib_ref] Electronic health record systems in ophthalmology: impact on clinical documentation, Sanders [/bib_ref] Placing additional demands on the health care provider must be counterbalanced with appropriate compensation. Mechanisms for incentives and funding need to be in place to ensure that data are entered within a specified time frame after screening, that data are entered consistently and completely, and that a quality assurance system is devised to verify data. Developing an integrated child health information database will require federal funding. ''Meaningful use'' standards should be applied to the development of this data system. Community and volunteer programs should be able to obtain reports from the system to demonstrate the effectiveness of their programs. Unique challenges will be encountered in monitoring homeless, undocumented, or transient children, as well as children who reside in nontraditional family settings, such as foster care. Additionally, appropriate eye care services need to be accessible for children who lack adequate insurance. [bib_ref] The challenges to ophthalmologic follow-up care in at-risk pediatric populations, Williams [/bib_ref] It should be possible to analyze data by subpopulations (e.g., uninsured, specific minorities), which will provide evidence regarding health disparity issues and facilitate the development of programs to decrease such disparities. # Conclusions Vision screening for preschool-aged children is endorsed by a number of organizations concerned with young children's vision and eye health issues. However, there is a fundamental lack of reliable data on the proportion of children in the population that receive preventive vision services, as well as the impact of vision screening programs on eye health for children aged between 36 and younger than 72 months. Current data collection approaches for vision screening are fragmented; the results from vision screenings are isolated from referrals and diagnostic care. The expert panel to the NCCVEH recommends that vision screening referral and outcome data be integrated with other child health data systems, such as existing state immunization information systems and EHRs. Demographic identifiers and results from vision screening for all children should be entered into the system to reduce duplication of services, and data should be accessible to appropriate individuals and agencies, while respecting applicable privacy laws. A standardized data collection, reporting format, and tracking mechanism will enable better monitoring of follow-up eye care for all children who are referred after a vision screening. Furthermore, this will enhance communication between providers and allow for population-level surveillance of children's vision health. Involvement of ophthalmologists and optometrists in the development of integrated data systems is essential to ensure that appropriate data elements are included and that data entry requirements are concise, practical, and useful for vision care tracking and surveillance. Optometrists and ophthalmologists are encouraged not only to participate but also to take on leadership roles in this realm. [fig] FIGURE 1: FIGURE 1. [/fig] [table] TABLE 1: Data items for unique identification of each child 10 Patient ID (previously listed as ''Medicaid Number'') Patient ID: assigning authority ID (i.e., owning source) Patient ID: type (e.g., medical record number, IIS ID) Source: United States Department of Health and Human Services, Centers for Disease Control and Prevention. Immunization Information System Recommended Core Data Elements Atlanta; 2007. http://www.cdc.gov/vaccines/programs/iis/func-stds.html#appB (Accessed on May 28, 2014). 10 26 Vision and Eye Health in 3-to 6-Year-Olds: Proposed Data SystemVHartmann et al. [/table] [table] TABLE 2: Data from eye care provider Data from initial eye examination Date of eye examination Provider's ID code Visual acuity OD Visual acuity OS Were any of the following diagnoses determined: Yes/No amblyopia Yes/No strabismus Yes/No other diagnosis If ''Other,'' please define: Were glasses prescribed? Yes/No If yes, please indicate: Refractive error: OD Refractive error: OS Correction prescribed OD: Correction prescribed OS: Time to next follow-up in months Was an additional referral to another specialist required? Yes/No If yes, what kind of specialist? Data from follow-up eye examination Date of follow-up eye examination Provider's ID code If glasses were prescribed at initial visit, did the child obtain them Yes/No If previously diagnosed with amblyopia, is this diagnosis confirmed? Yes/No 28 Vision and Eye Health in 3-to 6-Year-Olds: Proposed Data SystemVHartmann et al. [/table]	None	https://europepmc.org/articles/pmc4274341?pdf=render	Purpose This article provides a rationale for developing an integrated data system for recording vision screening and eye care follow-up outcomes in preschool-aged children. The recommendations were developed by the National Expert Panel to the National Center for Children’s Vision and Eye Health at Prevent Blindness and funded by the Maternal and Child Health Bureau of the Health Resources and Services Administration, US Department of Health and Human Services. Guidance is provided regarding specific elements to be included, as well as the characteristics and architecture of such a data system. Vision screening for preschool-aged children is endorsed by many organizations concerned with children’s health issues. Currently, there is a lack of data on the proportion of children screened and no effective system to ensure that children who fail screenings access appropriate comprehensive eye examinations and follow-up care. Results The expansion of currently existing, or developing integrated health information systems, which would include child-level vision screening data, as well as referral records and follow-up diagnosis and treatment, is consistent with the proposed national approach to an integrated health information system (National Health Information Infrastructure). Development of an integrated vision data system will enhance eye health for young children at three different levels: (1) the child level, (2) the health care provider level, and (3) an epidemiological level. Conclusions It is critical that the end users, the professionals who screen children and the professionals who provide eye care, be involved in the development and implementation of the proposed integrated data systems. As essential stakeholders invested in ensuring quality eye care for children, this community of professionals should find increasing need and opportunities at local, state, and national levels to contribute to cooperative guidance for data system development.
86850070b57ef315503db89f15059a1d637de6e6	pubmed	Executive Summary from Expert consensus on effectiveness and safety of iDPP-4 in the treatment of patients with diabetes and COVID-19	Executive Summary from Expert consensus on effectiveness and safety of iDPP-4 in the treatment of patients with diabetes and COVID-19 # Introduction The management of patients with diabetes during the COVID-19 pandemic is an aspect that has taken on particular relevance, as diabetic patients with SARS-CoV-2 infection have been found to have a higher risk of a worse prognosis and mortality. The reason for poorer outcomes in patients with diabetes is not yet entirely clear, but it may be due to their reduced immune response to SARS-CoV-2 as a result of chronic hyperglycaemia 2 and/or to the chronic low-grade inflammation associated with diabetes. [bib_ref] Type 2 diabetes and its impact on the immune system, Berbudi [/bib_ref] Some antidiabetic agents (ADA), such as dipeptidyl peptidase-4 (DPP-4) inhibitors, have provoked considerable interest as it has been suggested that they may play a role in reducing the chance of infection with the virus and mitigating the severity of complications associated with COVID-19. [bib_ref] COVID-19 and comorbidities: a role for dipeptidyl peptidase 4 (DPP4) in disease..., Bassendine [/bib_ref] The objective of this review and consensus document is to summarise all of the available data on the potential impact of DPP-4 inhibitors on the clinical outcomes of patients with diabetes during COVID-19, both in diabetic patients treated outside of the hospital setting and in those who required intrahospital management, and to establish recommendations based on the evidence available to date. The full document can be accessed via the following link: Appendix B see additional material. # Methodology Several scientific associations and one foundation, all connected with clinical diabetes management After reviewing and selecting the reference materials, conducting an appropriate analysis of the available evidence and agreeing the clinical questions to address, potential recommendations were established by consensus. ## Literature search A literature search was performed in the PubMed database from December 2019 to February 2021 based on the search strategy outlined in [fig_ref] Table 1: Search strategy approach [/fig_ref]. The results were supplemented with a second manual search. The reviewers carried out the literature selection, data analysis, assessment of the most relevant terms and the quality analysis independently. [fig_ref] Figure 1: PRISMA flow diagram of the article search and selection process [/fig_ref] shows the PRISMA flow diagram of how the article selection process # Oxford methodology The quality of the articles selected was assessed using the Oxford Centre for Evidence-Based Medicine (CEBM) Levels of Evidence (Oxford CEBM, 2009). # Results ## Can diabetes be considered an independent risk factor in the clinical course of patients with sars-cov-2? The data published to date suggest that diabetes does not appear to increase the risk of COVID-19 infection, but the presence of diabetes in patients with COVID-19 is a risk factor with regard to mortality, disease severity and need for admission to an intensive care unit (ICU) 1 (level of evidence 2a) [fig_ref] Table 2: COVID-19 disease outcomes by presence of diabetes [/fig_ref]. It is not fully clear whether this increase in risk is because of the diabetes per se or because patients with diabetes often have a greater prevalence of other risk factors conducive to a worse prognosis for COVID-19. It has been demonstrated that circulating levels of some cytokines such as interleukin-6 (IL-6) are higher in patients with COVID-19 and diabetes, presenting a worse prognosis than in patients without diabetes. This suggests that in the presence of an underlying proinflammatory environment, diabetes would be an independent risk factor for worse outcomes (level of evidence 5). 5 Expert consensus: Based on this, in diabetes, irrespective of adequate control of comorbidities such as obesity or cardiovascular disease, we would recommend raising awareness of the importance of optimal glycaemic control, caution in premature discontinuation of established therapy and optimisation of antidiabetic therapy, weighing up the possible effects of the drugs on inflammation. In patients with diabetes and COVID-19, factors to consider may include selecting drugs that guarantee little fluctuation in glycaemic control and have been found to be safe in different scenarios (pre-hospitalisation, hospitalisation, ICU). ## Do patients treated with dpp-4 inhibitors have a higher or lower risk of infection when exposed to sars-cov-2? Using a modelling-based focus, a recent publication demonstrated that the S1 domain of the SARS-CoV-2 spike glycoprotein might interact with the human DPP-4 membrane, enabling the entry of the virus. [bib_ref] Emerging WuHan (COVID-19) coronavirus: glycan shield and structure prediction of spike glycoprotein..., Vankadari [/bib_ref] However, a registry conducted in Italy explored the potential association between DPP-4 inhibitors for diabetes and the risk of COVID-19 infection and concluded that DPP-4 inhibitors do not appear to have any protective or harmful effect on COVID-19 incidence 7 (level of evidence 2b), backing up recent data on their neutral role on the incidence of respiratory infections. 8 ## Expert consensus: Although there is a possible interaction between SARS-CoV-2 and DPP-4, the use of DPP-4 inhibitors does not appear to either increase or reduce the risk of SARS-CoV-2 infection. ## Do patients treated with dpp-4 inhibitors have a higher risk of being hospitalised for sars-cov-2? A case-control study found that the rate of exposure to DPP-4 inhibitors among patients with type 2 diabetes mellitus (T2DM) with SARS-CoV-2 infection hospitalised for COVID-19 was comparable to that of matched patients in the same region or those from the local outpatient clinic. [bib_ref] Exposure to dipeptidyl-peptidase-4 inhibitors and COVID-19 among people with type 2 diabetes:..., Fadini [/bib_ref] These data suggest that DPP-4 inhibitors do not increase the risk of hospitalisation in patients with COVID-19, and they are considered a valid therapeutic option for the management of patients with diabetes and symptomatic COVID-19 (level of evidence 4). Expert consensus: According to the data that currently exist, DPP-4 inhibitors do not increase the risk of hospitalisation in patients with COVID-19. We therefore suggest maintaining treatment with DPP-4 inhibitors in high-or very high-risk epidemiological situations and in mild or moderate COVID-19 disease that does not require hospitalisation. At a physiological or mechanism-of-action level, is there evidence with regard to the possible advantages that DPP-4 inhibitors might offer in the course of the disease after infection? DPP-4 inhibitors have anti-adipogenic, anti-platelet and anti-inflammatory effects. Studies have found that starting DPP-4 inhibitors leads to a reduction in cytokine production, and a recent meta-analysis also identified a significant reduction in polymerase chain reaction (PCR) levels after treatment with DPP-4 inhibitors compared to placebo. 10 ## Expert consensus: The anti-inflammatory, anti-platelet and anti-adipogenic effects of DPP-4 inhibitors, as well as the possible modulating role of DPP-4 receptors on virus entry, are potential physiological mechanisms that could contribute to a more favourable clinical course of COVID-19 disease. ## Might the use of dpp-4 inhibitors have an impact on mortality? The results of the assessment of the studies suggest a beneficial or neutral effect from this group of ADAs (level of evidence 2a). Four meta-analyses also suggest a beneficial or neutral effect of DPP-4 inhibitors on mortality. A cohort study suggests a small (1.07 [1.01---1.13]) but significant increase in mortality, which can be explained by the large sample size and a probable selection bias in being prescribed preferentially to older, more frail patients [fig_ref] Table 3: Outcomes of studies with DPP-4 inhibitors in patients with COVID-19 [/fig_ref]. The possible effect of these drugs might be more apparent in hospitalised patients, as is reflected in the metaanalysis by Pal et al., [bib_ref] Dipeptidyl peptidase-4 inhibitor use and mortality in COVID-19 patients with diabetes mellitus:..., Pal [/bib_ref] which identified nine high-quality observational studies on 7008 patients with diabetes suffering from COVID-19. In the subgroup analysis, the authors observed that intrahospital use of DPP-4 inhibitors was associated with a reduction in mortality (adjusted OR: 0.27; 95% CI: 0.13---0.55; P = .0003). Given the potential positive impact of DPP-4 inhibitor use, particularly in hospitalised patients, various randomised studies have been launched to clarify this aspect (NCT04365517, NCT04341935 and NCT04371978). ## Expert consensus: Out-of-hospital use of DPP-4 inhibitors has been found not to increase the risk of mortality in patients with diabetes and COVID-19. Intrahospital use of DPP-4 inhibitors may be associated with a significant reduction in mortality in patients with diabetes and COVID-19. It would therefore be prudent to initiate or continue DPP-4 inhibitors in patients with COVID-19 if not contraindicated. ## Could the use of dpp-4 inhibitors increase the risk of developing severe disease? The meta-analysis by found that there is no increase in the risk of greater severity (level of evidence 2a). [bib_ref] A meta-analysis on the preadmission use of DPP-4 inhibitors and risk of..., Kow [/bib_ref] Other evidence that DPP-4 inhibitors do not increase patients' severity is found in the study Coronavirus Disease and Diabetes Outcome (CORONADO). In this study, no association was observed between severe clinical course of COVID-19 and treatment with DPP-4 inhibitors prior to admission (OR: 1.01; 95% CI: 0.75---1.34). However, use of these drugs at hospitalisation appears to significantly reduce the need for mechanical ventilation Expert consensus: Treatment with DPP-4 inhibitors in stable hospitalised patients appears to be a safe treatment option that does not affect the severity of the clinical course of the disease. ## Is the use of dpp-4 inhibitors safe in patients with sars-cov-2 infection compared to other antidiabetic drugs? Some reviews and recent guidelines [bib_ref] Sitagliptin treatment at the time of hospitalization was associated with reduced mortality..., Solerte [/bib_ref] indicate that DPP-4 inhibitors are very safe, and may even be potentially beneficial for most patients hospitalised with diabetes and COVID-19. DPP-4 inhibitors have been found to be safe drugs, and also do not require adjustment on days when patients with diabetes and COVID-19 feel ill, in comparison with other ADAs [fig_ref] Table 4: Recommendations with different antidiabetic drugs in patients with suspected COVID-19 [/fig_ref]. 14 Although only a randomised trial can definitively answer this question, based on molecular, pathophysiological and retrospective studies, the use of DPP-4 inhibitors is safe and certainly beneficial for metabolic control. Expert consensus: These data support the safety of DPP-4 inhibitors for diabetes control during the COVID-19 pandemic. DPP-4 inhibitors are a group of drugs that offer many advantages, including in severe cases of COVID-19, because they are well-tolerated, entail a low risk of hypoglycaemia and can be used, with dose adjustment if appropriate, in patients with decreased kidney function. In this sense, the use of DPP-4 inhibitors can be considered, including in patients hospitalised with diabetes and COVID-19. ## Given the anti-inflammatory effects of dpp-4 inhibitors, is there any subgroup of patients in whom dpp-4 inhibitors might have an impact on the complications associated with covid-19? In patients with COVID-19, the hypothesis has been suggested that due to their anti-inflammatory effect, they might help to prevent complications associated with COVID-19. [bib_ref] DPP4 and ACE2 in diabetes and COVID-19: therapeutic targets for cardiovascular complications?, Valencia [/bib_ref] Studies such as the SIDIACO Sitagliptin study ## Are there differences between dpp-4 inhibitors and other pharmacological groups for the treatment of diabetes in patients hospitalised with covid-19? DPP-4 inhibitors have been found to be safe drugs and do not require adjustment on days of illness in patients with diabetes and COVID-19, in comparison with other oral ADAs 16 ; their use in comparison with other oral ADAs has been associated with shorter ICU stay (level of evidence 2b) and possible benefits in hospitalised patients. ## Expert consensus: Based on the studies published to date, DPP-4 inhibitors could be considered to have a suitable profile for the treatment of diabetes in hospitalised patients. # Conclusions DPP-4 inhibitors are a group of drugs associated with many advantages in the context of the COVID-19 pandemic, including in severe cases, because they are well-tolerated, have a low risk of hypoglycaemia, do not require a dose adjustment on days of illness and can be used in patients with decreased kidney function. After evaluating all the available literature, there is no evidence of sufficient quality to conclusively recommend treatment with DPP-4 inhibitors in patients with diabetes and COVID-19. However, there is also insufficient evidence to advise against their use. The literature reviewed suggests that there might potentially be substantial benefits to treatment with DPP-4 inhibitors, and we are hopeful that this question will shortly be answered by the high-quality prospective, randomised clinical trials that are currently ongoing. ## Authorship All the authors contributed equally to the preparation of the article. # Funding Medical writing assistance was funded by the Menarini Group. However, none of its members attended the meetings held to review the literature and agree on decisions, nor did they influence the decisions made by the experts. ## Conflicts of interest Francisco Javier Carrasco-Sánchez: consultant and/or adviser for Boehringer-Lilly, Novo Nordisk, Sanofi, [fig] Figure 1: PRISMA flow diagram of the article search and selection process. was carried out. The clinical questions of interest were established based on this review. [/fig] [table] Table 1: Search strategy approach (MeSH descriptors).•Targeted search: Cross search of the MeSH term (Dipeptidyl-Peptidase IV Inhibitors) and the MeSH terms (COVID-19) and (Sars-CoV-2) Search extension with the MeSH terms (Dipeptidyl-Peptidase IV Inhibitors) and (DPP4) in free text with the MeSH terms (COVID) and (Sars CoV 2)•Extended search: this second search obtained more articles, but with less specificity [/table] [table] Table 2: COVID-19 disease outcomes by presence of diabetes. [/table] [table] Table 3: Outcomes of studies with DPP-4 inhibitors in patients with COVID-19. [/table]	None	https://europepmc.org/articles/pmc8570981?pdf=render	None
37974a45f7b1053f1b3299521a994a2ff2e7abaa	pubmed	Guidance for clinical neurophysiology examination throughout the COVID-19 pandemic. Latin American chapter of the IFCN task force – COVID-19	Guidance for clinical neurophysiology examination throughout the COVID-19 pandemic. Latin American chapter of the IFCN task force – COVID-19 # Introduction On December 31th, 2019, the Wuhan Municipal Health Commission notified the World Health Organization (WHO) of an outbreak of 27 cases of pneumonia of unknown cause in Wuhan City, Hubei Province, People's Republic of China [bib_ref] A novel coronavirus outbreak of global health concern, Wang [/bib_ref]. The results of the research suggested the diagnosis of viral pneumonia, and the genetic sequencing on January 9th, 2020 discovered a new strain of coronavirus [bib_ref] The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it..., Gorbalenya [/bib_ref]. On February 11th, 2020, WHO called the disease COVID-19, short for ''coronavirus disease 2019" and the International Committee on Virus Taxonomy called the virus ''severe acute respiratory syndrome coronavirus 2" SARS-CoV-2 [bib_ref] The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it..., Gorbalenya [/bib_ref]. COVID-19 is characterized by fever, dry cough, dyspnea, general discomfort and chest pain . The mortality rate is higher in people over 60 years, immunosuppressed or previously affected by other conditions such as obesity, diabetes, respiratory, cardiovascular or cancer diseases [bib_ref] COVID-19: what has been learned and to be learned about the novel..., Yi [/bib_ref]. The overall COVID-19 mortality rate ranges from 2.7 to 3.4% [bib_ref] Estimates of the severity of coronavirus disease 2019: a model-based analysis, Verity [/bib_ref] , while the reproduction number (the expected number of new cases of an infection caused by an infected individual) of COVID-19 (R0) is 2.68, suggesting a high level of contagiosity [bib_ref] The Italian coronavirus disease 2019 outbreak: recommendations from clinical practice, Sorbello [/bib_ref]. In America, the first case of COVID-19 was reported in Washington, D.C., USA, on January 15th, 2020, through the Centers for Disease Control (CDC). WHO declared the status of pandemic by COVID-19 on March 11th, . Until April 12th, 2020, more than one million people have been infected and more than 105,952 deaths have been reported . In America, United States has become the center of the pandemic with more than half million of cases and over 20,000 deaths, however, other Latin-American countries also have a high number of confirmed cases (World Health Organization, 2020a). Cases continue to increase due to the rapidly evolving situation, which is a challenge for health care, especially for severe COVID-19 patients and uninfected severely ill patients . The main route of transmission of SARS-CoV2 has been shown to be through respiratory secretions and direct contact with contaminated surfaces and material. The possibility of the transmission of the virus from asymptomatic carriers through the same routes after a close contact with non-infected people was also documented [bib_ref] Estimates of the severity of coronavirus disease 2019: a model-based analysis, Verity [/bib_ref]. Healthcare professionals (HP) are exposed to a close contact with possible asymptomatic or symptomatic carriers from which transmission is possible [bib_ref] Asymptomatic and human-to-human transmission of SARS-CoV-2 in a 2-family cluster, Li [/bib_ref]. Currently, the extent of those affected by this virus in the HP in Latin America is unknown, however, there are multiple reports of a high incidence [bib_ref] COVID-19 and the risk to health care workers: a case report, Ng [/bib_ref] [bib_ref] The Italian coronavirus disease 2019 outbreak: recommendations from clinical practice, Sorbello [/bib_ref]. On February 11th, 2020, China reported 3019 healthcare workers with COVID-19, corresponding to a proportion of 7.06% of cases in China with at least 6 deaths in that group [bib_ref] Risk factors of healthcare workers with corona virus disease 2019: a retrospective..., Ran [/bib_ref]. In Italy, the International Nursing Council reported on March 19th, 2020 2609 infected health workers. International media reported that Spain's Ministry of Health reported that 14% of COVID-19 cases reported were infected HP. This situation predisposes to the collapse of health systems, reduction of healthcare personnel and even the death of healthcare workers and their families. ## Justification The advent of the SARS-CoV-2 pandemic and the saturation of health services internationally pose a high occupational risk to all healthcare-related staff (Centers for Disease . WHO encourages countries to prepare hospitals and health facilities, protect their health staff, and decide what kind of social distancing methods should be implemented and for how long, among other actions (World Health Organization, 2019). In addition, an increasing number of COVID-19 patients with manifestations of central and peripherical nervous system condition have been reported [bib_ref] Evidence of the COVID-19 Virus Targeting the CNS: tissue distribution, host-virus interaction,..., Baig [/bib_ref] [bib_ref] Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan China, Mao [/bib_ref] [bib_ref] The spectrum of neurologic disease in the severe acute respiratory syndrome coronavirus..., Pleasure [/bib_ref]. Depending on the type of nervous system condition or secondary neurological complication, the assistance of a clinical neurophysiologist may be required. Patients who already have neurological diagnoses requiring studies by the clinical neurophysiology (CN) service during this pandemic should also be taken into consideration. For these two main reasons it is necessary to be prepared and act according to the needs of each patient. Since HP is at the forefront of defense in this pandemic, with SARS-CoV2 infection rates up to 29% [bib_ref] Novel coronavirus and central nervous system, Sun [/bib_ref] , this poses additional risk for intrahospital virus dissemination [bib_ref] The Italian coronavirus disease 2019 outbreak: recommendations from clinical practice, Sorbello [/bib_ref]. Based on the different healthcare systems, human resources, infrastructure and medical emergencies in demand of CN studies, and the lack of a guide for the management of this situation, it was decided to carry out these guidelines. ## Objective To establish guidelines to provide protection of HP conducting CN studies in outpatient or inpatient settings during the COVID-19 pandemic. In addition, to establish a protocol for the disinfection of equipment and supplies required in the CN studies. # Methodology We reviewed the state of the art of scientific articles and sources of official health organizations in English and Spanish of policies to protect HP with an emphasis on COVID-19 and developed recommendations adapted to the practice of CN. These practical guidelines were developed with the participation of experts in CN from Latin America under the coordination of The Latin American Chapter of the International Federation of Clinical Neurophysiology of the International Federation of Clinical Neurophysiology (LAC -IFCN). ## Definitions Coronavirus: Coronavirus are an extensive family of RNA viruses that can cause disease in both animals and humans. In humans, they cause respiratory infections that can range from the common cold to more serious diseases that can lead to death (World Health Organization, 2019). COVID-19: is an acute respiratory disease caused by SARS-CoV-2 (World Health Organization, 2020a). COVID-19 patient confirmed: A person with laboratory confirmation of COVID-19 infection, regardless of clinical signs and symptoms . Suspected case of COVID-19: A person who has some of the following conditions: A) an acute respiratory disease (fever and at least one sign/symptom of respiratory disease; e.g. cough, dyspnea), and a travel or residency history at a location reporting community transmission of COVID-19 for 14 days prior to the onset of symptoms; B) any acute respiratory disease that has been in contact with a probable or confirmed COVID-19 case in the last 14 days prior to the onset of symptoms; or C) a severe acute respiratory disease (fever and at least one sign/symptom of respiratory disease, e.g. cough, shortness of breath; and requiring hospitalization) in the absence of an alternative diagnosis that fully explains the clinical presentation (World Health Organization, 2020a). Probable case of COVID-19: A person who meets the following conditions: (A) a suspected case for whom the laboratory tests for the COVID-19 virus are inconclusive; or (B) a suspected case for whom the tests could not be carried out for any reason (World Health Organization, 2020a). ## General recommendations for clinical neurophysiological studies The following recommendations should be harmonized with current scientific knowledge, institutional, local, national and international medical policies in force. These guidelines address the most common diagnostic procedures for the practice of CN; however, other procedures may follow similar guidelines. The context in which these recommendations are implemented should be adapted to the different phases of the pandemic and health systems, which may vary rapidly in the affected regions. ## Recommendations for neurophysiology staff with risk factors for covid-19 Pregnant women and patients over 60 years of age with comorbidities such as obesity, diabetes mellitus, systemic high blood pressure, cardiovascular disease, chronic lung disease or immunosuppression states have an increased risk of contracting the disease and dying [bib_ref] Clinical Characteristics of 138 Hospitalized Patients with 2019 Novel Coronavirus-Infected Pneumonia in..., Wang [/bib_ref] [bib_ref] COVID-19: what has been learned and to be learned about the novel..., Yi [/bib_ref]. For this reason, CN staff with the above risk factors should avoid conducting CN studies as much as possible and take extreme precautions when there is no other option. ## Recommendations in case of psychiatric signs in cn staff induced by the covid-19 pandemic The pandemic and excess information from mass media including the preventive measures taken by governments has generated in a large part of the population anxiety, panic, fear, insomnia and depressive symptoms in the face of the likelihood of acquiring infection and fatal outcome if acquired [bib_ref] The mental health consequences of COVID-19 and physical distancing, Galea [/bib_ref] [bib_ref] Factors associated with mental health outcomes among health care workers exposed to..., Lai [/bib_ref]. For this reason it is advisable that there is the possibility of access to psychological and psychiatric support, for example, through an easily accessible telephone line where initial support can be provided to the HP, who has an increased risk of developing these symptoms [bib_ref] Factors associated with mental health outcomes among health care workers exposed to..., Lai [/bib_ref]. ## Considerations of clinical neurophysiological studies in any circumstance whether ambulatory, private offices or hospitals Due to the high risk of infection to patients and HP in the face of exposure, it is recommended to carefully evaluate each and every case to decide which, when and why CN tests are non-urgent elective tests and, therefore, could be postponed, including electroencephalograms (EEG), video-EEG, polysomnography (PSG), use of continuous positive airway pressure (CPAP) devices, evoked potentials (EP), neuromuscular ultrasound (US), electromyography (EMG), nerve conduction studies (NCS) and other CN tests (American Clinical Neurophysiology Society, 2020a). In the case of a demand for a CN study, the risk/benefit of conducting an ambulatory study should be evaluated. Performance of the study should be preferred through hospitalization if required by the emergency of the medical condition, and the result of the examination should impact decision-making in the treatment. An example is non-convulsive status epilepticus in children or adults [bib_ref] Yield of repeated intermittent EEG for seizure detection in critically ill adults, Fogang [/bib_ref] [bib_ref] Time to electroencephalography is independently associated with outcome in critically ill neonates..., Sánchez Fernández [/bib_ref]. If an outpatient study is needed in a private or public clinic, the guidelines for the protection of the HP and the prevention of transmission through the guidelines for disinfection of the facilities, equipment and material referred to in sections 13, 14 and 15 below shall be followed. Studies at the patient's home should follow the WHO's recommendations for the care of patients with suspected or confirmed COVID-19, for example in PSG studies with monitors 2 and 3 (American Academy of Sleep Medicine, 2020). ## Preventive covid-19 risk assessment process in the department of clinical neurophysiology prior to patient admission It is useful when evaluating the request for a CN study to call the patient or family relatives and perform clinical and epidemiological screening. The CN lab secretary or assistant should do the following survey, which is very easy to apply. 1. Does the patient have respiratory symptoms and/or fever, no matter whether mild? 2. Has the patient travelled in countries where COVID-19 cases have been detected in the last 14 days? 3. Has the patient been in contact with people who have been traveling or reside in countries with proven cases of COVID-19 in the last 14 days? 4. Has the patient been to places where 2 or more people with respiratory symptoms and/or fever have been detected in the last 14 days (home, workplace, school)? 5. Has the patient been in contact with healthy people who have been in contact with patients with proven COVID-19? 6. Has the patient been in contact with people with a proven or suspected COVID-19 infection in the last 14 days? Patients can be classified as: risk 1, if all answers are negative; risk 2, if any single of the answers to questions 1-5 is ''yes"; risk 3: if two or more answers to questions 1-5 are ''yes"; risk 4 (maximum risk) if the answer to question 6 is ''yes". In the event that all responses are negative, a ''risk 1" is assigned since the patient may still be asymptomatic infected and then could spread the disease. Depending on the risk, neurophysiology service personnel should take the necessary precautions in accordance with institutional and governmental standards. ## Considerations of clinical neurophysiology studies in hospitalized patients Medical condition scenarios that demand for CN studies are multiple and depend on multiple factors including the type of hospital, for example, if a general hospital or a specialized neurological hospital, pediatric or adult or mixed, etc. It is known that human coronaviruses can be spread from the respiratory tract to the central nervous system (CNS) through trans-neuronal and hematogenic pathways, resulting in encephalitis and neurological diseases [bib_ref] Estimates of the severity of coronavirus disease 2019: a model-based analysis, Verity [/bib_ref]. SARS-CoV2 was identified in the cerebrospinal fluid (CSF) in a patient confirmed with COVID-19 in China [bib_ref] Novel coronavirus and central nervous system, Sun [/bib_ref]. The authors proposed that invasion into the CNS, peripheral nervous system and muscle is responsible for some neurological symptoms or syndromes , including as the most common entities musculoskeletal injury (19.3%), impaired consciousness (14.8%) and acute cerebral vascular disease (5.7%) [bib_ref] Human coronaviruses: Viral and cellular factors involved in neuroinvasiveness and neuropathogenesis, Desforges [/bib_ref]. However, it has been reported that hyposmia, anosmia and dysgeusia may occur up to 11% of patients prior to the symptoms of nasal congestion [bib_ref] Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of..., Lechien [/bib_ref]. In general, all requests for CN studies should be reviewed by the physician performing or interpreting the studies to assess the benefit/risk ratio and appropriate time for conducting studies in patients with COVID-19, suspected COVID-19 or patients without COVID-19 infection. A driving plan for staff and patients should be in place, considering the following events: 1. Before the patient's arrival 2. When the patient reaches the clinic or department or attends the intra-hospital area 3. During staff visit to the department, or during the execution of the exam at the patient's bed. 4. When the patient is removed from the emergency room area or returned outside the COVID-19 care area (Centers for Disease Control and Prevention, 2020c). ## Eeg 1. EEG studies (with or without 20-min scalp surface video-EEG) should be conducted following the protection and infection prevention protocol. It is recommended that the physician reviews (remotely if possible) the recording before removing the electrodes and equipment to avoid repositioning in case a continuous EEG (cEEG) is required (with or without video-EEG 1. Several centers recommend rescheduling all elective surgeries, and only trauma, selected cancer and urgent neurosurgical procedures should be performed [bib_ref] Letter: The coronavirus disease 2019 global pandemic: a neurosurgical treatment algorithm, Burke [/bib_ref] [bib_ref] The Italian coronavirus disease 2019 outbreak: recommendations from clinical practice, Sorbello [/bib_ref]. ## Communication between neurophysiological, surgical and anesthesia teams is critical in all peri-operative periods in all cases [bib_ref] Medical error avoidance in intraoperative neurophysiological monitoring: The communication imperative, Skinner [/bib_ref]. 3. IONM staff need to avoid stay in the operative room during the intubation process or to be at least 2 meters away from the patient during this activity, and during the IONM [bib_ref] Barrier enclosure during endotracheal intubation, Canelli [/bib_ref]. 4. CN staff should take special attention to the cases of EMG of facial, laryngeal and pharyngeal muscles, oral cavity and intercostal muscles due to the increased risk of aerosolization or contamination, as well as medical complications. The role of the glass box used during endotracheal intubation ''aerosol box" for the placement of EMG electrodes has not been evaluated, although it has been proposed as an additional protective measure attached to PPE in patients with COVID-19 [bib_ref] Barrier enclosure during endotracheal intubation, Canelli [/bib_ref]. 5. Remote IONM could reduce the exposure of the physician interpreting the study [bib_ref] Intraoperative monitoring: Do you know where your neurophysiologist is, Galloway [/bib_ref]. ## Evoked potentials All elective diagnostic procedures should be rescheduled. If an urgent EP is needed the recommendations in section 11 should be followed. ## Transcranial magnetic stimulation All elective diagnostic procedures should be rescheduled. ## General protective procedures for healthcare personnel The HP should follow the policies to protect themselves and prevent intrahospital transmission. Precautions include rational use and appropriate selection of PPE (Figs. 1 and 2 and [fig_ref] Table 1: Recommendations of rational and appropriate use of Personal Protective Equipment [/fig_ref] ; training on how to put it on, remove it and discard it (World Health Organization, 2020d). In addition, care should be taken that the work area is in proper hygienic conditions . It is recommended to use physical barriers to reduce exposure to patients with COVID-19 or suspect cases, such as glass or plastic windows. This includes administrative areas where patients will first show up, such as triage areas or the registration desk at the CN department (World Health Organization, 2020b). HP access to COVID-19 patient rooms should be restricted if HP is not involved in direct care or will not perform a CN study. HP should consider grouping activities to minimize the number of times to enter a room and plan what activities will need to be done at the bed side . Some considerations about the PPE are as follows: Apron or Gown must be resistant to liquids and must be placed before entering the contaminated environment. After the study, the dressing apron (or gown) must be removed, inside the room and deposited in the corresponding container. Masks: They may be surgical or medical being flat or folded. The use of only medical or surgical masks is insufficient to provide the appropriate level of protection (World Health Organization, 2020b). Respirators (e.g. N95, FFP2 or equivalent standard) are useful when caring for multiple patients who have the same diagnosis and should be used without withdrawal, and evidence indicates that respirators can maintain their protection even when used for extended periods of time. However, using a respirator for more than 4 hours can cause discomfort and should be avoided (World Health Organization, 2020b). Surgical masks have a lifespan of 3 hours. The N95 respirator can be reused, however, the maximum possible number of safe reuses is unknown, so it is advisable to review the recommendations of the manufacturer, the respiratory protection program of the hospital and the infection control department (Centers for Disease Control and Prevention, 2020a). The CDC has recommended that the N95 must be discarded when it has been used in aerosol-generating procedures, when contaminated with blood, nasal or respiratory secretions, or other fluids from the patient (Centers for Disease Control and Prevention, 2020a). The N95 mask lasts 15 days, it must always be stored on paper to avoid moisture, and it is advisable to review the manufacturer's recommendations (Centers for Disease Control and Prevention, 2020a). Goggles and full-face screens or shields should properly cover the eyes and protect them from splashes or aerosols. Gloves made of latex, or nitrile in case of allergy, are recommended. ## Protective procedures for the cn technologist It is important to the CN technologist to know the policies to contain COVID-19 infection. As a first instance, technical staff should have theoretical knowledge of the infectious agent . In this way, they will be aware of the infection mechanism of the virus and will be able to recognize the means or routes of contagion. The CN technologist should also follow the health institution's hygiene recommendations. Before starting the diagnostic study, the CN technologist should: [fig_ref] Figure 2: How to put on and take off Personal Protective Equipment [/fig_ref]. At the site of the diagnostic study 1. Follow the policies of the area where the study will be carried out. 2. Check that the patient also follows the recommended protective policies to reduce the risk of contagion. 3. Conduct the study following international guidelines. 4. If a routine study requires conversion to a prolonged one, inform the CN medical staff to avoid relocations and decrease the exposure time. 5. In case the study is prolonged (e.g. cEEG or video-EEG) the number of technologists entering the area during the shift should be limited. Ensure that there is a distance greater than 2 m from the monitoring patient and use physical barriers if possible. 6. Consider using clear plastic bags to cover CN equipment. 7. Avoid maneuvers that promote airway handling. Avoid request of hyperventilation or use of CPAP . After the diagnostic study ## Protective procedures for the clinical neurophysiologist Clinical neurophysiologists shall coordinate the staff under their supervision and follow the principles of professional responsibility at the institutional, regional and national level of the practice of CN following international, ethical, safety and hygiene principles. Before the study 1. The physician should review and approve the indication of the studies based on risk/benefit assessment. 2. Promote communication between the patient and the diagnostic center and between other health personnel. 3. Rationally select and use the PPE. During and after the CN studies, the clinical neurophysiologist should follow the same principles as the technical CN staff, described in Section 11. 13. Hygiene policy for work areas, medical equipment and supplies SARS-CoV2 is an RNA virus that is wrapped with a fragile external lipid membrane. In general, wrapped viruses are less stable in the environment and are more susceptible to oxidizers such as chlorine. Persistence of coronaviruses on surfaces shows great variability, ranging from about 2 hours to 9 days. Survival time depends on different factors such as surface type, temperature, relative humidity and the specific strain of the virus (World Health Organization, 2020d). The SARS-CoV2 could be eliminated within 1 minute using common disinfectants such as 70% ethanol or sodium hypochlorite. has not yet been detected in drinking water supplies and, based on current evidence, the risk of infection from water supplies is low (World Health Organization, 2020d). According to the U.S. CDC, sterilization is the process that destroys or eliminates all microscopic life forms and is performed in hospitals or clinics using physical or chemical methods, e.g. dry heat, ethylene oxide gas, steam under pressure, hydrogen peroxide plasma and liquid chemicals. Disinfection is the process that eliminates most or all microorganisms, except bacterial spores on inanimate objects, these are eliminated in health facilities by using chemical liquids or wet pasteurization. Cleaning is the removal of visible dirt (e.g. organic and inorganic material) from objects and surfaces and is usually done manually or mechanically using water with detergents or enzymatic products (Centers for Disease . Manufacturer policies, hygiene and hazardous waste management policies of national institutions and regulations on the use or reuse of diagnostic inputs and equipment are recommended. E.g., use of EEG electrode sets or disposable EMG needles. 14. Environmental disinfection, operating room and areas of clinical neurophysiology study Evidence-based strategies for attenuation of environmental contamination involve a combination of deep cleaning with surface disinfectants and ultraviolet (UV) light. UV radiation has proven to reduce intra-hospital bacterial and viral contamination of both surfaces and air . In general, cleaning and disinfection measures should be implemented on any surface that had contact with the patient. Hospital grade cleaning agents are recommended [fig_ref] Table 2: Survey of medical grade disinfectants [/fig_ref] and it is suggested that the bathrooms be cleaned at least twice a day and when needed. Dirty surfaces should first be cleaned with a detergent and then applied to the hospital grade disinfectant, in accordance with the manufacturer's recommendations for volume and contact time. After contact time has elapsed, the disinfectant is rinsed with clean water. SARS-CoV2 will be inactivated after 5 minutes of contact with household laundry disinfectants (World Health Organization, 2020d). Cleaning staff should use appropriate PPE. See [fig_ref] Table 1: Recommendations of rational and appropriate use of Personal Protective Equipment [/fig_ref] (World Health Organization, 2020d). Health risks associated with the use of germicides in hospital spaces range from irritation of mucous membranes to death [bib_ref] Acute accidental poisoning with a hospital disinfectant: 45 cases, 13 deaths, Chataigner [/bib_ref] [bib_ref] Epidermal toxicity of disinfectants, Hess [/bib_ref]. ## Policy for disinfection of the neuro-diagnostic equipment Neuro-diagnostic equipment [fig] Figure 1: COVID-19 Personal Protective Equipment (PPE) for healthcare personnel. Center for Disease Control, USA. https://www.cdc.gov/coronavirus/2019-ncov/hcp/using-ppe. html. [/fig] [fig] Figure 2: How to put on and take off Personal Protective Equipment (PPE), World Health Organization. https://www.who.int/csr/resources/publications/putontakeoffPPE/en/. [/fig] [table] Table 1: Recommendations of rational and appropriate use of Personal Protective Equipment (PPE) in health personnel and patients during clinical neurophysiology studies. Adaptation of the WHO recommendations (World Health Organization, 2020c). [/table] [table] 1: Dispose the non-reusable CN (e.g. electrodes) material. 2. Plan the cleaning procedure for equipment and reusable material. See Section 13. 3. Remove the PPE equipment (Fig. 2) following the recommendations of its dispensing or reuse in the area where you conducted the study, it can be a separate room, but avoid walking in other areas. 4. Wash hands with appropriate technique. 5. Proceed to the disinfection process of diagnostic equipment and electrodes with a new appropriate PPE equipment. Table 1. 6. Remove the PPE. Fig. 2. 7. Perform hand hygiene. [/table] [table] Table 2: Survey of medical grade disinfectants. Severe acute respiratory syndrome coronavirus 2 is sensible to all this medical grade disinfectants (Acosta-Gnass and Stempliuk, 2008), considering that it is a RNA virus with an external lipid membrane.Note: B-bacteria, VL-lipophilic viruses, VH-hydrophilic viruses, M-mycobacteria, H-fungal, E-spores, IE-enzymatic inactivation, DP-denaturation of proteins, IAN-inactivation of nucleic acids. [/table]	None	None	None
12a04240c0ba17dce30c6b72e8da134f05e0bf7d	pubmed	Vaccination for seasonal influenza in patients with cancer: recommendations of the Italian Society of Medical Oncology (AIOM)	Vaccination for seasonal influenza in patients with cancer: recommendations of the Italian Society of Medical Oncology (AIOM) [bib_ref] Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in..., Garten [/bib_ref] [bib_ref] Genetic divergence of influenza A NS1 gene in pandemic 2009 H1N1 isolates..., Campanini [/bib_ref] [bib_ref] Epidemiology and outcomes of serious influenza-related infections in the cancer population, Cooksley [/bib_ref] [bib_ref] Response to influenza virus vaccination during chemotherapy in patients with breast cancer, Meerveld-Eggink [/bib_ref] [bib_ref] Epidemiology and outcomes of serious influenza-related infections in the cancer population, Cooksley [/bib_ref] # Methods We reviewed available data present in the literature, including recommendations by national health authorities, on impact of influenza in patients with cancer and their capacity to mount protective immunological responses to vaccination. Data on available vaccines, strategies to improve the efficacy of influenza vaccination, and treatment of established infection were also reviewed. In addition, experts from the Italian society of Virology and the Italian Health Authority, who are listed among authors, provided additional biological, clinical, and epidemiologic information which greatly helped in clarifying some issues in the absence of clear-cut information from the literature. results available vaccines and their potential side-effects Two types of influenza vaccines are available: (i) the inactivated, injectable vaccine approved for use in subjects older than 6 months, including healthy people, pregnant women, and people with chronic medical conditions; (ii) the live attenuated influenza vaccine (LAIV) administered as a nasal spray. LAIV is approved for use in healthy people from 2 to 49 years of age who are not pregnant. Trivalent inactivated Influenza vaccines may include adjuvants to enhance immunogenicity, and are usually administered as a single shot in immunocompetent individuals, while immunosuppressed subjects may need booster administration. Seasonal influenza vaccines contain antigens that match the three different influenza strains co-circulating during the seasonal epidemics (A H1N1, A H3N2, and influenza B). Due to the constant emergence of antigenic drift variants under herd immunity pressure, the Influenza vaccine needs yearly update to include the escape variants detected during each seasonal epidemic which are predicted to circulate during the next winterspring season. This update is organized by the WHO through the network of sentinel practitioners and reference laboratories (INFLUNET). If the viruses in the vaccine are closely matched to those circulating in the community, vaccine effectiveness is greater. However, even when the viruses are not closely related, the vaccine can still be expected to provide some cross-protection against different, but related, strains of influenza viruses. Based on the limited cross-protection between the two influenza B lineages and the inability to accurately predict which influenza B lineage will circulate, a quadrivalent influenza vaccine including both influenza B strains [bib_ref] A clinical trial of intravenous peramivir compared with oral oseltamivir for the..., Ison [/bib_ref] has recently been approved by the FDA and the European Medicines Agency. Pharmaceutical companies will likely transition to predominantly producing the quadrivalent vaccine. Over the years, hundreds of millions of people worldwide have received seasonal influenza vaccines, essentially without serious consequences. The most common side-effects reported are soreness, redness, tenderness, or swelling of the injection site. Less common are mild arthromyalgia, low-grade fever, and nausea. When such problems occur, they start soon after vaccination and persist for1-2 days. On rare occasions, Influenza vaccination has been associated with more serious complications, such as severe allergic reactions. Before inactivation, influenza viruses are cultured in chicken eggs, so administration of influenza vaccines in subjects with allergy to chicken egg proteins should be avoided. Influenza vaccination has been reported to increase the risk of Guillain-Barré syndrome (GBS) up to 8.8-fold over background rates, mainly based on the experience in 1976 when mass immunization was conducted to prevent an A H1N1 influenza epidemic [bib_ref] Influenza vaccine and Guillain-Barre syndrome-is there a risk?, Nelson [/bib_ref]. Enhanced surveillance for GBS, conducted in 2009-2010, suggested that influenza vaccines were of public health benefit, albeit being associated with a small increased risk of GBS [bib_ref] Influenza vaccine and Guillain-Barre syndrome-is there a risk?, Nelson [/bib_ref]. ## Response and timing of vaccination in cancer patients Successful immunization depends on an intact immune system that can produce antibodies and T-cell response upon antigen exposure. Patients with cancer are considered functionally immunosuppressed, due to their underlying disease and/or cancer therapy. As a consequence, they may have a suboptimal serologic response to influenza vaccination. Although antiviral prophylaxis has been recently used for prevention of influenza virus infection in specific clinical settings such as perivaccine prophylaxis, postexposure prophylaxis, family cluster prophylaxis, as well as seasonal prophylaxis [bib_ref] A clinical trial of intravenous peramivir compared with oral oseltamivir for the..., Ison [/bib_ref] , vaccination is the most effective method for widespread prevention of influenza infection. Indeed, the CDC's Advisory Committee on Immunization Practice (ACIP) in the United States recommends seasonal influenza vaccination for adults without contraindications, who have disease-or medication-related immunosuppression (http:// www.cdc.gov/flu/about/disease/high_risk.htm). However, knowledge of serologic response to seasonal influenza vaccine remains scanty in patients with cancer and is particularly sparse in those with solid tumors [bib_ref] Influenza vaccination in patients with cancer: an overview, Boehmer [/bib_ref]. Tumor heterogeneity, timing of influenza vaccination relative to different chemotherapy treatments, and a general lack of data concerning the vaccine efficacy against influenza infection, or its complications, make it difficult to compare the clinical studies so far reported in the literature. The results of eight controlled clinical trials looking at the efficacy of influenza vaccination in pediatric cancer patients were reviewed [bib_ref] Influenza vaccination in children being treated with chemotherapy for cancer, Goossen [/bib_ref]. Children receiving chemotherapy were able to generate immune responses to the vaccine, albeit more weakly than healthy children, children with asthma or children with cancer who had completed chemotherapy more than 1 month before vaccination. Influenza vaccine was safely administered, and there were no reports of persistent adverse reactions in any of the studies, although patients receiving chemotherapy had a higher incidence of general malaise following vaccination. None of these studies reported on clinical outcome. Seroprotection (antibody titer >40) and seroconversion (at least a fourfold rise in HI titers) were achieved in patients with an established diagnosis of lymphoproliferative disorders [bib_ref] Influenza vaccine in chronic lymphoproliferative disorders and multiple myeloma, Rapezzi [/bib_ref] [bib_ref] Immunogenicity of influenza vaccination in patients with non-Hodgkin lymhoma, Centkowski [/bib_ref] , irrespective of the previous chemotherapy administration. Another recent review and meta-analysis conducted to assess influenza vaccination in immunocompromised patients showed a significantly lower incidence of influenza-like illness after vaccination in HIV patients, cancer patients, and transplant recipients compared with placebo or no vaccination [bib_ref] Influenza vaccination for immunocompromised patients: systematic review and meta-analysis by aetiology, Beck [/bib_ref]. An early study investigated the serologic response to bivalent inactivated influenza vaccination in 17 patients with malignancies [bib_ref] Responses of patients with neoplastic diseases to influenza virus vaccine, Ganz [/bib_ref]. Protective immunity against each of the two influenza A strains in the vaccine was achieved by 41% and 47% of patients, respectively. A study conducted on 41 patients with lung cancer showed a rate of response to the inactivated trivalent seasonal influenza vaccination of 78% [bib_ref] Seroconversion after influenza vaccination in patients with lung cancer, Anderson [/bib_ref] similar to that seen in healthy subjects [bib_ref] Influenza vaccination and chemotherapy: a shot in the dark?, Ring [/bib_ref]. Chemotherapy within the previous 4 weeks, or systemic corticosteroid medication had no significant effect on protective HI response. However, no large trials exist to replicate this information. Data regarding timing of influenza vaccination with regard to chemotherapy administration in adults with solid tumors and hematological malignancies are limited to three studies: one published in 1977 [bib_ref] Influenza immunization of adult patients with malignant diseases, Ortbals [/bib_ref] , two in recent years [bib_ref] Response to influenza virus vaccination during chemotherapy in patients with breast cancer, Meerveld-Eggink [/bib_ref] [bib_ref] Evaluation of pandemic H1N1 (2009) influenza vaccine in adults with solid tumor..., Mackay [/bib_ref]. Overall, 126 patients have been investigated in such studies. Despite the paucity of data in a heterogeneous patient population, it can be suggested that tor patients with solid tumors, if possible, vaccination should be given mid-cycle, preferably 2 weeks after chemotherapy and/or before administration of the subsequent cycle. For patients with hematologic malignancies, the highest serologic response appears to occur following vaccination administered when the leukocyte count is normal and just before initiation of a cycle. In a recently published review article, Polleya et al. recommend vaccination at the furthest possible time point away from treatment during a given cycle [bib_ref] Utility of influenza vaccination for oncology patients, Pollyea [/bib_ref]. Studies, mostly conducted in children, comparing patients who have completed treatment with those who are still receiving treatment, show superior responses in those who have finished treatment [bib_ref] Influenza immunization in immunosuppressed children, Gross [/bib_ref] [bib_ref] Influenza immunization of children with neoplastic diseases, Steinherz [/bib_ref] [bib_ref] Immune response after influenza vaccination in children with cancer, Matsuzaki [/bib_ref]. All these studies indicate that, in general, both chemotherapynaïve and -treated cancer patients show reduced responses to influenza vaccination compared with healthy subjects, but that a considerable number of cancer patients do actually reach the cutoff level for seroprotection. Unfortunately, this is not the case in patients treated with Rituximab in which an impaired immune response to influenza vaccine is reported to be associated with persistent memory B-cell depletion [bib_ref] Impaired response to influenza vaccine associated with persistent memory B cell depletion..., Bedognetti [/bib_ref] [bib_ref] A prospective study of the factors shaping antibody responses to the AS03-adjuvanted..., Hottinger [/bib_ref] [bib_ref] Seroprotective titers against 2009 H1N1 influenza A virus after vaccination in allogeneic..., Issa [/bib_ref] [bib_ref] Rituximab blocks protective serologic response to influenza A (H1N1) 2009 vaccination in..., Yri [/bib_ref] [bib_ref] Seasonal and pandemic (A/H1N1 2009) MF-59-adjuvanted influenza vaccines in complete remission non-Hodgkin..., Bedognetti [/bib_ref]. Thus, in the context of rituximab-including therapies, alternative or better-defined prophylactic/therapeutic approaches are needed. ## Influenza vaccination in patients with solid tumors receiving targeted therapies Limited data are available on the efficacy of influenza vaccination in patients receiving immunotherapies or biologic agents alone or in combination with chemotherapy. The VACANCE study [bib_ref] Immunogenicity and safety of the influenza A H1N1v 2009 vaccine in cancer..., Rousseau [/bib_ref] showed that biologic agents given in combination with cytotoxic drugs did not seem to negatively affect seroprotection. In the same study, patients on targeted therapy alone, especially multikinase inhibitors, had better immune responses than other treatment groups. The latter results are in keeping with a recently published report [bib_ref] Cancer patients treated with sunitinib or sorafenib have sufficient antibody and cellular..., Mulder [/bib_ref] showing that a single shot of influenza vaccination is safe and effective in mounting an antibody immune response in patients treated with sunitinibor sorafenib, and this immune response is comparable with healthy controls. Standard influenza vaccination can be therefore recommended for these patients. ## Strategies to improve the efficacy of influenza vaccination Cancer patients are fragile subjects and influenza vaccine may be less effective due to the impaired immune system. For this reason, they should not be exposed to the LAIV, and the trivalent inactivated vaccine is recommended for annual influenza prophylaxis. Vaccination against influenza can reduce severe illness and complications in immunocompetent individuals, but data demonstrating vaccine effectiveness in immunocompromised individuals are limited [bib_ref] Influenza vaccine in chronic lymphoproliferative disorders and multiple myeloma, Rapezzi [/bib_ref]. Among HIV-positive people with low CD4+ T-cell counts, the administration of inactivated trivalent vaccine does not induce protective antibody titers and a second dose of vaccine does not improve their immune responses [bib_ref] Antibody response after influenza vaccination in HIV-infected individuals: a consecutive 3-year study, Kroon [/bib_ref]. The lack of benefit of one versus two doses of inactivated influenza trivalent vaccine has also been documented in 70 patients with hematological tumors [bib_ref] Vaccination of patients with haematological malignancies with one or two doses of..., Ljungman [/bib_ref]. A recent study [bib_ref] A prospective study of the factors shaping antibody responses to the AS03-adjuvanted..., Hottinger [/bib_ref] demonstrated that two doses of adjuvanted vaccine A/H1N1 was required in 197 cancer patients undergoing chemotherapy, to achieve a similar seroprotection rate (82.3% versus 87%) to that achieved in 138 controls given one dose. Aging decreases the immune response after influenza vaccination, and adjuvants or higher doses of antigen are supposed to improve the immune response with better protection against influenza. In the VACANCE study, including 65 cancer patients receiving cytotoxic and/or targeted therapies [bib_ref] Response to influenza virus vaccination during chemotherapy in patients with breast cancer, Meerveld-Eggink [/bib_ref] , one or two doses of AS03A-adjuvanted H1N1v vaccine resulted in seroprotection rates of 48% and 73%, respectively, and seroconversion rates of 44% and 73%, respectively. Thus, two doses of adjuvanted vaccine improved immunoprotection in this population. There was no suggestion of a potential detrimental effect on tumor therapy by the nonspecific inflammatory stimulus due to adjuvants. The unique immunological characteristics of the skin with its dense network of immune-stimulatory antigen-presenting cells, together with progress in immunization techniques, offer possible ways of improving immunogenicity in low responders, as well as reducing dosage in healthy adults [bib_ref] Intradermal influenza vaccine and new devices: a promising chance for vaccine improvement, Ansaldi [/bib_ref]. A study by Jo et al. [bib_ref] Dose sparing strategy with intradermal influenza vaccination in patients with solid cancer, Jo [/bib_ref] showed that intradermal injection of one-half the dose of a trivalent inactivated split vaccine, elicited immune responses comparable with those elicited by a full dose of intramuscular vaccine among cancer patients. An open-label study of Fluzone® high-dose vaccine versus the Fluzone® standard dose is currently ongoing in children with cancer or HIV receiving two injections of either dose (www.clinicaltrial.gov: NCT01205581). Vaccination apart, protection of cancer patients could be increased by reducing the likelihood of infection. While patients' isolation is not practically feasible, and would not be ethical, vaccination of household contacts and health care personnel is of pivotal importance for increasing the level of herd immunity in the local environment with consequent reduction of influenza virus circulation and likelihood of infection. Moreover, strict preventive measures should be adopted in oncology wards when hospitalized patients develop influenza-like illness, even before the results of viral testing are known. All hygiene precautions (hand washing, surgical masks, etc.) should be enforced together with restrictions on visitors suspected of having respiratory illness. Leukemic children receiving maintenance chemotherapy (lasting 2-3 years) have been reported to be more susceptible to viral infections, probably due to their higher exposure to infected people during school or daycare contacts. Thus, appropriate therapies, together with continued surveillance and implementation of preventive practices, are essential for their care. ## Antivirals for documented or suspected infection Antiviral treatment started as soon as there is suspicion of influenza may make influenza infection milder, shorten the duration of illness, and decrease complications in all populations. Oseltamivir and zanamivir target the neuraminidase enzyme and are effective treatments for influenza infection. Both drugs are typically given for 5 days, but longer duration of therapy have been advocated in patients undergoing chemotherapy or with reduced lymphocyte counts as prolonged viral shedding may occur in these subjects, and when severe influenza (i.e. influenza pneumonia or illness requiring ICU-level care) is documented (http://www.cdc.gov/h1n1flu/recommendations.htm). Antiviral resistance to oseltamivir and zanamivir among circulating influenza viruses is currently low, but this can emerge during treatment especially when protracted for long periods [bib_ref] Surveillance Group for New Influenza A/H1N1v Investigation in Italy. First case in..., Campanini [/bib_ref] [bib_ref] Oseltamivir-induced resistant pandemic A/H1N1 influenza virus in a child with cystic fibrosis..., Esposito [/bib_ref]. In patients with cancer who develop fever or influenzalike illness, early antiviral therapy should be given empirically without awaiting laboratory confirmation. On the other hand, the administration of antiviral drugs may represent the only feasible strategy for the prevention and treatment of influenza in cancer patients who may not benefit from prophylactic vaccination (e.g. patients receiving rituximab-including therapies). # Discussion It should be emphasized that influenza vaccination in patients with cancer is safe, minimally invasive, and inexpensive. The AIOM recommends vaccination against seasonal influenza for cancer patients without contraindications. Both untreated . Recommendations and statements on the use of vaccination for seasonal influenza in patients with cancer Influenza vaccination in patients with cancer is safe, minimally invasive, and inexpensive. It should be widely utilized in patients with cancer both untreated and receiving active therapy, including biologic agents for solid tumors. The ideal time to administer the vaccination during a treatment cycle is unclear. Vaccination of household contacts and health care personnel is highly recommended as it bears significant implications in increasing the level of herd immunity in the microenvironment with consequent reduction of influenza virus circulation and likelihood of infection. Strict preventive measures should be adopted in oncology wards in the presence of hospitalized patients who develop influenza-like illness. Trivalent inactivated vaccine should be given. Data suggest an increased seroprotection rate by means of vaccines with adjuvants, an higher doses of antigen, or a second dose of vaccine. A quadrivalent vaccine has been recently approved by the United States and European health authorities. Cancer patients treated with rituximab-containing regimens have persisting perturbations of B-cell compartments and an impaired immune response to influenza vaccine, but also to other common vaccines. Thus, special efforts are needed to improve preventive/ therapeutic strategies for these refractory patients, including prophylactic antivirals. Prospective randomized, controlled trials to better define the serological response and the clinical benefits of influenza vaccination are needed in this patient population. patients and patients undergoing active treatment in any phase of antineoplastic therapy should be vaccinated. Vaccination of all household contacts and health care personnel is also recommended. Well-designed prospective studies are needed to identify optimal immunogenic strategies for seasonal influenza vaccination in different clinical conditions, together with optimal timing of vaccination relative to chemotherapy administration. A summary of the AIOM recommendations is reported in funding Partially supported by Progetto 2011-11961 Associazione Italiana per la Ricerca sul Cancro (AIRC).	None	http://www.annalsofoncology.org/article/S0923753419365706/pdf	ABSTRACT Background Influenza virus causes annual epidemics in the winter–spring season with significant morbidity in the general population and important mortality in high-risk groups, including cancer patients. Opinions on the suitability of patients with malignancies not undergoing active treatment and in different phases of antineoplastic therapy, to receive influenza vaccination, vary considerably among oncologists, sometimes even within one center. Methods We reviewed available data, including recommendations by national health authorities, on impact of influenza in patients with cancer and their capacity to mount protective immunological responses to vaccination, thus allowing, on behalf of Italian Association of Medical Oncology, to make suitable recommendations for the prevention and treatment of seasonal influenza. Results and discussion Patients with cancer often have disease- or treatment-related immunosuppression, and as a consequence, they may have a suboptimal serologic response to influenza vaccination. The protective effect of the different preparations of influenza vaccines in patients with cancer has not been widely investigated, especially in adult patients harboring solid tumors. The optimal timing for administration of influenza vaccines in patients receiving chemotherapy is also not clearly defined. However, since vaccination is the most effective method, along with antiviral drugs in selected patients, for preventing influenza infection, it has to be recommended for cancer patients. Implementing vaccination of close contacts of oncology patients would be an additional tool for enhancing protection in fragile patient populations.
146a75d8ac6f3b2000405bcdfbc31eaaea9d52d5	pubmed	Good practices recommendations from the Brazilian Society of Nephrology to Peritoneal Dialysis Services related to the new coronavirus (Covid-19) epidemic	Good practices recommendations from the Brazilian Society of Nephrology to Peritoneal Dialysis Services related to the new coronavirus (Covid-19) epidemic ## Resumo Considerando a nova epidemia de coronavírus (Covid-19), a Sociedade Brasileira de Nefrologia, representada pelo Comitê de Diálise Peritoneal, em concordância com a diretoria e o Departamento de Diálise, desenvolveu uma série de recomendações de boas práticas clínicas para os serviços de diálise peritoneal a serem consideradas durante o período da epidemia de Covid-19, com o objetivo de minimizar a disseminação da doença, proteger pacientes e funcionários e garantir a qualidade do tratamento prestado e acompanhamento adequado para os pacientes em DP. As recomendações aqui sugeridas devem ser adaptadas a cada realidade de serviço e às condições estruturais e de recursos humanos e dependem da provisão financeira adequada do sistema público de saúde para sua plena implementação. Palavras-chave: Covid-19; Infecções por Coronavirus; Diálise Peritoneal; Estratégias de eSaúde. # Abstract Considering the new coronavirus epidemic , the Brazilian Society of Nephrology, represented by the Peritoneal Steering Committee, in agreement with the and the Dialysis Department, developed a series of recommendations for good clinical practices for peritoneal dialysis (PD) clinics, to be considered during the period of the Covid-19 epidemic. We aim to minimize the disease spread, protecting patients and staff, and ensuring the quality of the treatment provided and adequate follow-up for PD patients. The recommendations suggested at this moment must be adapted to each clinic's reality and the conditions of the structural and human resources, dependent on the adequate financial provision of the public health system for its full implementation. ## Keywords: Covid-19; Coronavirus infections; Peritoneal dialysis; eHealth Strategies. # Introduction The Steering Committee of the Brazilian Society of Nephrology (SBN), together with the Peritoneal Dialysis Committee, prepared recommendations for peritoneal dialysis services concerning coronavirus pandemic. The recommendations contained herein must be adapted to the context and the reality of each service, and depend on adequate funding from public health systems for its complete implementation. - Reinforce for patients the instructions concerning the material used in therapy. Home storage and use at home must be maintained according to the local protocol. - All materials used in each PD session in the clinic or hospital must be cleaned with 70% alcohol before use. - Disposable of fluid bags, circuits, and all other required PD supplies generate by Covid-19 patients must be done following local regulatory rules. - For cases of patients who need to be evaluated in person at the unit, the SBN reinforces the need to maintain technical recommendations for good practices, adapted to the context and local reality, and with adequate funding from the public health system, previously published for hemodialysis services compiled and adapted for peritoneal dialysis, as mentioned below geneRAl cARe foR pResentIAl seRvIce - PD units must educate patients and collaborators on primary preventive care. Emphasize and intensify frequent hand hygiene with 70% alcohol gel or with soap and water for about 20 to 60 seconds. They should also instruct patients and collaborators to avoid touching their eyes, mouth, and nose without having done hand hygiene; avoid close contact with infected individuals; using social etiquette, cover mouth and nose when sneezing or coughing, with a disposable handkerchief and despise it as soon as possible, or use the angle formed by the arm and forearm (elbow); clean and disinfect frequently touched objects and surfaces; avoid sharing personal objects (such as toothbrushes, cutlery, plates, and glasses); and, if infected, avoid contact with other people, choosing to stay at home whenever possible 12,13 . - We recommend intensifying the cleaning of objects and surfaces frequently used by the public, such as door handles, chair arms, and elevator buttons. Recent evidence suggests that some coronaviruses can remain infectious on inanimate surfaces for up to 9 days. Disinfecting surfaces with 0.1% sodium hypochlorite or 62-71% ethanol significantly reduces coronaviruses' infectivity after 1 minute of exposure [bib_ref] Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents, Kampf [/bib_ref]. ## Considerations - Patients and employees should be encouraged to avoid public transportation, if possible. When necessary, wear a cloth mask. - PD units should encourage their patients to vaccinate for influenza, in the absence of contraindications. - Dialysis units should take administrative procedures to reduce, as far as possible, the number of caregivers and companions. - Patient companions and employees with respiratory symptoms should be discouraged from attending the PD Unit. - Rooms should be kept ventilated, as well as the Dialysis Unit. - Meetings via video conference should be encouraged whenever possible. - Care for PD patients in face-to-face outpatient consultation: contact the patient and family for a pre-screening before the consultation via telephone, looking for respiratory symptoms (if any, advise the patient and family to not attend the unit); educate them on signs and symptoms of severity and to seek care according to the reference of each municipality if there is a worsening of the condition. - If patients with suspicion of the disease arrive at the unit, they must undergo a medical evaluation and receive instructions before entering the dialysis clinic. After evaluation, the patient should be treated under the clinical condition and with the current recommendations of the local health authorities and the Ministry of Health. These patients must not stay in the unit; monitoring can be carried out later by telephone 12 . - To evaluate the suspected case, the healthcare professional (doctors and nurses) must wear a disposable apron, surgical mask, goggles and/ or face shield and disposable gloves. - Patients with respiratory symptoms and their companions must wear a surgical mask during the evaluation before entering the dialysis unit. - Other members of the multidisciplinary care team must wear a surgical mask. If the service provides contact that is more direct with the patient, follow the same recommendations as to the second item. We also suggest that the other employees (maintenance, cleaning, receptionists, and security guards) of the dialysis unit also wear a surgical mask. The surgical mask should be replaced with a new one whenever it becomes wet. - Healthcare professionals in the dialysis unit, responsible for assisting confirmed or suspected cases, should wear masks (type N95) whenever performing aerosol-generating procedures, such as orotracheal intubation, non-invasive ventilation, cardiopulmonary resuscitation or manual ventilation before intubation. - If possible, designate a toilet for the exclusive use of the suspected case. If this is not possible, clean the frequently touched surfaces of the bathroom (s) (faucet, handle, trash can cover, counters) with soap and water or disinfectant, according to the procedures described in RDC 56, of 6 August of 2008. ## Final remarks The aforementioned measures serve as a source of information and alert to mitigate the virus spread and promote adequate assistance to the population with chronic kidney disease undergoing peritoneal dialysis during the Covid-19 pandemic. These measures can, and should, be revised as the health situation changes.	None	https://www.scielo.br/j/jbn/a/RVQBy5LtnLP7CJPkSt445WL/?lang=en&format=pdf	ABSTRACT Considering the new coronavirus epidemic (Covid-19), the Brazilian Society of Nephrology, represented by the Peritoneal Steering Committee, in agreement with the and the Dialysis Department, developed a series of recommendations for good clinical practices for peritoneal dialysis (PD) clinics, to be considered during the period of the Covid-19 epidemic. We aim to minimize the disease spread, protecting patients and staff, and ensuring the quality of the treatment provided and adequate follow-up for PD patients. The recommendations suggested at this moment must be adapted to each clinic’s reality and the conditions of the structural and human resources, dependent on the adequate financial provision of the public health system for its full implementation.
a897ff988e78abbc9541b3ea7f678a74e3a04f89	pubmed	Canadian Guidelines for Controlled Pediatric Donation After Circulatory Determination of Death—Summary Report*	Canadian Guidelines for Controlled Pediatric Donation After Circulatory Determination of Death—Summary Report* [bib_ref] National recommendations for donation after cardiocirculatory death in Canada: Donation after cardiocirculatory..., Shemie [/bib_ref] [bib_ref] Transplantation Society: Pediatric deceased donation-a report of the transplantation society meeting in..., Martin [/bib_ref] [bib_ref] Policies on donation after cardiac death at children's hospitals: A mixed-methods analysis..., Antommaria [/bib_ref] [bib_ref] Neonatal organ donation: Has the time come?, Brierley [/bib_ref] [bib_ref] Pediatric donation after circulatory determination of death: A scoping review, Weiss [/bib_ref] # Methods The guideline was developed by a multidisciplinary guideline development committee that included seven topic-specific working groups (WGs). Two patient-family partners, professional society partners, and an international expert provided external review. Funding was provided by Canadian Blood Services. No guideline development member disclosed any financial conflicts of interest with for-profit entities, though several were or are paid donor physicians associated with governmental notfor-profit organ donation organizations (ODOs), and others have active research and academic activities in organ donation. The guideline development committee adhered to a rigorous development process based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methods and consistent with recommendations from several national and international bodies [bib_ref] A guide to the Canadian Medical Association handbook on clinical practice guidelines, Palda [/bib_ref] [bib_ref] Guidelines 2.0: Systematic development of a comprehensive checklist for a successful guideline..., Schünemann [/bib_ref]. The scope of the guideline included only controlled pDCD (e.g., after planned withdrawal of life-sustaining therapies [WLSTs]). Specifically, we defined uncontrolled pDCD, or donation after cardiac arrest outside of a WLST setting, to be outside the scope of these guidelines. The guideline development committee and WGs judged the quality of evidence and created evidence-todecision tables before making either "strong" or "conditional" recommendations according to the GRADE approach [bib_ref] GRADE guidelines: 15. Going from evidence to recommendation-determinants of a recommendation's direction..., Andrews [/bib_ref]. In cases where the guideline development committee felt that there was insufficient evidence or the balance of benefits and harms was likely neutral, no recommendation was made. In addition to GRADEd recommendations, the guideline development committee formulated Good Practice Statements (GPSs) in cases where there was a large body of indirect evidence strongly supporting the net benefit of the recommendation or there was no reasonable comparator [bib_ref] Guideline panels should not GRADE good practice statements, Guyatt [/bib_ref]. Full consensus by all guideline development committee and WG members was achieved for all recommendations. This report is a summary that does not include all the recommendations or the justifications. For all recommendations, justifications, complete GRADE tables for actionable recommendations, and a comprehensive description of the guideline development process, please refer to the full report available at http://www.organsandtissues.ca/s/english-expert/leading-practices-public-awareness-and-education. For a global review of the pDCD literature, please refer to the associated scoping review (5). ## Recommendations ethics and wlst # Good practice statements. 1) pDCD is a medically and ethically viable pathway to provide access to deceased organ donation. 2) The option of deceased donation, including pDCD, should be routinely incorporated into end-of-life (EOL) care. 3) Healthcare systems should establish processes to ensure pDCD access. 4) Throughout the WLST and donation process, healthcare professionals must respect the dignity of the dying process. 5) The discussions and process of deceased donation should respect the beliefs and values of the surrogate decision makers and other loved ones involved. 6) In recognition of diversity of perspectives on pDCD, healthcare professionals should be allowed to conscientiously object to participation in pDCD. a) In the case of healthcare professional objection, institutions should work to honor the surrogate decision makers' wishes to donate. Justification. The option to offer DCD as part of EOL care is universally supported by professional societies and ODOs that have examined the issue [bib_ref] Guidelines for the withdrawal of life-sustaining measures, Downar [/bib_ref] , including two specific endorsements from the American Academy of Pediatrics. Despite this broad consensus, some authors have expressed concerns around ethical aspects of pDCD [bib_ref] Donation after cardiocirculatory death: A call for a moratorium pending full public..., Joffe [/bib_ref] [bib_ref] Organ donation after cardiac death: Are we willing to abandon the dead-donor..., Rady [/bib_ref]. Some individuals within the healthcare team may have differing views on the meaning and permissibility of deceased organ and tissue donation (OTD) based on societal, cultural, religious, and other personal beliefs [bib_ref] An explanation and analysis of how world religions formulate their ethical decisions..., Setta [/bib_ref]. These concerns justify the above recommendation to allow conscientious objection by healthcare professionals to not participate in pDCD, consistent with other policy and position statements [bib_ref] A call for full public disclosure for donation after circulatory determination of..., Nakagawa [/bib_ref]. However, considering the important role donation can play in the lives of donor families, these objections should not prohibit substitute decision makers and families from participating in pDCD if they so desire, which is why we emphasize that institutions should work to accommodate these requests using the principles of effective referral. ## Decision-making process for wlst good practice statements. 7) The decision to pursue WLST must not be influenced by donation potential and should proceed according to accepted medical practices. 8) The ODO, organ recovery, and transplant team must not be involved in the decision to pursue WLST or have direct contact with surrogate decision makers before WLST decisions are finalized. a) Treating teams may contact ODOs to assess eligibility prior to the decision to pursue WLST, as long as there is no direct contact between the ODO and surrogate decision makers. 9) The decision to pursue WLST should be made before any discussion of OTD that is initiated by healthcare professionals. b) If surrogate decision makers initiate organ donation discussions prior to the decision to pursue WLST, information may be provided, but consent discussions should be deferred until WLST decisions have been finalized. 10) Safeguards should be in place to ensure that mitigation of conflict of interest for the case where a patient who is a potential donor and a patient who is a potential recipient are being cared for in the same care unit. Justification. In order to avoid real or perceived conflicts of interest, decisions pertaining to OTD must be kept as separate as possible from decisions regarding WLST. As is universally supported in the literature, the above recommendations support that WLST decision-making follow established, best practices regardless of pDCD potential . One area we believe merits particular attention is when a patient who is a potential donor and a patient who is a potential recipient are simultaneously cared for in the same unit. This possibility is more likely in pediatric than adult practice given the smaller number of recovery and transplant hospitals. We acknowledge this as a potential conflict and encourage systems to ensure ethical safeguards if the substitute decision maker is motivated to pursue donation in this setting. Measures to mitigate this potential conflict will depend on local context but could include ethics consultation or a second opinion from an uninvolved clinician. ## Eligibility # Good practice statements. ## 11) individual transplant programs, in collaboration with pediatric and neonatal healthcare professionals and ODOs, should determine criteria for donor eligibility, limits of warm, and cold ischemic time. Special consideration should be given for neonatal patients who are potential donors. 12) Coroners must be notified prior to donation proceedings according to provincial laws. If coroner evaluation and approval to pursue pDCD is required, this should be done prior to consent discussions with the surrogate decision makers. Justification. We chose to limit our recommendations related to pDCD eligibility. Further national recommendations will require input from multidisciplinary groups, including transplant surgeons and physicians caring for recipients of pDCD organs, in order to form organ-specific recommendations. Current recommendations from groups such as the Canadian Society of Transplantation should inform these discussions, including those on high-risk donors. These criteria will be subject to change based on center experience, further research, and recommendations from organ-specific transplantation groups. ## Consent for pdcd good practice statements. 13) Consent discussions for pDCD can include members of the care team, representatives of the ODO, or healthcare professionals from both groups. a) As stated in GPS 9 above, all discussions of organ donation initiated by healthcare providers must be deferred until after WLST decisions are finalized. 14) The person or team discussing consent should have extensive knowledge of the local process and should clearly identify their institutional affiliations. 15) Consent conversations with surrogate decision makers should include the opportunity to discuss beliefs and values around all aspects of pDCD, including death and death determination. 16) At minimum, the following information should be provided to surrogate decision makers regarding the pDCD process: a) Logistics of the process, including that WLST may be delayed due to pDCD logistics, and where WLST will occur, b) The procedures and methods of determining death, including that these practices conform to accepted medical and legal standards, c) Which organs are potentially eligible for recovery, d) That consenting for pDCD does not guarantee organ recovery or transplantation, e) If organ recovery is not possible, tissue donation may remain an option, f) How EOL care would proceed if they decline organ donation or if recovery does not occur after attempted donation, g) That the treating team has no influence over allocation, which may include allocation to adult or pediatric recipients, h) That surrogate decision makers will be supported if they consent to or decline pDCD, and i) That consent can be withdrawn at any time, including after the determination of death. 17) Tests and interventions prior to death (antemortem interventions) to facilitate donation in pDCD require specific and informed consent from the surrogate decision makers for each intervention. a) Antemortem interventions should only be undertaken with disclosure and consideration of risks and benefits to the patient who is a potential donor. b) Antemortem interventions should not be intended to hasten death. c) Antemortem interventions should pose no more risk to the patient than routine intensive care practices. 18) Antemortem interventions should be recognized as providing nonmedical benefit to the patient who is a potential donor by allowing realization of interest and intent to donate despite the fact that these interventions provide no medical benefit to the patient who is a potential donor. This justifies surrogate decision maker's authority to consent to interventions that pose no increased risk beyond routine intensive care practices despite no medical benefit to the patient who is a potential donor. Justification. How best to engage in consent discussions was carefully considered for these recommendations. There is significant practice variability concerning which healthcare professionals should be present during consent discussions. Regardless of whether an ODO representative is present during the consent request, we recommend that person have detailed knowledge of the local processes and procedures. Further discussion of training requirements for people requesting consent can be found under Actionable Recommendation 1. Furthermore, the stage in the EOL pathway at which ODOs are to be notified varies across jurisdictions, often related to requirements of mandatory reporting laws. The laws and local practices of reporting of a patient who is a potential donor should be carefully considered when establishing a pDCD protocol. The understanding of consent for pDCD also requires an understanding of the distinction between consent for interventions before (ante) and after (post) mortem. It is outside the scope of these guidelines to extensively review the legal framework governing pDCD consent, but deceased donation in Canada is governed by provincial tissue gift legislation. Similar to the concept of "authorization" used more commonly in the United States, permission to proceed with donation under gift acts is different from, and legally less demanding than informed consent for treatment of a living patient [bib_ref] The principles of gift law and the regulation of organ donation, Glazier [/bib_ref]. Consideration of benefit or harm posed to the patient, which forms the basis of informed consent to treatment, cannot be applied in the context of postmortem organ recovery any more than it can applied to the processes of cremation or embalming [bib_ref] The principles of gift law and the regulation of organ donation, Glazier [/bib_ref]. pDCD, however, includes both authorization for postmortem organ recovery and consent for antemortem interventions that do require full informed consent. A question that is often raised in pDCD considerations is if substitute decision makers or families can give valid consent for a procedure that might cause harm or discomfort to the donor while providing medical benefit only to the organ recipient. Several authors [bib_ref] Neonatal organ donation: Has the time come?, Brierley [/bib_ref] [bib_ref] Premortem interventions in dying children to optimise organ donation: An ethical analysis, Brierley [/bib_ref] , including the 2013 American shared position statement from the American Thoracic Society, the Society for Heart and Lung Transplantation, the Society of Critical Care Medicine, the Association of Organ Procurement Organizations, and the United Network of Organ Sharing, answer in the affirmative. Their rationale is that if the process presents potential risk of harm that is similar to routine intensive care practices, and the procedure is in line with parental values, an assumption of altruism is legitimate [bib_ref] Neonatal organ donation: Has the time come?, Brierley [/bib_ref]. The benefit to the patient who is a potential donor is therefore allowing donation to proceed in order to fulfill family or surrogate desire to donate, and it is this benefit that justifies assumption of risk without direct medical benefit. This is consistent with the ethical reasoning supporting children's participation in medical research where there is no hope for direct benefit to them. Furthermore, not allowing patients' substitute decision makers or families to accept this level of risk in order to act altruistically in this circumstance would limit their autonomy [bib_ref] A call for full public disclosure for donation after circulatory determination of..., Nakagawa [/bib_ref]. These arguments, however, are not universally accepted, and others claim that altruism on the part of an incompetent child cannot be assumed based on parental values [bib_ref] Donation after cardiocirculatory death: A call for a moratorium pending full public..., Joffe [/bib_ref]. We conclude that divergent opinions regarding the ethical acceptability of such antemortem interventions would be a justifiable reason for healthcare professionals to excuse themselves from pDCD proceedings through conscientious objection. It is impossible to specifically recommend how to weigh these risks and benefits in all the nuanced situations that will arise for individual patients (e.g., heparin administration to a patient with a remote history of an intracranial hemorrhage). It is the responsibility of the treating team, with appropriate ethical oversight, to ensure that protection of the interests of the patient who is a potential donor remains the primary concern throughout these situations. Any test of organ eligibility or those specific for allocation (e.g., human leukocyte antigen matching) should be considered an antemortem test and should not be performed until consent for the pDCD process and required investigations has been obtained. For further information regarding general best practices in organ donation consent, please consult the recent report from Canadian Blood Services. Actionable Recommendation. "Should trained professionals versus professionals without specific training be used for approaching families for consent in the setting of pediatric donation after circulatory death?" 19) The panel did not make a recommendation regarding minimal required training of professionals approaching families for consent in the setting of pediatric donation after circulatory death. Justification. Although several observational reports [bib_ref] Successful international collaboration improves family donation conversations resulting in increased organ donation, Mulvania [/bib_ref] [bib_ref] Appointing 'trained donation practitioners' results in a higher family consent rate in..., Jansen [/bib_ref] [bib_ref] Do trained specialists solicit familial authorization at equal frequency, regardless of deceased..., Dubay [/bib_ref] [bib_ref] Factors influencing families' consent for donation of solid organs for transplantation, Siminoff [/bib_ref] [bib_ref] Communicating effectively about donation: An educational intervention to increase consent to donation, Siminoff [/bib_ref] [bib_ref] Requesting organ donation: An interview study of donor and nondonor families, Dejong [/bib_ref] [bib_ref] Improving the request process to increase family consent for organ donation, Gortmaker [/bib_ref] [bib_ref] Attitudes toward financial incentives, donor authorization, and presumed consent among nextof-kin who..., Rodrigue [/bib_ref] [bib_ref] Discriminant variables between organ donors and nondonors: A post hoc investigation, Rosel [/bib_ref] [bib_ref] Obtaining organ donation: Who should ask?, Von Pohle [/bib_ref] [bib_ref] Analysis of factors influencing organ donation consent rates, Klieger [/bib_ref] [bib_ref] Improving consent rates for organ donation: The effect of an inhouse coordinator..., Salim [/bib_ref] suggest that trained requesting is effective at increasing consent rates, the only randomized controlled trialshowed no effect of involving trained ODO staff at the time of consent. None of these studies were exclusive to pediatrics or even DCD. Only one (33) of 13 references examined family satisfaction after the consent process as an outcome. Considering the lack of conclusive evidence supporting benefit, and the substantial system investment that would be required to have trained requesters present at every consent conversation, we chose to not recommend for or against this intervention. For further information on effective requesting techniques in deceased donation, please refer to the recently published report from Canadian Blood Services. 24) Psychosocial, spiritual, and bereavement support should be provided to surrogate decision makers regardless of WLST location. 25) Wherever WLST occurs, surrogate decision makers and other loved ones should be given the option to be physically present with the patient who is a potential donor until the determination of death is complete. 26) The organ recovery team should not be physically present in the room until the determination of death has been completed and the surrogate decision makers are escorted from the bedside. 27) If a patient who is a potential donor is hospitalized where pDCD is not available, and the surrogate decision makers are motivated to donate, consideration should be given for patient transfer to a hospital that performs pDCD. ## Procedures for wlst in the context of pdcd Justification. The fiduciary responsibilities of ICU clinicians are first and foremost to act in the best interest of his or her patient, and we therefore strongly support that in the event of a conflict in management goals between organ donation and optimal EOL care, care for the dying child should always take precedence. As universally supported in the published literature, WLST practices should be provided with minimal deviations from standard practice, including full support available for families . Our group did not specifically deliberate on the issue of whether the practice of surgical preparation of the patient who is a potential donor (sterilization of the surgical field, draping, etc.) represented acceptable contact between the recovery team and the donor prior to death determination. In line with other recommendations, if this practice is required by the recovery team, it should be treated as an antemortem intervention requiring specific informed consent, and the recovery team should in no way otherwise influence EOL care. Also if practiced, this contact should not alter the recommendation that the recovery team not be physically present in the room at the time of death determination, and they should leave the operating room after surgical preparation is completed and before the parents enter. ## Time from wlst to determination of death good practice statements. 28) A maximum time limit from the start of WLST to death, beyond which organs will not be recovered, should be established in collaboration with ODOs and local transplant teams. Justification. The duration of acceptable warm ischemic time (WIT) should be locally informed and based on organspecific concerns [bib_ref] British Transplantation Society: Summary of the British Transplantation Society Guidelines for transplantation..., Andrews [/bib_ref] [bib_ref] In-hospital logistics: What are the key aspects for succeeding in each of..., Murphy [/bib_ref]. Current practice in most pDCD centers recommends WIT of 30-90 minutes, depending on the organ to be recovered. Adult practices may vary from 1 to 4 hours depending on multiple factors, including limitations of access to operating rooms. Our guideline committee did not consist of transplant surgeons or posttransplantation physicians who could provide meaningful expertise into the effects of various WIT thresholds on specific organs, and we therefore specifically chose not to make recommendations regarding the length of acceptable WIT. Actionable Recommendation. "Should formal predictive tools versus no formal tool (clinical judgment) be used for predicting time of death within 30 or 60 minutes of WLST?" 29) The panel did not make a recommendation regarding use of tools to predict the time from WLST to death. Justification. Though a prediction tool developed by Shore et al [bib_ref] Development of a bedside tool to predict time to death after withdrawal..., Shore [/bib_ref] has shown reasonable predictive value, it remains to be tested against clinical judgment or prospectively validated. Prediction tools cause no direct harm to a patient, may provide important information to the clinical team and surrogate decision makers, and are low cost. The risk, however, is if clinicians choose whether or not to pursue donation proceedings based solely on such a tool without understanding its strengths and limitations. Although future iterations may result in improved sensitivity and specificity, we currently do not recommend for or against the use of death prediction tools. ## Minimum standards required for death determination in pdcd Definition of Death Used for these Recommendations. There is currently no Canadian federal, provincial, or territorial statute mandating how clinicians determine when a patient is dead. As there is also no widely accepted medical standard from Canadian professional societies, we have chosen, for the purposes of this guideline, to use the following definition taken from recently proposed guidelines at the World Health Organization: The definition of death by circulatory determination: The permanent loss of capacity for consciousness and all brainstem functions, as a consequence of permanent cessation of circulation. Permanence is defined as loss of function that will not resume spontaneously and will not be restored through intervention [bib_ref] The International Guidelines for Determination of Death phase 1 participants, in collaboration..., Shemie [/bib_ref]. This definition is consistent both with current accepted Canadian medical practice and the definitions used in the current clinical practice recommendations governing donation circulatory death in adults [bib_ref] National recommendations for donation after cardiocirculatory death in Canada: Donation after cardiocirculatory..., Shemie [/bib_ref]. Good Practice Statements. The following includes a summary of current Canadian laws and practices governing deceased donation. These laws and recommendations should be understood to represent the minimum standards necessary to determine death. They do not preclude additional standards, as long as those standards are accepted prior to implementation by all stakeholders. 30) The dead donor rule must be respected within the context of pDCD. 31) Death must be determined by two physicians in accordance with accepted medical practice. a) The two physicians must confirm their determinations concurrently at the end of a hands-off period of observation during circulatory arrest. ## 32) No physician who has active involvement in transplant procedures or allocation of donated organs shall take any part in donor death determination. 33) The minimum level of physician qualification required to determine death in pDCD is as follows: a) They possess the requisite skills and training. A particular level of specialty certification is not required, but skills and training should include ability to interpret monitoring used. b) At least one of these physicians must be an attending physician staff in the ICU of the patient and possess full and current licensure for independent medical practice in the relevant Canadian jurisdiction. c) The second physician could be on an educational register (e.g., residents, fellows), as long as they have the requisite skills and training. 34) The following criteria must be met before organ recovery: a) Circulatory arrest, defined as the absence of anterograde arterial circulation. See actionable recommendations 37 and 38 for the specifics of how to determine that absence. b) A hands-off period of continuous observation of circulatory arrest during which no interventions are undertaken to facilitate donation. See recommendation below for duration of hands-off period. c) At the end of this period, death is legally determined, and organ recovery may commence. ## 35) Recovery and transplantation of the heart in pDCD is consistent with the dead donor rule, as death is based on the permanent cessation of circulation. 36) The same criteria should apply to all potential pDCD donors including those undergoing withdrawal of mechanical circulatory support such as extracorporeal mechanical oxygenation (ECMO). Justification. The definition of death used for these guidelines represents both current accepted Canadian practice and is consistent with evolving international consensus [bib_ref] The International Guidelines for Determination of Death phase 1 participants, in collaboration..., Shemie [/bib_ref]. The details of how cessation of circulation is determined and for how long are detailed below in actionable recommendations 37 and 38. pDCD, practiced according to these practices and definitions, respects the dead donor rule, defined as "vital organs should only be taken from dead patients and, correlatively, living patients must not be killed by organ retrieval" [bib_ref] Ethical, psychosocial, and public policy implications of procuring organs from non-heart-beating cadaver..., Youngner [/bib_ref]. We have chosen to recommend that although the first physician determining death in pDCD must have a full, unrestricted license to practice, the second may be a trainee on an educational register. This recommendation considers that the death determination in pDCD requires skills or training that would be readily available to a resident or fellow undergoing training in a PICU or neonatal ICU (NICU). If the second physician is on an educational register, he or she should be reminded that they are not obligated to participate and that a decision to participate or no will not affect their evaluation. Also, the second physician need not be from a certain specialty, as long as he or she possesses the capacity to determine death in this setting, specifically the ability to interpret an arterial catheter waveform tracing. In GPS 32, active involvement in transplant procedures or allocation is defined as any involvement in postmortem surgical recovery procedures, discussions of which patient on the transplant wait list will receive the donated organs, or participation in any part of the transplantation procedure (including anesthesia of the recipient). Consultant physicians who might be involved in evaluating the patient for donor eligibility and might also care for a potential recipient (e.g., nephrologists) would be excluded from participating in the determination of death. As addressed in GPS 10, it is possible that intensive care physicians will be involved directly or indirectly with the care of both donor patients and those who receive transplanted organs from the same donor due to the limited number of PICUs in Canada. Ethical safeguards should be developed in these cases. Regarding GPS 36, in the past, when DCD was more commonly referred to as "donation after cardiac death," authors argued that determining death by irreversible loss of cardiac function precluded DCD cardiac transplantation [bib_ref] Pediatric organ donation and transplantation policy statement: More questions, not answers, Verheijde [/bib_ref] [bib_ref] Donating hearts after cardiac death -reversing the irreversible, Veatch [/bib_ref]. However, our guidelines specifically define death as permanent loss of circulation in the donor. Whether the heart remains unresuscitated in the donor or is removed and resuscitated in another patient does not alter donor outcome: body and brain circulation remains permanently ceased in the dead donor [bib_ref] The circulatory-respiratory determination of death in organ donation, Bernat [/bib_ref]. Thus, cardiac pDCD practiced according to these guidelines would respect the dead donor rule. Actionable Recommendation. "Should arterial line versus palpable pulses and auscultation be used for confirmation of lack of anterograde circulation?" 37) We recommend that a well-functioning arterial catheter be used to confirm arrest of anterograde arterial circulation for the determination of death. (strong recommendation, low certainty in evidence) Justification. Although not specific to a pDCD setting, data from studies designed to test clinicians ability to determine between low and nonpulsatile states suggest that even experienced PICU physicians commit errors [bib_ref] Reliability of pulse palpation by healthcare personnel to diagnose paediatric cardiac arrest, Tibballs [/bib_ref] [bib_ref] The influence of time on the accuracy of healthcare personnel to diagnose..., Tibballs [/bib_ref] [bib_ref] Checking the carotid pulse check: Diagnostic accuracy of first responders in patients..., Eberle [/bib_ref]. The panel strongly felt that palpation of pulse was an inadequate method to confirm lack of circulation. Arterial catheter monitoring is commonly used, easily interpreted, and objective. The recommendation to rely on arterial catheter monitoring assumes a functioning and verified arterial catheter. No other confirmation of loss of anterograde circulation (e.g., electrical asystole) is necessary when a well-functioning arterial catheter is in place. Although auscultation or palpation should not be used to confirm lack of circulation, they could be applied to verify that an observed flat waveform corresponds with the clinical state. We make no recommendation as to the required site of the arterial catheter. Please see the full report for consideration of situations when an arterial catheter is not possible for technical reasons or due to surrogate decision maker refusal, including the use of other modalities such as echocardiography. Justification. Currently, all Canadian adult and pediatric centers performing DCD use 5-minute hands-off period. During this 5-minute period, also sometimes referred to as a "no touch" period, no healthcare professional should have any physical contact with the patient, and the physicians determining death should be constantly observing the method used to confirm absent circulation. The period of time commences when no visible pulsatility is observable on a well-functioning arterial catheter waveform or after the last evidence of anterograde circulation (e.g., last opening of the aortic valve by echocardiography). If evidence of circulation is detected during the 5-minute hands-off period, the observation period should recommence until 5 full minutes of absent circulation are observed. This period is longer than any reported case of autoresuscitation after WLST [bib_ref] A systematic review of autoresuscitation after cardiac arrest, Hornby [/bib_ref] [bib_ref] Vital signs after cardiac arrest following withdrawal of life-sustaining therapy: A multicenter..., Dhanani [/bib_ref] , and organs transplanted after this ischemic time have acceptable outcomes [bib_ref] Transplantation of kidneys from paediatric DCD donors: A comparison with DBD donors, De Vries [/bib_ref] [bib_ref] Liver transplantation in children using organ donation after circulatory death: A case-control..., Hong [/bib_ref] [bib_ref] Early experience with lung transplantation using donors after cardiac death, Mason [/bib_ref]. However, based on the low quality of the reviewed autoresuscitation evidence and the fact that no reports compared organ outcomes using 5-versus 10-minute hands-off times, we chose to make a conditional recommendation. ## Ante and postmortem interventions good practice statements. Antemortem. ## 39) Any intervention or test that may pose discomfort to the patient who is a potential donor should be managed with analgesia and/or sedation as per standard ICU practices. 40) Consideration should be given to the timing of administration of any antemortem pharmacologic intervention in order to minimize any potential risks. Postmortem. ## 41) Interventions that do or may reinstitute oxygenated brain blood flow after death must not be performed, including cyclic ventilation after reintubation for lung donation. 42) Only the organ recovery team may carry out postmortem surgical interventions. Justification. The above recommendations emphasize that any antemortem intervention, including transfer of a patient who is a potential donor, carries the same requirements for informed consent, minimization of risk, and respect for the comfort of the patient as in routine care of ICU patients. Refer to the "Consent for Antemortem Interventions" section above for additional discussion. Regarding postmortem interventions, our primary concern was the need to avoid interventions that might reestablish oxygenated brain blood flow. Absence of oxygenated brain blood flow is the key component of the determination of death, so procedures that potentially reestablish that flow could violate the dead donor rule. Understanding that risk, we recommend that tracheal reintubation is permissible as long as cyclic ventilation is not provided. Through cardiopulmonary interactions, cyclic ventilation has the theoretical risk of restoring oxygenation and brain circulation, and its avoidance has been recommended by other groups. Actionable Recommendation. "Should Heparin versus no anticoagulation be used for pDCD as an ante mortem intervention?" 43) The panel did not make a recommendation regarding the universal administration of heparin in the setting of pDCD. Justification. Given the lack of available evidence for benefit in pediatric or adult patients [bib_ref] Outcomes of kidney transplant recipients from donation after circulatory death donors without..., Kamal [/bib_ref] [bib_ref] Favorable outcomes of donation after cardiac death in lung transplantation: A multicenter..., Cypel [/bib_ref] and concerns regarding any antemortem interventions that could cause harm to a patient who is a potential donor, we make no recommendation regarding routine antemortem heparin administration pDCD. If given, practices such as dose and timing of administration should be determined jointly by intensive care teams, ODOs, and transplant programs to ensure that harm to a patient who is a potential donor is minimized. Actionable Recommendation. "Should regional oxygenated perfusion techniques versus no such techniques be used for improving organ outcome in controlled pDCD?"We recommend that regional perfusion not be used in the setting of pDCD (strong recommendation, very low certainty in evidence). Justification. Although not practiced in Canada, other jurisdictions have employed perfusion techniques (e.g., modified ECMO) that provide oxygenated blood flow to abdominal organs after death but prior to organ recovery, while excluding blood brain flow. Reports of this practice were considered indirect to our question, since they were almost exclusive to adult donors [bib_ref] Donation after circulatory determination of death: The university of michigan experience with..., Rojas-Peña [/bib_ref] [bib_ref] In situ normothermic regional perfusion for controlled donation after circulatory death-the United..., Oniscu [/bib_ref] [bib_ref] Liver transplantation using uncontrolled non-heart-beating donors under normothermic extracorporeal membrane oxygenation, Jiménez-Galanes [/bib_ref] [bib_ref] Applicability and results of Maastricht type 2 donation after cardiac death liver..., Fondevila [/bib_ref] [bib_ref] Liver transplantation from Maastricht category 2 non-heart-beating donors, Otero [/bib_ref] [bib_ref] Victims of cardiac arrest occurring outside the hospital: A source of transplantable..., Sánchez-Fructuoso [/bib_ref] [bib_ref] Normothermic recirculation reduces primary graft dysfunction of kidneys obtained from non-heartbeating donors, Valero [/bib_ref] [bib_ref] Kidney from uncontrolled donors after cardiac death with one hour warm ischemic..., Reznik [/bib_ref] [bib_ref] Extracorporeal support for organ donation after cardiac death effectively expands the donor..., Magliocca [/bib_ref] [bib_ref] Experience in renal and extrarenal transplantation with donation after cardiac death donors..., Farney [/bib_ref] , and often involved antemortem interventions such as cannulation that would be in conflict with current Canadian pDCD practice. Given the low quality of the evidence reporting benefit, risk of the significant consequence of reestablishing brain blood flow through inadequate aortic occlusion, and the cost/ resources involved, we feel that regional perfusion techniques should not be used for pDCD [bib_ref] Donation after circulatory determination of death: The university of michigan experience with..., Rojas-Peña [/bib_ref] [bib_ref] Extracorporeal support for organ donation after cardiac death effectively expands the donor..., Magliocca [/bib_ref]. Although we do not recommend its use in standard practice, regional perfusion techniques could be considered as part of a research protocol with research ethics board approval. Oversight should include techniques to ensure the absence of brain blood flow during regional perfusion. Actionable Recommendation. "Should bronchoscopy versus no bronchoscopy be used for ante mortem evaluation of lung function in potential pDCD donors?" 45) The panel did not make a recommendation for or against the routine use of antemortem bronchoscopy in the setting of pDCD. Justification. Although bronchoscopy is frequently practiced in neurologic determination of death and DCD organ donation, its association with graft or recipient outcome in pDCD is not well described [bib_ref] Fiberoptic bronchoscopy in brain-dead organ donors, Riou [/bib_ref] [bib_ref] Initial experience with lung donation after cardiocirculatory death in Canada, Cypel [/bib_ref] [bib_ref] Assessment of lungs for transplantation: A stepwise analysis of 476 donors, Alvarez [/bib_ref]. We acknowledge that antemortem bronchoscopy prior to controlled pDCD is likely a low risk procedure, but there are no published reports evaluating adverse events rates in this setting. This balance of considerations led us to not recommend for or against antemortem bronchoscopy. The possibility of postmortem bronchoscopy either in situ or ex vivo is unreported in the current literature but would likely be of similar benefit as a pretransplant bronchoscopic evaluation while eliminating risk conferred to the patient who is a potential donor. ## Cardiac pdcd Good Practice Statements. [bib_ref] British Transplantation Society: Summary of the British Transplantation Society Guidelines for transplantation..., Andrews [/bib_ref] Considering the lack of published experience in cardiac pDCD: a) Cardiac transplant programs should establish criteria for acceptance of heart donation, ex vivo cardiac protocols, and heart allocation in pDCD, b) Consideration should be given to initiate cardiac pDCD program as either research protocols with research ethics board oversight or through programs that oversee innovative therapies. Justification. Although there is minimal published experience with cardiac pDCD, recent innovative reports of adult cardiac DCD using ex vivo heart preservation suggests that this option may evolve as a viable clinical pathway in the near future [bib_ref] Adult heart transplantation with distant procurement and ex-vivo preservation of donor hearts..., Dhital [/bib_ref]. We considered this lack of evidence when recommending that future Canadian cardiac pDCD should be undertaken under the supervision of a clinical trial or innovative therapy program. ## Neonatal dcd good practice statements. 47) Unless otherwise stated, the above GPSs and actionable recommendations that apply to infants and children should also apply to neonates, provided expertise in neonatal EOL care can be provided. 48) Diagnoses such as anencephaly or other similar severe, lifelimiting neurologic disorders, for whom NDD is impossible, do not preclude consideration as potential candidates for pDCD. 49) Centers not providing pDCD should establish a clear process for transfer to hospitals with pDCD programs including consideration of transfer of the mother of the patient who is a potential donor, ongoing provision of EOL care, limitation of economic burden on surrogate decision makers, and repatriation of the body. Justification. In general, we felt that there are more similarities than differences between neonatal and pediatric DCD practice. As with all potential DCD donors, optimal EOL care should remain the fundamental concern in a neonatal pDCD process. The particular relational and ethical aspects of neonatal death require the expertise of a clinician trained to deal with these EOL issues [bib_ref] Organ donation from children: Time for legal, ethical and cultural change, Brierley [/bib_ref] [bib_ref] Organ donation after cardiac death: The subtle line between patient and donor..., Devictor [/bib_ref]. Also, even less is known about the rate of the dying process after WLST in neonates and how that might affect completion of pDCD in this population, which should be discussed with surrogates during the consent process. One of the potential differences between neonatal and other populations is the relatively large numbers of regional, nontertiary NICUs that do not offer pDCD (compared with relatively small number of PICUs) in which many potential neonatal pDCD donors may be initially hospitalized. If parents of children hospitalized in NICUs that do not offer pDCD wish to pursue pDCD, clear protocols for transfer would be necessary, including consideration that the mother might not yet be eligible for transfer or discharge [bib_ref] Donation after cardiac death: The potential contribution of an infant organ donor..., Labrecque [/bib_ref]. We recommend that pDCD can be offered to patients born with anencephaly or other similar severe, life-limiting neurologic disorders. In 2016, the Canadian Paediatric Society reaffirmed its position statement (83) that recommends against allowing deceased organ donation in this population based on the impossibility to complete a NDD examination in the setting of a functional brain stem. This statement, however, was based solely on NDD. Since pDCD is unaffected by the fact that these patients do not fulfill NDD criteria, we recommend that pDCD can be offered to the substitute decision makers of patients born with this condition. pDCD Implementation and Oversight Good Practice Statements. [bib_ref] Ethical, psychosocial, and public policy implications of procuring organs from non-heart-beating cadaver..., Youngner [/bib_ref] pDCD programs should seek out formal institutional approval within the existing hospital reporting structure. 51) There should be an integrated, collaborative approach to pDCD implementation with all hospital stakeholders, family and/or public partners, regional ODOs, and transplant programs. 52) Local coroners should be contacted early in the process of developing local pDCD procedures. 53) Communication and education of staff should be considered a priority during the development and implementation of a pDCD protocol. 54) pDCD case management review, including regular debriefing and a periodic quality assurance process, should occur. 55) Support for healthcare professionals involved in pDCD should be provided. Justification. The establishment of a pDCD program should involve multidisciplinary collaboration with oversight from appropriate local authorities. The need for communication and education of all involved stakeholders has also been broadly emphasized in recent publications and was a frequently expressed sentiment during our pDCD symposium [bib_ref] Donation after cardiac death in pediatric critical care, Kolovos [/bib_ref] [bib_ref] Organ donation after cardiac death: The subtle line between patient and donor..., Devictor [/bib_ref]. Quality control for this low-frequency, high-impact event is critical for pDCD programs. This process should involve medical and ethical oversight, ideally with linkage to measures of www.pccmjournal.org November 2017 - Volume 18 - Number 11 donor family experiences and transplant outcomes. Establishing robust ethical oversight also decreases the potential impact of institutional bias toward organ donation. Organ donation and transplantation activity are often a high-profile endeavor within a healthcare system, and the positive exposure associated with these programs may lead to a perception that donation activity takes precedence over ethical safeguards. The recognition and mitigation of this source of potential conflict interest is an important aspect of maintaining professional and public trust in the donation system. Although we do not provide specific recommendation for documentation, inherent in the quality assurance component of recommendation 54 is the assumption that the process of pDCD be well documented. We encourage teams developing pDCD practices to visit the Canadian Blood Services website link listed below to see sample clinical and administrative checklists as well as documentation tools. # Conclusion These recommendations are the result of a 3-year development process and represent the first pediatric-specific, national guideline governing pDCD practice. The process was transparent and based on the best available evidence that was synthesized into recommendations using the most rigorous methods possible. Review of this literature highlighted several knowledge gaps that hopefully will be addressed by further research in the field [bib_ref] Pediatric donation after circulatory determination of death: A scoping review, Weiss [/bib_ref]. For further information regarding our methods and the justifications behind our recommendations, please visit http://www.organsandtissues.ca/s/english-expert/ leading-practices-public-awareness-and-education for the full report in English and French, as well as tools to facilitate pDCD implementation. For questions regarding establishing a pDCD program, please contact Dr. Weiss or Canadian Blood Services. Although no guideline can perfectly address all concerns held by all stakeholders, it is our sincere hope that application of these guidelines can increase the number of organs available to Canadians, while also offering the meaningful possibility of organ donation to families experiencing the loss of a child. # Acknowledgments Development of these guidelines would not have been possible without the tenacious administrative support from: Clay Gillrie, Lisa McCarthy-Tamblyn, Sylvia Torrance, Stephanie Currie-McCarragher, Debbie White, and Kerry Phillips. Jennifer Wolfsmith and Emilie Therien provided invaluable input as patient partners. Dr. Marcelo Cypel responded to questions regarding lung donation after circulatory determination of death (DCD). We sincerely appreciate and honor the gift made by deceased donors and their loved ones, including Frank Fontana and his family. Without their selflessness, organ donation and transplantation would not be possible. Members of the pediatric DCD (pDCD) Working Groups: The members of the pDCD guideline development were divided into the following working groups: 1) Ethics and Legal, 2) WLST, 3) Death Determination, 4) Eligibility, 5) Ante and post mortem interventions,	None	https://europepmc.org/articles/pmc5671796?pdf=render	Objectives: Create trustworthy, rigorous, national clinical practice guidelines for the practice of pediatric donation after circulatory determination of death in Canada. Methods: We followed a process of clinical practice guideline development based on World Health Organization and Canadian Medical Association methods. This included application of Grading of Recommendations Assessment, Development, and Evaluation methodology. Questions requiring recommendations were generated based on 1) 2006 Canadian donation after circulatory determination of death guidelines (not pediatric specific), 2) a multidisciplinary symposium of national and international pediatric donation after circulatory determination of death leaders, and 3) a scoping review of the pediatric donation after circulatory determination of death literature. Input from these sources drove drafting of actionable questions and Good Practice Statements, as defined by the Grading of Recommendations Assessment, Development, and Evaluation group. We performed additional literature reviews for all actionable questions. Evidence was assessed for quality using Grading of Recommendations Assessment, Development, and Evaluation and then formulated into evidence profiles that informed recommendations through the evidence-to-decision framework. Recommendations were revised through consensus among members of seven topic-specific working groups and finalized during meetings of working group leads and the planning committee. External review was provided by pediatric, critical care, and critical care nursing professional societies and patient partners. Results: We generated 63 Good Practice Statements and seven Grading of Recommendations Assessment, Development, and Evaluation recommendations covering 1) ethics, consent, and withdrawal of life-sustaining therapy, 2) eligibility, 3) withdrawal of life-sustaining therapy practices, 4) ante and postmortem interventions, 5) death determination, 6) neonatal pediatric donation after circulatory determination of death, 7) cardiac and innovative pediatric donation after circulatory determination of death, and 8) implementation. For brevity, 48 Good Practice Statement and truncated justification are included in this summary report. The remaining recommendations, detailed methodology, full Grading of Recommendations Assessment, Development, and Evaluation tables, and expanded justifications are available in the full text report. Conclusions: This process showed that rigorous, transparent clinical practice guideline development is possible in the domain of pediatric deceased donation. Application of these recommendations will increase access to pediatric donation after circulatory determination of death across Canada and may serve as a model for future clinical practice guideline development in deceased donation.
c24e9eeffe624c83926dc4bac4859418e1e723ca	pubmed	DEGRO practical guidelines for radiotherapy of breast cancer V	DEGRO practical guidelines for radiotherapy of breast cancer V tions. Based on the German interdisciplinary S3 guidelines, updated in 2012, this publication addresses indications, sequence to other therapies, target volumes, dose, and fractionation of radiotherapy. Results International and national guidelines are in agreement that locally advanced, at least if regarded primarily unresectable and inflammatory breast cancer should receive neoadjuvant systemic therapy first, followed by surgery and radiotherapy. If surgery is not amenable after systemic therapy, radiotherapy is the treatment of choice followed by surgery, if possible. Surgery and radiotherapy should be administered independent of response to neoadjuvantAbstractAim The purpose of this work is to give practical guidelines for radiotherapy of locally advanced, inflammatory and metastatic breast cancer at first presentation. Methods A comprehensive survey of the literature using the search phrases "locally advanced breast cancer", "inflammatory breast cancer", "breast cancer and synchronous metastases", "de novo stage IV and breast cancer", and "metastatic breast cancer" and "at first presentation" restricted to "clinical trials", "randomized trials", "meta-analysis", "systematic review", and "guideline" was performed and supplemented by using references of the respective publica- systemic treatment. In patients with a de novo diagnosis of breast cancer with synchronous distant metastases, surgery and radiotherapy result in considerably better locoregional tumor control. An improvement in survival has not been consistently proven, but may exist in subgroups of patients. Conclusion Radiotherapy is an important part in the treatment of locally advanced and inflammatory breast cancer that should be given to all patients regardless to the intensity and effect of neoadjuvant systemic treatment and the extent of surgery. Locoregional radiotherapy in patients with primarily distant metastatic disease should be prescribed on an individual basis. Keywords Locally advanced breast cancer · Inflammatory breast cancer · Synchronous distant metastases · Radiotherapy · Guidelines ## Degro-leitlinien für die radiotherapie des mammakarzinoms v Therapie des lokal fortgeschrittenen und inflammatorischen Mammakarzinoms sowie lokale Therapie bei Vorliegen synchroner Fernmetastasen ## Zusammenfassung Ziel Ziel der Arbeit ist die Entwicklung von Praxis-Leitlinien zur Strahlentherapie des lokal fortgeschrittenen einschließlich des inflammatorischen Mammakarzinoms sowie zur lokalen Therapie bei synchroner Fernmetastasierung. Methoden Es erfolgte eine Literaturübersicht basierend auf den Suchbegriffen "locally advanced breast cancer", "inflammatory breast cancer", "breast cancer and synchronous metastases", "de novo stage IV and breast cancer" und "metastatic breast cancer" sowie "at first presentation". Stratifiziert wurde nach "clinical trials", "randomized trials", "meta-analysis", "systematic review" und "guideline", ergänzt von kürzlich veröffentlichten Abstracts. Ergänzend zu den Stellungnahmen der deutschen interdisziplinären S3-Leitlinie der Deutschen Krebsgesellschaft und der AWMF zum Mammakarzinom von 2012 bezieht diese Publikation Stellung zu den Indikationen, zur zeitlichen Abfolge mit anderen Therapien, zum Zielvolumen sowie zur Dosis und Fraktionierung der Strahlentherapie. Ergebnisse Internationale und nationale Leitlinien stimmen darin überein, dass Patientinnen mit einem lokal fortgeschrittenen, zumindest primär als irresektabel eingestuften, sowie Patientinnen mit einem inflammatorischen Mammakarzinom zunächst eine neoadjuvante Systemtherapie erhalten sollen, gefolgt von einer Operation und einer Strahlentherapie. Falls nach der Systemtherapie eine Operation nicht durchführbar ist, sollte zunächst eine Radiotherapie erfolgen und anschließend noch einmal die Möglichkeit ei-ner Operation bedacht werden. Operation und Bestrahlung erfolgen unabhängig vom Ansprechen auf die neoadjuvante Systemtherapie. Bei Patientinnen mit primärer Fernmetastasierung führt die lokale Behandlung mittels Operation und/ oder Strahlentherapie zur besseren lokalen Tumorkontrolle. Ein Überlebensvorteil besteht wohl nicht, möglicherweise aber doch für einige Subgruppen der Patientinnen. Schlussfolgerung Eine Strahlentherapie ist wichtiger Bestandteil der Behandlung lokal fortgeschrittener und inflammatorischer Mammakarzinome für alle betroffenen Patientinnen, unabhängig von der Intensität und dem Ergebnis der neoadjuvanten systemischen Therapie und des Ausmaßes einer eventuellen Chirurgie. Bei Patientinnen mit primärer Fernmetastasierung muss im Tumorboard die Indikation zur lokoregionären Strahlentherapie individuell gestellt werden. ## Schlüsselwörter lokal fortgeschrittenes Mammakarzinom · Inflammatorisches Mammakarzinom · Synchrone Fernmetastasierung · Strahlentherapie · Leitlinien Tumors larger than 5 cm or tumors infiltrating the chest wall or skin (T3/T4), fixated axillary lymph nodes (N2), involved infra-or supraclavicular lymph nodes, or involved lymph nodes in the internal mammary chain (N3) are regarded as locally advanced breast cancer and are generally considered as not amenable for primary surgery. Inflammatory breast cancer (T4d) accounts for approximately 10-15 % of locally advanced breast cancer. Historical results with radiotherapy as sole treatment reported 5-year survival rates in locally advanced breast cancer without systemic treatment of approximately 30 % and in inflammatory breast cancer of 5 % [bib_ref] Prospective randomized trial of paclitaxel alone versus 5-fluorouracil/doxorubicin/cyclophosphamide as induction therapy in..., Buzdar [/bib_ref]. Distant metastases at the time of breast cancer diagnosis are detected in about 4 % of all breast cancer patients, but are observed in 14 % of T3 and 26 % of T4 patients (Munich Cancer Registry 2013). Nowadays, primary systemic treatment is considered standard of care for breast cancer patients with locally advanced and inflammatory breast cancer, as well as in patients with synchronous distant metastases [bib_ref] Significant cardiotoxicity of trastuzumab in adjuvant systemic therapy of elderly patients with..., Pohl [/bib_ref] [bib_ref] Timing of radiotherapy following breastconserving surgery: outcome of 1393 patients at a..., Corradini [/bib_ref]. Response to systemic treatment, especially pathologically complete response (pCR), has been shown to be associated with improved survival in all these situations [bib_ref] Breast conservation and prolonged chemotherapy for locally advanced breast cancer: the University..., Merajver [/bib_ref]. The development of modern neoadjuvant treatment in less advanced breast cancer was based on experience in locally advanced and inflammatory breast cancer. Randomized clinical trials have focused on further development of more effective systemic treatment regimen, whereas radiotherapy was an integrated part of the treatment in these trials, since its importance for locoregional control was not challenged. This has changed to some extent, since a substantial portion of the patients are mean-overall survival of 13 % and distant metastasis-free survival of 15 % indicating some curative potential. Chemotherapy and hormonal treatment each produced a significant prolongation of the time to locoregional recurrence, time to distant metastases, and overall survival. Combined treatments provided the largest therapeutic effect. The 10-year overall survival was improved by 8-15 % by the addition of systemic treatments. A number of subsequent trials, designed to optimize systemic chemotherapy by introducing anthracyclines and taxanes, led to a stepwise improvement of 5-year survival in locally advanced cancer to about 70 % and in inflammatory cancer to about 40 % [bib_ref] Modern outcomes of inflammatory breast cancer, Rehman [/bib_ref] [bib_ref] Management of inflammatory breast cancer: focus on radiotherapy with an evidence-based approach, Scotti [/bib_ref]. In case of resectability after neoadjuvant chemotherapy, mastectomy followed by radiotherapy was performed in most patients. Importantly, subgroup analyses revealed that patients with a pCR in their mastectomy specimen had a substantially better overall survival than patients with partial response or stable disease [bib_ref] Breast conservation and prolonged chemotherapy for locally advanced breast cancer: the University..., Merajver [/bib_ref] [bib_ref] Prognostic factors in inflammatory breast cancer and therapeutic implications, Palangie [/bib_ref]. This observation was the starting point for the use of pCR rates as a surrogate marker for overall survival in the further development of neoadjuvant treatment in breast cancer [bib_ref] Current and future role of neoadjuvant therapy for breast cancer, Untch [/bib_ref]. In these trials, incremental numbers of patients with moderately advanced breast cancers (e.g., cT2 disease) were included. The pCR rates in the recent German neoadjuvant chemotherapy breast cancer trials [bib_ref] Impact of treatment characteristics on response of different breast cancer phenotypes: pooled..., Von Minckwitz [/bib_ref] were increased to an average of 21 %, showing considerable differences by the subtype of breast cancer. The pCR rates were on average lower in T3/T4 tumors and inflammatory cancer ranging between 13 and 16 %. In estrogen-receptor-negative cancers and undifferentiated cancers (G3), a substantially higher likelihood to achieve a pCR was observed as compared to estrogen-receptor-positive and well-differentiated cancers (odds ratios 3.8 and 5.8). The highest pCR rate of 41 % was seen in patients with HER-2-positive tumors receiving 8-12 cycles of trastuzumab. The pCR rate achieved in inflammatory breast cancer is in the same range as for other locally advanced stages. This is probably a consequence of the higher likelihood of inflammatory cancer of being poorly differentiated, estrogen receptor negative, and HER-2 positive [bib_ref] Impact of treatment characteristics on response of different breast cancer phenotypes: pooled..., Von Minckwitz [/bib_ref]. Using double HER-2-blocking therapies pCR rates in hormone-receptor-negative, undifferentiated tumors as high as 63 % [bib_ref] Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally..., Gianni [/bib_ref] have been reported. The results of the neoALTTO and ALTTO trials, however, shed some doubts whether higher pCR rates necessarily indicate better overall survival, since in spite of an observed doubling in the pCR by double HER-2 blockade in the neoALTTO trial [bib_ref] Pattern of rash, diarrhea, and hepatic toxicities secondary to lapatinib and their..., Azim [/bib_ref] , no benefit in overall survival was observed in the ALTTO trial testing the same regimen in the adjuvant setting. Indeed a meta-analysis including almost 12,000 patients from 12 trials testing primary systemic therapy came to the same conclusion that albeit pCR is associated with a significantly improved overall survival, it is not a suitable surrogate parameter for overall or progression-free survival on a triallevel basis [bib_ref] Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC..., Cortazar [/bib_ref]. while amenable for surgery after partial or complete clinical remission following neoadjuvant systemic treatment. Especially in case of pCR after mastectomy the impact of radiotherapy has been questioned. The aim of this paper is to review the role of radiotherapy in locally advanced and inflammatory breast cancer, and for patients with synchronous distant metastases and to provide practical treatment guidelines relating to and supplementing the current German S3 guidelines and the previous practical DEGRO guideline [bib_ref] DEGRO practical guidelines for radiotherapy of breast cancer II. Postmastectomy radiotherapy, irradiation..., Sautter-Bihl [/bib_ref]. ## Locally advanced and inflammatory breast cancer ## Infobox 1 - RT-6 statement of the German S3 guideline (radiotherapy of locally advanced unresectable breast cancer) For patients with primarily inoperable or inflammatory breast cancer primary systemic therapy followed by surgery and postoperative radiotherapy is recommended (LOE 1b); recommendation grade A. - If surgical resectability is not achieved after systemic treatment, radiotherapy-optionally also combined with concurrent systemic treatment-is indicated (GCP). RT-4d statement of the German S3 guideline (radiotherapy after mastectomy) - After neoadjuvant therapy, radiotherapy is indicated in accordance to the pretreatment T and N classification independent of the degree of response to the neoadjuvant treatment (LoE 2a); recommendation grade A. ## Development of neoadjuvant chemotherapy Although inflammatory breast cancer has a poorer outcome compared to other locally advanced breast cancers in prospective clinical trials and most retrospective evaluations treatment for both entities have mostly been identical. No more than sparse results of subgroup analyses were available from some reports. Therefore, differential treatment recommendations for locally advanced and inflammatory breast cancer cannot generally be given. In 1997 the EORTC published the results of a phase III trial [bib_ref] Hormonal therapy prolongs survival in irradiated locally advanced breast cancer: a European..., Bartelink [/bib_ref] on the treatment of locally advanced and inflammatory breast cancer. A total of 410 patients were randomized for either radiotherapy, radiotherapy plus chemotherapy (CMF), radiotherapy plus tamoxifen, or radiotherapy plus tamoxifen plus CMF. Surgery was not part of the planned treatment and was reserved for salvage treatment in case of local recurrence. Radiotherapy alone resulted in a 10-year tional guidelines [bib_ref] AGO) (2014) AGO diagnosis and treatment of patients with primary and metastatic..., Awmf ; Interdisziplinäre S3-Leitlinie Für Die Diagnostik [/bib_ref] recommend breast surgery after neoadjuvant systemic treatment regardless of the response to the neoadjuvant treatment if complete resection appears possible. Whether mastectomy or breast-conserving surgery is preferable after neoadjuvant chemotherapy is another unanswered question. In a meta-analysis of randomized trials on neoadjuvant chemotherapy compared to adjuvant chemotherapy, overall survival and disease-free survival were identical. However, the rate of breast-conserving therapy was significantly higher in neoadjuvantly treated patients [bib_ref] Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis, Mauri [/bib_ref]. This increase in breast conservation rates was associated with a significantly higher rate of locoregional recurrence, which was, however, predominantly observed in three trials in which radiotherapy without surgery was more frequently used in the neoadjuvant arms of the trials. Although locally advanced primarily unresectable and inflammatory breast cancers were not treated in these trials, the result indirectly support the assumption that locally advanced and inflammatory breast cancers should, whenever possible, receive intensive locoregional treatment consisting of complete resection and locoregional radiotherapy. Results of breast-conserving surgery after neoadjuvant chemotherapy in locally advanced and inflammatory breast cancer have been reported from a number retrospective evaluations [bib_ref] Breast conservation therapy for patients with locally advanced breast cancer, El-Dinma [/bib_ref]. Breast-conserving surgery in these cohorts was generally restricted to selected patients, whose tumors responded well to neoadjuvant treatment, were confined to one quadrant of the breast, and had no more signs of inflammatory disease. In this selected subgroup of patients after 5-10 years, in-breast recurrence rates between 2 and 23 % have been reported [bib_ref] Breast conservation therapy for patients with locally advanced breast cancer, El-Dinma [/bib_ref] , indicating that breast-conserving surgery is justifiable in appropriate patients. The need of radiotherapy for patients with locally advanced breast cancer with residual disease after neoadjuvant treatment is not disputed in view of the convincing evidence from the EBCTCG meta-analysis [bib_ref] Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and..., Mcgale [/bib_ref] showing a significant survival advantage for postmastectomy radiotherapy in patients with T4 tumors or involved axillary lymph nodes. The need for radiotherapy in case of pCR after neoadjuvant chemotherapy has been challenged. The best available evidence to answer the question whether radiotherapy is necessary after mastectomy in case of pCR comes from two retrospective studies. Huang et al. [bib_ref] Postmastectomy radiation improves localregional control and survival for selected patients with locally..., Huang [/bib_ref] assessed the clinical outcome of 676 breast cancer patients who had received six different neoadjuvant chemotherapy regimens within clinical trials followed by mastectomy and axillary dissection. Of these patients, 134 received no postmastectomy radiotherapy, whereas 542 underwent postmastectomy radiotherapy. As expected in a nonrandomized comparison, patients receiving radiotherapy had significantly more advanced T and N stages representing a bias in disadvantage of radiotherapy. In spite Locoregional treatment after neoadjuvant chemotherapy Regardless of response to neoadjuvant treatment, the question arises to which extent additional local treatment further improves outcome. Results of randomized trials directly answering the question for the need of surgery and radiotherapy in this situation are not available. National and international guidelines [bib_ref] AGO) (2014) AGO diagnosis and treatment of patients with primary and metastatic..., Awmf ; Interdisziplinäre S3-Leitlinie Für Die Diagnostik [/bib_ref] recommend radiotherapy for patients presenting with persistent unresectability after neoadjuvant chemotherapy, since radiotherapy has a curative potential in this situation [bib_ref] Hormonal therapy prolongs survival in irradiated locally advanced breast cancer: a European..., Bartelink [/bib_ref]. Resectability should be assessed 6-12 weeks after completion of radiotherapy. Surgery is advised if a R0 resection seems achievable, although the benefit of surgery in this clinical setting has formally not been shown. In stage III breast cancer patients with resectable disease after neoadjuvant chemotherapy, the effect of surgery and radiotherapy was investigated in three small randomized trials [bib_ref] Combination chemotherapy with mastectomy or radiotherapy for stage III breast carcinoma: a..., Perloff [/bib_ref] [bib_ref] Ten-year results utilizing chemotherapy as primary treatment in nonmetastatic, rapidly progressing breast..., Mourali [/bib_ref] [bib_ref] Multimodal treatment for locally advanced breast cancer. Result of chemotherapy-radiotherapy versus chemotherapy-surgery, De Lena [/bib_ref]. Patients were randomized after neoadjuvant chemotherapy (two trials with anthracyclines, one trial with CMF) to undergo either mastectomy or radiotherapy. Overall survival, disease-free survival, and locoregional tumor control were similar with both treatments. However, the locoregional recurrence rate at 2-5 years reached 40-60 % with either treatment, indirectly indicating that patients should receive both surgery and radiotherapy. In none of these trials results according to response to the neoadjuvant treatment were reported. Thus, the question remains open whether surgery and radiotherapy are required in case of clinical complete response (cCR) or pCR after neoadjuvant chemotherapy. Merajver et al. [bib_ref] Breast conservation and prolonged chemotherapy for locally advanced breast cancer: the University..., Merajver [/bib_ref] treated 90 stage III breast cancer patients with nine cylces of an anthracycline-based neoadjuvant chemotherapy. After the last cycle of chemotherapy, a biopsy was taken from the initial tumor region. In case of pCR, patients received radiotherapy of the chest wall and regional lymph nodes without any surgery. Patients with residual tumor in the biopsy underwent mastectomy followed by the same radiotherapy. The omission of surgery in patients with pCR was not associated with a higher locoregional recurrence rate, which was approximately 20 % at the 5-year follow-up. [bib_ref] Is radiotherapy an option for early breast cancers with complete clinical response..., Daveau [/bib_ref] extracted from their prospective databases the outcome of stage III breast cancer patients with cCR after neoadjuvant chemotherapy who had received radiotherapy but no surgery and compared this with the outcome of patients with pCR after chemotherapy, who had received mastectomy and postoperative radiotherapy. The outcomes in terms of overall survival, disease-free survival, and distant metastases-free survival were almost identical. A trend towards better locoregional tumor control was observed for patients receiving surgery in addition to radiotherapy. In the absence of evidence from randomized trials, national and interna-1 3 DEGRO practical guidelines for radiotherapy of breast cancer V Timing of radiotherapy Radiotherapy in locally advanced or inflammatory breast cancer was administered after neoadjuvant chemotherapy and mastectomy in most clinical investigations. In case of remaining unresectability after completion of chemotherapy, radiotherapy is given followed by surgical resection, if clinically possible. Interestingly, the optimal timing of radiotherapy in the management of locally advanced breast cancer and IBC has not been systematically investigated. In a number of phase II trials, sequential radiotherapy after neoadjuvant chemotherapy as well as concurrent chemoradiation were analyzed in stage II and III breast cancer [bib_ref] On behalf of A. Primary systemic therapy and whole breast irradiation for..., Kaidar-Person [/bib_ref]. Overall survival, disease-free survival, and locoregional control in these trials were not substantially different from published data for postoperative radiotherapy. The pCR rates in these trials vary between 16 % [39] and 45 % [bib_ref] Retrospective analysis of locally advanced noninflammatory breast cancer from Chennai, South India,..., Shanta [/bib_ref]. On average, trials using concurrent chemoradiation reported higher pCR rates than trials on sequential chemoradiation. In none of these trials were HER-2 antagonists used for HER-2-positive cancer. Unfortunately, subgroup analyses differentiating pCR rates by molecular subtypes are not available from most of these trials. The available data indicate that, similar to the observations for neoadjuvant chemotherapy, pCR rates after additional radiotherapy are higher in hormone-receptor-negative disease than in hormone-receptor-positive breast cancer. However, the reported pCR rates of 18 % (n = 57) in the data of Adams et al. [bib_ref] Preoperative concurrent paclitaxel-radiation in locally advanced breast cancer: pathologic response correlates with..., Adams [/bib_ref] and 29 % (n = 241) in the data of Matuschek et al. [bib_ref] Long-term outcome after neoadjuvant radiochemotherapy in locally advanced noninflammatory breast cancer and..., Matuschek [/bib_ref] for hormone-receptor-positive breast cancer compare favorably to the experience in the German neo-adjuvant chemotherapy trials, in which a pCR of 13 % (n = 2150) was reported for hormone-receptor-positive disease. Interestingly enough, pCR rates increased with incremental intervals from completion of radiotherapy to surgery in the data of Matuschek et al. [bib_ref] Long-term outcome after neoadjuvant radiochemotherapy in locally advanced noninflammatory breast cancer and..., Matuschek [/bib_ref] , indicating that cancer cell death after radiotherapy takes several months for completion and occurs typically postmitotic in breast cancer. The reported acute and late toxicities in the trials on sequential or concurrent chemoradiation in breast cancer were mostly grade I and II. In early breast cancer, sequential and concurrent adjuvant chemoradiation were tested in a number of randomized controlled trials in which breast-conserving surgery was generally performed. In a Cochrane review of these trials [bib_ref] Fraction size in radiation treatment for breast conservation in early breast cancer, James [/bib_ref] , concurrent chemoradiation resulted in significantly more skin reactions (odds ratio 1.46, 95 % CL 1.00-2.14), esophagitis (odds ratio 1.44, 95 % CL 1.03-2.02), and hematotoxicity (odds ratio 1.43, 95 % CL 1.01-2.03) compared to sequential treatment, whereas late toxicity was comparable. No difference was seen in overall survival and locoregional recurrence rates. Whether these results can be transferred to the neoadjuvant of this negative selection, locoregional tumor control and cause-specific survival were significantly better in irradiated patients with T4 tumors or more than four involved axillary lymph nodes associated with a trend towards an improved overall survival. Of 46 patients with locally advanced cancers, who had a pCR after neoadjuvant chemotherapy, 11 received radiotherapy. The actuarial locoregional recurrence rate at 10 and 14 years was 3 % in irradiated patients compared to 33 % without radiotherapy (p = 0.006). McGuire et al. [bib_ref] Postmastectomy radiation improves the outcome of patients with locally advanced breast cancer..., Mcguire [/bib_ref] identified 106 patients with stage II-III breast cancer (69 % stage III, no inflammatory cancers) treated with neoadjuvant chemotherapy (92 % anthracycline-based chemotherapy, 38 % with taxane) mastectomy and axillary lymph node dissection, who had a pCR. Of these, 34 patients underwent postmastectomy radiotherapy and 72 no radiotherapy. Irradiated patients had significantly larger tumors than unirradiated patients. Regardless of this unfavorable bias, patients receiving postmastectomy radiotherapy experienced significantly better locoregional tumor control (absolute ~ + 20 %), distant metastases-free survival (absolute ~ + 37 %), and overall survival (absolute ~ + 40 %) 5 year after treatment. Both studies, although not randomized, led consistently to the recommendation in national and international guidelines [bib_ref] AGO) (2014) AGO diagnosis and treatment of patients with primary and metastatic..., Awmf ; Interdisziplinäre S3-Leitlinie Für Die Diagnostik [/bib_ref] to use radiotherapy in patients with a pCR after neoadjuvant chemotherapy. Whether a comparable benefit can also be expected for patients with HER-2-positive breast cancer receiving anti-HER-2 therapies is unknown. In absence of reliable evidence regarding this question, radiotherapy is also advised in these patients in the guidelines. Attempts to identify subgroups of patients with locally advanced breast cancer based on molecular profiling, like in early breast cancer, have not been successful so far [bib_ref] Local recurrence after breast-conserving therapy in relation to gene expression patterns in..., Kreike [/bib_ref]. Although it has been shown that luminal A and B breast cancers have lower propensity for locoregional recurrences than HER-2-positive and triple-negative breast cancers [bib_ref] Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is..., Nguyen [/bib_ref] , radiotherapy decreases the locoregional recurrence rate independent of the molecular subtype approximately by the factor 3-4 [bib_ref] Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk..., Kyndi [/bib_ref]. However, there is some evidence that the benefit of radiotherapy in terms of locoregional control translates into a smaller survival benefit in HER-2 positive and triple negative compared to hormone-receptor-positive breast cancer [bib_ref] Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk..., Kyndi [/bib_ref] [bib_ref] Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast..., Darby [/bib_ref]. Currently, differential indications for radiotherapy based on molecular profiles are not recommended in national or international guidelines outside from clinical trials. ## Comments and conclusion of the degro panel - The DEGRO panel recommends locoregional radiotherapy as part of the treatment for all patients with locally advanced and inflammatory breast cancer regardless of the response to neoadjuvant systemic treatment. This is in accordance with the German S3 guideline. Target volumes, dose, and fractionation of radiotherapy The vast majority of patients with locally advanced and inflammatory breast cancer in clinical trials received chest wall radiotherapy and radiotherapy to the regional lymph nodes. In the German neoadjuvant trials [bib_ref] Impact of treatment characteristics on response of different breast cancer phenotypes: pooled..., Von Minckwitz [/bib_ref] , radiotherapy was administered according to the current German S3 guidelines at that time. Although no information on the actually administered radiotherapy has been published from any of these trials, most likely radiation oncologist treated patients in adherence to the guidelines, permitting the conclusion that all patients with locally advanced and inflammatory breast cancer received radiotherapy of the chest wall and the majority radiotherapy of the supra-and infraclavicular lymph nodes. Most likely, only a minority of the patients has received radiotherapy to the internal mammary lymph nodes in these trials. Recently, new data emerged, indicating that radiotherapy of the internal mammary lymph nodes results in a small, but statistically significant survival benefit [bib_ref] An intergroup trial of regional nodal irradiation in early breast cancer, Whelan [/bib_ref] [bib_ref] Irradiation of the internal mammary and medial supraclavicular lymph nodes in stage..., Poortmans [/bib_ref] [bib_ref] Adjuvant radiotherapy of regional lymph nodes in breast cancer-a metaanalysis of randomized..., Budach [/bib_ref]. This benefit was more pronounced in patients receiving both chemotherapy and endocrine therapy [bib_ref] Irradiation of the internal mammary and medial supraclavicular lymph nodes in stage..., Poortmans [/bib_ref] , but which was less substantial in N3 disease. Radiotherapy of the internal mammary lymph nodes (IMC) was not significantly associated with increased cardiotoxicity after a median follow-up of 10.9 years. However, trastuzumab or other anti-HER2 agents were not given in this trial. Based on this new data, the DEGRO panel has already published recommendation for the treatment of the regional lymph nodes in breast cancer [bib_ref] DEGRO practical guidelines: radiotherapy of breast cancer III-radiotherapy of the lymphatic pathways, Sautter-Bihl [/bib_ref]. The DEGRO panel recommends radiotherapy of the chest wall or breast and the supra-and infraclavicular lymph nodes in all patients with locally advanced and inflammatory breast cancer regardless of the response to systemic therapy. Radiotherapy of the internal mammary lymph nodes should be considered in patients, who do not receive anti-HER2 treatments. If a surgical resection after neoadjuvant treatment is not possible or declined by the patient, most investigators defined the macroscopic tumor with some safety margin (exact description mostly not published) as clinical target volume for an additional boost dose. In the majority of clinical trials on radiotherapy after mastectomy in locally advanced breast cancer, conventionally fractionated radiotherapy with 1.8-2.0 Gy in 5 fractions per week to total doses of 45.0-50.4 Gy was used. Hypofractionated radiotherapy with 2.3-3.7 Gy per fraction in 2-5 fractions per week to total doses of 30-50 Gy were applied preferentially in the United Kingdom, Scandinavia, and Canada. Since from today's point of view the total dose in some of these hypofractionated regimens was not adequately reduced in relation to the increase in dose per fraction, long-term side effects, especially plexopathia, were frequently reported [bib_ref] Radiation-induced brachial plexopathy and hypofractionated regimens in adjuvant irradiation of patients with..., Galecki [/bib_ref]. setting in locally advanced breast cancer is unknown in the absence of randomized trials. Since in locally advanced and inflammatory breast cancer mastectomy is considered as the standard surgical procedure, many patients, especially those of younger age, wish immediate or sequential breast reconstruction. However, the optimal sequencing of breast reconstruction and radiotherapy is another unanswered question. Three options have been investigated: - mastectomy followed by radiotherapy followed by reconstructive surgery; - mastectomy with immediate reconstructive surgery followed by radiotherapy; - radiotherapy followed by mastectomy with immediate reconstructive surgery. In the absence of randomized trials, all comparisons remain inconclusive. From the available data for the different strategies, the oncological outcome is presumably similar [bib_ref] Immediate versus delayed reconstruction following surgery for breast cancer. Cochrane, D'souza [/bib_ref]. There seems to be a tendency that early complications are more frequently observed in patients having radiotherapy first. Late complications occur more often in patients undergoing breast reconstruction first [bib_ref] Impact of sequencing of postmastectomy radiotherapy and breast reconstruction on timing and..., Adesiyun [/bib_ref]. If an immediate autologous reconstruction is planned, radiotherapy before mastectomy and immediate reconstruction is theoretically advantageous, because the autologous tissue used for reconstruction does not receive radiotherapy at any time and consequently will not develop radiation-induced fibrosis. This approach was tested in a prospective multi-institutional investigation in Düsseldorf: Gerlach et al. [bib_ref] Remission rates in breast cancer treated with preoperative chemotherapy and radiotherapy, Gerlach [/bib_ref] reported the early results of a preoperative chemoradiation in 132 breast cancer patients (90 % stage II and III) of whom 82 received transverse rectus abdominus myocutaneous (TRAM) or latissimus dorsi flab reconstruction at a median time of 8 weeks after completion of radiotherapy. In a nonrandomized comparison with 62 patients receiving neoadjuvant chemotherapy without radiotherapy before breast surgery, they did not find a higher rate of surgical complications. Roth et al. [bib_ref] Retrospective study of neoadjuvant versus adjuvant radiochemotherapy in locally advanced noninflammatory breast..., Roth [/bib_ref] confirmed these results in the long-term follow-up on the complete cohort of 315 patients and reported a favorable long-term oncological outcome compared to a similar group of patients treated with postoperative radiotherapy. ## Comments and conclusions of the degro panel - The optimal timing of radiotherapy is not well investigated. Most data are available for conducting radiotherapy after neoadjuvant systemic treatment and mastectomy, or in case of persistent unresectability after completion of neoadjuvant treatment. - If immediate autologous reconstruction is intended, radiotherapy and concurrent chemoradiation before surgery are alternative options. lymph node metastases maybe considered, if the dose to the brachial plexus is kept below a 2 Gy equivalent dose (α/β = 3 Gy) of about 54 Gy. Radiotherapy should be delivered in supine position using a dedicated breast board. ## Comments and conclusions of the degro panel - The clinical target volume (CTV) at the chest wall should include the intercostal spaces in the region of the (resected) breast. - The CTVs for the radiotherapy of the regional lymph nodes should be based on published international consensus guidelines [bib_ref] Delineation of target volumes and organs at risk in adjuvant radiotherapy of..., Nielsen [/bib_ref] ; however, adaptations may be necessary in locally advanced and inflammatory disease to ensure that any macroscopic disease is included into the CTV with adequate safety margins. - 3D-CRT or IMRT treatment planning is recommended using algorithms providing a reliable dose prediction in the lungs, lung chest wall, and lung-heart interface (e.g., Monte Carlo or Collapsed cone). If IMRT is used, which may be especially advantageous if the internal mammary lymph nodes need to be irradiated , b, c), low dose exposure to large parts of the lungs and contralateral breast should be kept as small as possible. ## Locoregional radiotherapy in patients with synchronous distant metastases Radiotherapy to the breast, axillary, infra, and supraclavicular lymph nodes in metastatic breast cancer is frequently performed to obviate or relieve symptoms, but is not thought to have an impact on survival [bib_ref] Treatment of breast cancer, Hortobagyi [/bib_ref]. However, according to the results of a number retrospective studies on breast cancer [bib_ref] Does aggressive local therapy improve survival in metastatic breast cancer?, Khan [/bib_ref] [bib_ref] Complete excision of primary breast tumor improves survival of patients with metastatic..., Rapiti [/bib_ref] [bib_ref] Surgical removal of the primary tumor increases overall survival in patients with..., Gnerlich [/bib_ref] [bib_ref] Does local surgery have a role in the management of stage IV..., Carmichael [/bib_ref] [bib_ref] Association of surgery with improved survival in stage IV breast cancer patients, Blanchard [/bib_ref] [bib_ref] Effect of primary tumor extirpation in breast cancer patients who present with..., Babiera [/bib_ref] [bib_ref] Surgical resection of the primary tumor is associated with increased long-term survival..., Fields [/bib_ref] [bib_ref] Breast cancer with synchronous metastases: survival impact of exclusive locoregional radiotherapy, Scodan [/bib_ref] , local treatment of the primary tumor by radiotherapy or surgery or both may improve overall survival. The data on surgical treatment of the primary site were comprehensively reviewed by Ruiterkamp et al. [bib_ref] The role of surgery in metastatic breast cancer, Ruiterkamp [/bib_ref] , whereas the present paper focuses on the effect of radiotherapy with/or without surgery. Le Scodan et al. [bib_ref] Breast cancer with synchronous metastases: survival impact of exclusive locoregional radiotherapy, Scodan [/bib_ref] retrospectively analyzed the outcome of 581 patients with metastatic breast cancer of whom Modern hypofractioned regimens that were tested predominantly in early breast cancer, like the START A (3.2 Gy per fraction, 2-3 times per week to 41.6 Gy) and the START B scheme (2.66 Gy per fraction, 5 times per week to 40 Gy) implemented an adequate reduction of the total dose [bib_ref] The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for..., Haviland [/bib_ref]. As a consequence these schedules should not be associated with a higher probability of severe late effects than conventionally fractionated regimens. Indeed, at a median follow-up of almost 10 years cosmetic results with hypofractionation were not impaired, and in the few patients receiving supra-and infraclavicular lymph node irradiation, only in 1 out of 211 patients (95 % CL 0-2.6 %) in the START A trial, and in none out of 82 patients (95 % CL 0-4.4 %) in the START B trial was plexopathia reported [bib_ref] The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for..., Haviland [/bib_ref]. Since plexopathia may occur as late as 25 years after radiotherapy [bib_ref] Hypofractionation in radiotherapy. An investigation of injured Swedish women, treated for cancer..., Friberg [/bib_ref] , its final incidence is expected to be higher. None of the patients in the randomized trials on hypofractionation compared to conventional fractionated radiotherapy in early breast cancer received radiotherapy of the internal mammary lymph nodes. Radiation-induced heart toxicity is particularly associated with radiotherapy of the internal mammary lymph nodes [bib_ref] Risk of ischemic heart disease in women after radiotherapy for breast cancer, Darby [/bib_ref]. Since one cannot exclude that hypofractionated radiotherapy to the internal mammary lymph node may increase cardiac toxicity and hypofractionated radiotherapy to the supra-and infraclavicular lymph nodes increase late incidence of plexopathia, the DEGRO panel recommends conventionally fractionated radiotherapy with 1.8-2.0 Gy per fraction 5 times per week to total doses of Gy for the therapy of the regional lymph nodes in the adjuvant situation. Because chest wall radiotherapy is almost always indicated at the same time, the same fractionation regimen should be used for radiotherapy of the chest wall. If radiotherapy is administered without previous surgery the same arguments regarding the dose and fractionation apply as regional nodal irradiation is generally indicated. An additional sequential boost dose of 10-20 Gy to the macroscopic tumor volume is recommended in this situation as conventionally fractionated percutaneous radiotherapy or as brachytherapy. Alternatively, the boost dose may be given as simultaneous integrated boost using 2.2-2.4 Gy per fraction. A boost dose to remaining macroscopic Treatment plan irradiating the right chestwall (including a tissue expander) and the right supraclavicular and mammary interna lymph node regions. a axial view. b sagittal view. c coronal view of the better locoregional tumor control in the arm with locoregional treatment. Subgroup analyses did not indicate different results depending on hormone receptor status, HER-2 expression status, site of metastases, and number of metastatic lesions. The second randomized trial was conducted by a group from Turkey [bib_ref] Local Surgery for Metastatic Breast Cancer, Soran [/bib_ref]. Patients with metastatic breast cancer at the time of diagnosis were randomized to undergo locoregional treatment (n = 140) consisting of breast-conserving surgery followed by radiotherapy or mastectomy without radiotherapy or to receive no locoregional treatment (n = 138). The groups were comparable regarding age, BMI, hormone receptor and HER-2 status, tumor type, and size. Median follow-up was 21 months. After 54 months overall survival was 35 % with locoregional treatment and 31 % without locoregional treatment (p = 0.24). In the subgroups of hormone-receptor-positive disease, young patients (< 50 years), and patients with a solitary bone metastasis, overall survival was significantly improved. Patients with triplenegative disease had significantly worse survival in the arm with locoregional treatment. The partially conflicting results of the randomized trials that have not yet been fully published, which in synopsis with the retrospective investigation do not allow for a final conclusion. Overall, the benefit is probably limited; however, subgroups may have an advantage. Different mechanisms have been discussed about how locoregional treatment of the primary site could prolong survival. Uncontrolled locoregional disease can induce edema, infection, and thromboses and result in life-threatening problems. The persistent primary tumor could be a source of continuous seeding of further distant disease. Recent experimental data indicate that radiation-induced tumor cell necrosis can result in an improved dendritic-cell-mediated antitumoral immune response [bib_ref] Radiation induces an antitumour immune response to mouse melanoma, Perez [/bib_ref]. ## Comments and conclusions of the degro panel - Based on the available data, no general recommendations can be given for locoregional treatment outside of clinical trials. The decision of who is a candidate for locoregional radiotherapy should be made in an interdisciplinary board. The optimal dose and fractionation of radiotherapy in this situation has not been investigated. - In patients with longer life expectancy, the same radiotherapy regimens as recommended for locally advanced and inflammatory breast cancer should be used. ## Compliance with ethical guidelines Conflict of interest The corresponding author states that there are no conflicts of interest. The accompanying manuscript does not include studies on humans or animals. 320 received locoregional treatment after detection of distant metastases. Locoregional therapy comprised radiotherapy in 249 patients (78 %), surgery of the primary tumor with adjuvant irradiation in 41 patients (13 %), and surgery alone in 30 patients (9 %). Median follow-up was 39 months. A 3-year overall survival rate of 43.4 % was observed in patients receiving locoregional treatment of the primary, but only 26.7 % in patients receiving no locoregional therapy (p < 00002). The advantage in overall survival in favor of locoregional treatment was notably marked in patients with visceral metastases, whereas no survival benefit was seen in patients with bone metastases. Treatment of the primary tumor was an independent prognostic factor in multivariate analysis (hazard ratio: 0.70; 95 % CI: 0.58-0.85; p < 0.0002). Radiotherapy of the breast or chest wall and the infra-and supraclavicular lymph nodes was used in most patients. A mean total dose of 48.7 Gy was given within 4-5 weeks to the majority of patients. Most patients, who did not receive breast surgery (n = 249), obtained an extra boost irradiation to the primary tumor site with an average dose of 23 Gy. A trend towards longer survival was observed for patients receiving both surgery and radiotherapy. A group of investigators from India reported the preliminary results of a randomized controlled trial . Patients with synchronous metastatic breast cancer were treated with anthracycline-based chemotherapy with or without taxane. Patients with complete or partial response to chemotherapy (n = 350) were randomized to undergo locoregional treatment or not. Patients allocated to locoregional treatment received breast conservation surgery or mastectomy plus axillary lymph node dissection followed by radiotherapy. Patients randomized to the control arm were followed up without surgery or radiotherapy. Both groups received standard endocrine therapy after completion of chemotherapy, if indicated. Stratification by endocrine receptor status, site of metastases (visceral vs. bone vs. both), and number of metastatic lesions (≤ 3 vs. > 3) resulted in a well-balanced distribution of these factors in the treatment arms. At a median follow-up of 17 months, the median survival time was almost identical in both arms (18.8 and 20.5 months, HR = 1.07, 95 %CI = 0.82-1.40, p = 0.60). After adjustment for known prognostic factors using the Cox model, still no survival benefit could be detected for the additional use of locoregional treatment. Actuarial locoregional progression at 2 years as first event was observed in 11 % of patients with locoregional treatment and in 52 % without locoregional treatment (p < 0.001), whereas distant progression at 2 years as first event was observed in 72 % of patients with locoregional treatment and in 52 % without locoregional treatment (p = 0.01). The latter observation should not be misinterpreted in a manner that local therapy results in a higher rate of distant metastases, but that the increased rate of distant metastases as first event is simply a consequence	None	https://link.springer.com/content/pdf/10.1007/s00066-015-0843-1.pdf	None
9e4639816edc0739bfc7eacaccae20a68c825f24	pubmed	Summary version of the Standards, Options and Recommendations for palliative or terminal nutrition in adults with progressive cancer (2001)	Summary version of the Standards, Options and Recommendations for palliative or terminal nutrition in adults with progressive cancer (2001) The majority of patients with advanced cancer develop malnutrition. This malnutrition has an important impact on quality of life, performance status and immune status. It can be responsible for increased morbidity, particularly infectious complications and thus mortality. In five to more than 20% of patients with cancer, death can be directly related to cachexia in the terminal phase(Inagaki et al, 1974;Bozzetti, 1995). ## Objectives The objective is to define recommendations for the management of nutrition in adult patients with progressive cancer in the terminal phase. The main questions addressed are: What are the different choices for management (oral feeding and artificial nutrition)? What are the possible options for feeding considering the clinical status and the preferences of the patient and their family? What are the expected benefits and what criteria should be used for follow-up and decision-making? The aim of these recommendations is to describe the modalities for palliative nutritional management and artificial nutrition in the palliative phase. The aim of such management is to conserve or restore the best possible quality of life and to control any symptoms that are a source of discomfort or distress. The primary objective cannot be to increase survival at any cost, or solely to improve the nutritional status of the patient. The adverse effects caused by nutritional interventions, particularly artificial nutrition, are sometimes responsible for a deterioration in the quality of life and thus can have a detrimental effect on the real objective of palliative care. Decisions on whether or not to initiate, continue or interrupt active nutritional management are particularly difficult. Not supplying or stopping nutrition is often interpreted by the patient, their family and/or the carers as an abandonment. Food is strongly associated with the image of a potential source of life and of energy. # Methodology The general methodology used has already been described [bib_ref] SOR: project methodology, Fervers [/bib_ref]. For this specific SOR, a multidisciplinary working group was set up by the French National Federation of Cancer Centres (Fédération Nationale des Centres de Lutte Contre le Concer -FNCLCC) to review the best available evidence on palliative or terminal nutrition in adults with progressive cancer. Medline s was searched using a specific strategy for the period 1991 to April 2001. Web sites specialised in nutrition and palliative care were also searched. The contents pages of the journals: Supportive Care in Cancer and European Journal of Palliative Care were screened from 1996 to 2000 (5 years). In addition, the reference lists of the articles selected were analysed, and the members of the working group provided references from their personal sources. Following the selection and critical appraisal of the articles, the working group produced a document with the proposed 'Standards', 'Options' and 'Recommendations' (SORs) for palliative and terminal nutrition in adults with progressive cancer. When all the members of the working group agree, based on the best available evidence, that a procedure or intervention is beneficial, inappropriate or harmful, it is classified as a 'Standard', and when the majority agree, it is classified as an 'Option' [fig_ref] Table 1: Definition of Standards, Options and Recommendations [/fig_ref]. In the SORs, there can be several 'Options' for a given clinical situation. 'Recommendations' provide additional information that enable the available options to be ranked using explicit criteria (e.g. survival, toxicity) with an indication of the level of evidence. These recommendations thus help clinicians to select an appropriate option. Thus, clinicians can make choices for the management of patients using this information and taking into consideration local circumstances, skills, equipment, resources and/or patient preferences. The adaptation of the SOR to the local situation is allowable if the reason for the choice is sufficiently transparent and this is crucial for successful implementation. Inclusion of patients in clinical trials is an appropriate form of patient management in oncology and is recommended frequently within the SORs, particularly in situations where only weak evidence exists to support a procedure or an intervention. The type of evidence underlying any 'Standard', 'Option' or 'Recommendation' is indicated using a classification developed by the FNCLCC based on previously published methods. The level of evidence depends not only on the type and quality of the studies reviewed, but also on the concordance of the results . When no clear scientific evidence exists, judgement is made according to the professional experience and consensus of the expert group ('expert agreement'), and this is then validated by the peer-review process. The document was then peer-reviewed by independent experts, and their comments were integrated in the final version. The French summary version was based on the full version that has been published [bib_ref] Standards, Options and Recommendations for nutritional support in palliative or terminal care..., Bachmann [/bib_ref] and both are available on the FNCLCC web site (http://www.fnclcc.fr). The document will be updated when new scientific evidence becomes available or when there is new expert agreement. ## Definition of palliative care Palliative care and its organisation should be defined in a consensual manner and controlled by regulations (standard). Nutritional management is defined as a supportive treatment, and in a palliative setting is part of the global management aimed at maintaining or restoring 'well-being' (standard). Patients with a life expectancy of less than a month can be considered to be in the terminal phase of their illness (recommendation, expert agreement). Patients with a life expectancy of at least 3 months or more, or with an illness no longer responsive to curative treatment, are considered to be in the palliative phase (recommendation, expert agreement). ## Clinical symptoms and prognostic factors Gastrointestinal symptoms and nutritional problems are often observed in patients with advanced cancer (standard, level of evidence: B2). Functional scores (Karnofsky index and the WHO performance status) have a good prognostic value in cancer and should be used (standard, level of evidence: B2). Anorexia is a poor prognostic factor in patients with advanced cancer (standard, level of evidence: B2). A Karnofsky score of 50% or lower, or a performance status higher than 2, is associated with a short life expectancy in patients with advanced cancer (recommendation, level of evidence: C). Dyspnoea is indicative of a poor short-term (weeks) prognosis (recommendation, level of evidence: C). The prognostic value of certain biological factors and quality of life scores should be assessed in future prospective studies (recommendation, expert agreement). ## Organisation of management In France, patients with advanced stage, progressive cancers are cared for in hospital wards and specific palliative care units or at home (standard). Wherever the patient is cared for, the management should be multidisciplinary and the strategy should be discussed with all the different actors involved (standard). The patients and/or their families should be offered appropriate support and whenever possible, their preferences should be respected (standard). Locally written procedures should be available for nutritional management (recommendation, expert agreement). ## Oral feeding Dietary advice may help to increase feeding and to improve the management of symptoms that interfere with feeding. Specific diets (e.g. low-salt diet) should be stopped or made less strict in order to allow for patients' food preferences (standard). Standard oral supplementation will increase the nutritional uptake in patients with cancer undergoing active treatment (recommendation, level of evidence: B2). Increasing the oral supplementation of eicosapentaenoic acid (EPA) may improve the nutritional status of patients with cachexia secondary to pancreatic cancer (recommendation, level of evidence: B2). ## Symptomatic treatments Medical treatment of symptoms is necessary in palliative management (standard). Most of these treatments (apart from the appetite stimulants) have not been evaluated in randomised controlled Recommendations Additional information to enable the available options to be ranked using explicit 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-quality randomised clinical trials that give consistent results ## Level b There exist 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 do not exist or there is only a series of cases ## Expert agreement The data do not exist for the method concerned, but the experts are unanimous in their judgement trials in palliative nutritional management (standard). Megesterol acetate, medroxyprogesterone acetate and corticosteroids have an appetite stimulating effect (recommendation, level of evidence: B1) and they may improve the quality of life for patients in the palliative stage (recommendation). Patients with bowel obstruction may benefit from a by-pass procedure, if they suffer from distressing vomiting that cannot be controlled by medical treatment and/or if their life expectancy is prolonged (43 months) (recommendation, level of evidence: C). ## Pharmaco-nutritional treatment of cachexia Fish oil derivatives (EPA) may slow the rate of progression of the cachexia (recommendation, level of evidence: B1) these should be evaluated in future studies (recommendation). ## Enteral nutrition Enteral nutrition in a palliative setting can slow down nutritional deprivation, avoid dehydration and improve the quality of life in patients with head and neck cancer (standard, level of evidence: C). The optimal modalities for delivery, administration and follow-up are the same as those for enteral nutrition when given for other indications (standard, expert agreement). In the terminal or palliative stage, any complications and discomfort resulting from enteral nutrition should be considered. In the event of any change of treatment, the reasons for the change should be discussed with the patients and their families and their preferences taken into consideration (standard, expert agreement). Gastrostomy in terminal-stage patients is associated with a risk of complications that can be contrary to the objectives of palliative care. It is not recommended in this situation (recommendation, level of evidence: C). ## Parenteral nutrition Parenteral nutrition in the palliative setting can slow down nutritional deprivation, avoid dehydration and improve the quality of life in patients with a malignant bowel obstruction and/or other causes of food intolerance (standard, level of evidence: C). The modalities for delivery, administration and follow-up are the same as those for parenteral nutrition when used for other indications (standard, expert agreement). The benefits expected from parenteral nutrition should be reassessed at regular intervals or each time that a complication related to the technique or the illness occurs (recommendation, expert agreement). There is no justification for parenteral nutrition in patients with a Karnofsky index of 50% or less, or with a performance status score higher than 2 (recommendation, expert agreement). ## Hydration Dehydration in the terminal phase is often neither painful nor uncomfortable (standard, level of evidence: C). If hydration is administered to control symptoms, the least invasive route should be chosen, for example, the subcutaneous route, if intravenous access is not available (recommendation, expert agreement). Mouth washing is an important component of the management (recommendation, expert agreement). Symptoms can usually be controlled by the subcutaneous administration of 0.5 -1.0 l of 0.9% saline solution per 24 h (recommendation, level of evidence: C). ## Therapeutic indications Routine palliative artificial nutrition is not justified in patients in the terminal phase of their disease since they often do not feel hungry or thirsty, and the benefits have not been demonstrated (standard, expert agreement). The objective of artificial nutrition in a palliative situation is to improve the quality of life (recommendation, expert agreement). This goal may be achieved using artificial nutrition in patients who are unable to eat or to absorb nutrients for a prolonged period of time, and in some of these patients increased survival has been observed (recommendation, level of evidence: C). Artificial nutrition should not be started if the patient's life expectancy is less than 3 months and/or there is any severe, permanent functional deficit (Karnofsky index of 50% or less, or a performance status higher than 2) (recommendation, expert agreement). ## Treatment evaluation The evaluation of the quality of the nutritional management in patients with cancer in the palliative setting should include assessment of functional scores, quality of life and the patient's (or their family's) satisfaction (standard, expert agreement). Measurement of the nutritional status and the complication rate cannot be used to justify decisions about artificial nutrition, but can be used to assess its quality (standard, expert agreement). Clinical trials using appropriate, validated methodology should be performed to evaluate this management (recommendation, expert agreement). [table] Table 1: Definition of Standards, Options and Recommendations [/table]	None	https://www.nature.com/articles/6601092.pdf	None
0d979f13a2e380812ec6dde94218bbce7c81567d	pubmed	Development of the Korean Academy of Medical Sciences Guideline for Rating Physical Impairment	Development of the Korean Academy of Medical Sciences Guideline for Rating Physical Impairment # Introduction ods from those guides, we developed a new KAMS Guideline for Impairment Evaluation (KAMS Guideline) compatible to Korean way of thinking and culture. We developed the KAMS Guideline according to the following basic principles. The KAMS Guideline should be scientific, objective, valid, reasonable and practical. Objectivity was the most important value. Impairment evaluation should be done when the symptoms are fixed. The impairment should be re-evaluated every 2 yr, when we expect any changes in symptoms, even though the symptoms are stable at present. Medically measurable impairment should be fixed, rigid, un-recovered symptoms after a thorough medical treatment. Causes of the impairment may not be trauma. The impairment may come from congenital disorders or diseases. The impairment should be evaluated by medical specialists who are expert in their fields. We proposed the maximum whole person impairment rating of a certain organ or a part of body system according to the following principles. 1) It was 100% whole person impairment rating when total loss of function of a given organ may cause death, such as liver, lung, heart, and so on. The degree of whole person impairment was rated by a relative degree of impairment or dysfunctions of a given organ. 2) When total loss of any function of a given organ could not cause death, such as eyes, nose, ears, mouth, arms, legs, and so on, the degree of whole person impairment was rated by two references, i.e., AMA Guides and the Korean consensus [bib_ref] Results of questionnaires on the medical expert's recognition of disability in Korea, Lim [/bib_ref]. When there are multiple impairments, we can adjust them by the following manner. Body systems in impairment evaluation were classified into 11 systems instead of 8 systems of the International Classification of Functioning, Disability and Health (ICF) frame [bib_ref] The changing concept of impairment and disability, Jung [/bib_ref] [bib_ref] International classification of functioning, disability and health (ICF), Choi [/bib_ref]. When the impairments were in the same organ or body system, we rated the most severe impairment only. When the impairments occurred in different organs or body systems, the final degree of physical impairment was the combination of the impairments. If a minor impairment occurs independently and it is not a subset of the major impairment, the impairments can be combined. If the minor impairment always accompanies with the major impairment, we rated the most severe impairment only. # Results In March 2007, we had a workshop on the basic concepts and knowledge on the disability evaluation and welfare system for the disabled. We invited more than 100 board certified specialists from 15 medical societies for this study. We organized 13 committees with the medical specialists. In each committee, they prepared a basic frame for the disability evaluation through monthly intrinsic meetings. In May 2007, we had an international symposium on the disability evaluation. We invited three foreign speakers from Australia, Japan, and U.S.A. They gave us some important aspects of the disability evaluation system. We also presented the basic frame of the KAMS Guideline at the symposium in detail and discussed the subjectivity, validity, and weak points of the guideline. We proposed the maximum whole person impairment rating of a certain organ or a part of body system. The Korean consensus on the impairment was reported in 2006 [bib_ref] Results of questionnaires on the medical expert's recognition of disability in Korea, Lim [/bib_ref]. A questionnaire survey was conducted on the severity of the two different physical impairments in the Korean public. They thought that the vegetative state was a severe impairment than quadriplegia. Paraplegia was regarded as severe than loss of the legs. Loss of one arm was considered severe than lumbar multi-segment fusion. They also thought that loss of one leg, hearing loss, mental retardation, and loss of one arm were almost the same degree of impairment . A questionnaire survey was also conducted by Korean doctors on the severity of different physical impairments. The degree of impairment was severe in quadriplegia than in total blindness. Loss of vision was regarded as a severe impairment than paraplegia . Although the Korean public thought that loss of the legs was severe than loss of the arms (40.9:26.0), the Korean doctors answered that the loss of arms was severe than loss of the legs (24.2:55.9). By the results of questionnaires and AMA Guides, we decided the maximal degree of whole person impairment in a certain organ or a part of body by the following steps. If the rate of AMA Guides was similar to the result of the questionnaire survey, we accepted the rate of AMA Guides. If the rate of AMA Guides differed from the result of the survey, the degree was modified after a discussion at the steering committee. For example, the committee decided the relative importance of the arms and legs 50:50. There were not enough reasons to change the existing standards now, since the public consensus differed from the doctors' opinions. If there were signifi-cant differences between the Korean consensus and the AMA Guides, the degree of impairment was determined after thorough discussion within the steering committee. Although the loss of vision was 100% loss of work ability in the Industrial Accident Compensation Insurance Act, the rate of physical impairment was 85%, the same as the AMA Guides. The hearing loss was rated as 60%, higher than the rate of the AMA Guides (35%), lower than the rate of the Industrial Accident Compensation Insurance Act (Grade 4, 90%) [fig_ref] Table 3: Summary of the whole person impairment rating in some different physical impairments... [/fig_ref]. We had several business meetings with the government. The Korean Welfare of Disabled Persons Act approved only 15 types of disabilities, grading them into 6 steps. The basic frame of the KAMS Guideline differed from the present the Korean Welfare of Disabled Persons Act. There is a need to develop a new system; however, sudden change of the disabil- . Summary of the questionnaire on the severity of different physical impairments by Korean doctors ity evaluation system may cause a great confusion. Besides the subjectivity and validity of the guidelines, it is a big dilemma making a new system without destroying the present grading system. Finally we reported the KAMS Guideline for the 15 types of disabilities with an appendix including the remaining types of disabilities. # Discussion The guidelines for impairment evaluation are a sum of science and consensus. The KAMS Guidelines are medically evaluating guidelines for physical impairment, the same as the AMA Guides. To be scientific, we benchmarked the AMA Guides. The AMA Guides are scientific with public trust, which can be used as a global standard (4). To get objectivity, we avoided a decision based on subjective symptoms. We actively developed some scoring methods, summation of several scores representing the degree of objective signs or results of many different tests. To be valid, we introduced a comprehensive measurement representing the whole function instead of focal details. To be reasonable, we made the sum of different impairments of the body region which was never larger than a loss of the body region. We also reflected the results of the questionnaire survey. The degree of physical impairment is influenced by the society and culture [bib_ref] Current status and direction of the expansion of statutory disabilities in the..., Suh [/bib_ref] [bib_ref] National variability in permanent partial impairment ratings, Patel [/bib_ref]. Criteria of impairment or non-impairment may be different depending on the society and culture. The degree and status of the impairment can be changed by the environment, too. The concept and criteria assessing the degree of physical impairment differ from country to country. To be practical, we considered the public transport system for the disabled in Korea. We also considered medical environment of Korea, since we cannot objectively measure all impairments by rarely deployed expensive equipments. We measured medically assessable physical impairments, although the kinds and criteria of the physical impairment may vary greatly. We did not include impairments from dental problems. We also excluded some physical impairment, which originated from the concept of herbal or oriental medicine. The medically assessable physical impairments should be fixed permanently, but not temporarily. The term permanent means that the impairment is not expected to change by more than 3% over the ensuing year for the whole body impairment rating. We could not confirm the whole person impairment rates, when the experts could not come to an agreement. We left them till an agreement is possible by a new method or criteria. To objectively demonstrate the physical impairment, we should confirm any objective evidences by current medical diagnostic methods. Objective evidences include not only structural or anatomical abnormalities, but also functional disturbances. Medically demonstrated evidences may include an agreement of at least 70% of the experts. For the controversial kinds of impairment, a special committee may discuss and decide them. Since the cardiopulmonary functions are usually dynamic, symptoms and the degree of impairment of these functions may depend on the treatment. In this situation, it is very difficult to differentiate disorders from the impairment. Anyway, the degree of impairment may be increased by improper treatment, which may promote voluntary improper treatment for higher degree of impairment. In the KAMS Guideline, we tried to induce proper treatment by making the history of medical treatment as one of the scoring components. We tried to avoid faking by scoring methods, summation of several scores representing the degree of objective signs or results of many different tests. Assurance of the objectivity by scoring methods and promotion of the proper treatment can be distinctive methods. We reserved impairment rating on the pain untill a valid measurement is developed, since the pain cannot be assessed objectively yet [bib_ref] Pain, impairment, and disability in the AMA guides, Robinson [/bib_ref] [bib_ref] Merits and shortcomings of the American Medical Association Guides to the Evaluation..., Rondinelli [/bib_ref]. Body systems in impairment evaluation can be important to adjust the degree of impairments when there were multiple different physical impairments. Those can be used to decide whether or not, or extent of welfare service according to the impairment pattern, rate or body systems. In the Industrial Accident Compensation Insurance Act, the whole person is classified into 10 regions (eye, ear, nose, mouth, head and neck, mental and nervous system, chest and abdomen, body column, arms, and legs), which is further divided into 25 body systems according to whether the impairment is structural or functional. McBride's method classified the whole person into 14 body systems, while the AMA Guides divided it into 15 body systems. The Korean Welfare of Disabled Persons Act divided into physical impairment and mental impairment. Physical impairment was further divided into internal and external, and finally into 15 subclasses. In ICF of WHO, impairment due to body function or structure was listed in 8 chapters [bib_ref] International classification of functioning, disability and health (ICF), Choi [/bib_ref]. In the future, many countries are expected to use the ICF classification system. However, the ICF system is not yet practical. In the KAMS Guideline, body systems were classified 11 systems instead of the ICF chapters. Although we proposed the maximum whole person impairment rating of a certain organ or a part of body system, the final rate of the maximum whole person impairment will be determined by another survey, which will be done on the next year. The concept and criteria measuring disability or physical impairment may depend on the purpose. In general, medically evaluated physical impairments represent the degree of difficulty in usual activities of daily living except job or work. The KAMS Guideline is for assessment of the physical impairment; in other words, a medical impairment. The medical impairment can be measured objectively and scientifically by doctors. It can be used for a reward of impairment when we do not need to consider occupation or workability. The rate of labor loss represents a competence of a certain occupation or workability; in other words, an economical impairment. The rate of labor loss can be calculated by multiplying the medical impairment by a labor coefficient. The labor coefficient may be developed often considering the difficulty or importance of a certain job or a task and the function of a certain organ or part of body. The rate of labor loss can be used for a compensation or reparation of the economic loss by the physical impairment. For proper welfare for the disabled, we need other kinds of impairment representing the individual variable demands in addition to the medical impairment, which usually lacks individual socioeconomic and environmental factors. The welfare impairment can be calculated by multiplying the medical impairment by a welfare coefficient. The welfare coefficient may be developed often considering the need of self-care, education or rehabilitation. Study provided that regulations of the 23 acts related to impairment assessment and analyzed according to the authorities in charge . There were a total of eleven authorities in charge by 2005: nine departments, one office and one committee. The many authorities and acts that apply different impairment assessment standards and levels give rise to a variety of subjects. In addition, the disabled experience inconvenience and loss in expenses because they have to have different impairment diagnoses for the same impairment. Furthermore, there are also problems such as fraudulent acquisition and illegal supply and demand of impairment levels that utilize the complex process conversely. In particular, analysis of impairment levels according to organs of the body in 15 acts led to the conclusion that there are diverse structures of levels by each act for the impairment condition of the same organ and that there is a lack of consistency. In addition, only Development of the KAMS Guideline for Rating Physical Impairment S225 [table] Table 3: Summary of the whole person impairment rating in some different physical impairments in the KAMS Guideline [/table]	None	None	Systematic and effective welfare for the disabled is possible when there are scientific and objective criteria demonstrating either presence or severity of the impairment. We need our own scientific criteria suitable for our culture and society, since the impairment is influenced by them. In 2007, we established the Developing Committee of Korean Academy of Medical Sciences (KAMS) Guideline for Impairment Rating under KAMS supervision. We included all fixed and permanent physical impairments after a sufficient medical treatment. The impairment should be stable and medically measurable. If not, it should be reevaluated later. We benchmarked the American Medical Association Guides. The KAMS Guideline should be scientific, objective, valid, reasonable and practical. In particular, we tried to secure objectivity. We developed the KAMS Guideline for Impairment Rating.
98809731f3f5e6fe93f8f4d425a4ac686833bd38	pubmed	The measurement of adult blood pressure and management of hypertension before elective surgery	The measurement of adult blood pressure and management of hypertension before elective surgery ## Recommendations - General practitioners should refer patients for elective surgery with mean blood pressures in primary care in the past 12 months less than 160 mmHg systolic and less than 100 mmHg diastolic. - Secondary care should accept referrals that document blood pressures below 160 mmHg systolic and below 100 mmHg diastolic in the past 12 months. - Pre-operative assessment clinics need not measure the blood pressure of patients being prepared for elective surgery whose systolic and diastolic blood pressures are documented below 160/100 mmHg in the referral letter from primary care. - General practitioners should refer hypertensive patients for elective surgery after the blood pressure readings are less than 160 mmHg systolic and less than 100 mmHg diastolic. Patients may be referred for elective surgery if they remain hypertensive despite optimal antihypertensive treatment or if they decline antihypertensive treatment. - Surgeons should ask general practitioners to supply primary care blood pressure readings from the last 12 months if they are undocumented in the referral letter. - Pre-operative assessment staff should measure the blood pressure of patients who attend clinic without evidence of blood pressures less than 160 mmHg systolic and 100 mmHg diastolic being documented by primary care in the preceding 12 months. (We detail the recommended method for measuring non-invasive blood pressure accurately, although the diagnosis of hypertension is made in primary care.) - Elective surgery should proceed for patients who attend the pre-operative assessment clinic without documentation of normotension in primary care if their blood pressure is less than 180 mmHg systolic and 110 mmHg diastolic when measured in clinic. The disparity between the blood pressure thresholds for primary care (160/100 mmHg) and secondary care (180/110 mmHg) allows for a number of factors. Blood pressure reduction in primary care is based on good evidence that the rates of cardiovascular morbidity, in particular stroke, are reduced over years and decades. There is no evidence that peri-operative blood pressure reduction affects rates of cardiovascular events beyond that expected in a month in primary care. Blood pressure measurements might be more accurate in primary care than secondary care, due to a less stressful environment and a more practised technique. What other guideline statements are available on this topic? There is detailed evidence-based guidance on the diagnosis and treatment of hypertension in the community from, for example, the National Institute for Health and Care Excellence . There is little guidance on a 'safe' blood pressure for planned anaesthesia and surgery. ## Why was this guideline developed? There is no national guideline for the measurement, diagnosis or management of raised blood pressure before planned surgery. There is little evidence that raised pre-operative blood pressure affects postoperative outcomes. Local guidelines vary from area to area. Hypertension is a common reason to cancel or postpone surgery. In our sprint audit, 1-3% of elective patients had further investigations precipitated by blood pressure measurement, of whom half had their surgery postponed. Across the UK this would equate to~100 concerned and inconvenienced patients each day, with associated costs to the NHS and the national economy [bib_ref] Fourth National Audit Project. Major complications of airway management in the UK:..., Cook [/bib_ref] [bib_ref] The 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia:..., Cook [/bib_ref]. This guideline is the first collaboration between the AAGBI and the British Hypertension Society; these two organisations have very different perspectives. Members of the British Hypertension Society are concerned with the long-term reduction in rates of cardiovascular disease, particularly strokes. Anaesthetists are more focused on immediate complications, in the perioperative period. This guideline aims to prevent the diagnosis of hypertension being the reason that planned surgery is cancelled or delayed. As such, it should also be of interest to hospital managers and commissioners of hospital care. mon terminology in diagnosis and referral, explaining the impact of anaesthesia on blood pressure and vice versa to the wider, non-anaesthetic community. At the same time, it will review current best practice on the measurement, diagnosis and treatment of hypertension. Why does this statement differ from existing guidelines? # Introduction The National Institute for Health and Care Excellence (NICE) has described hypertension as 'one of the most important preventable causes of premature morbidity and mortality in the UK' [1]. The Association of Anaesthetists of Great Britain and Ireland (AAGBI), together with the British Hypertension Society, felt there was a need for a nationally agreed policy statement on how to deal with raised blood pressure in the pre-operative period. We have based this statement on a consensus view with the backing of graded evidence, where such evidence is available. Hypertension is almost always asymptomatic and it is diagnosed following screening in general practice. Managing hypertension pre-operatively is a complex matter of balancing the risks of anaesthesia, treatment and delay for the individual patient. Most cases of hypertension are primary, i.e. with no other medical cause. For the remainder, the cause for hypertension may be associated with the reason for the proposed operation. Cancellations and postponements of planned surgical procedures have been a major and long-standing problem for healthcare worldwide. The quantifiable loss of resource is pitted against unquantifiable and significant psychological, social and financial implica-tions of postponement for patients and their families. Although guidelines exist for the treatment of elevated blood pressure, there remains a paucity of literature and accepted guidelines for the peri-operative evaluation and care of the patient with hypertension who undergoes non-cardiac surgery [bib_ref] Hypertension, hypertensive heart disease and perioperative cardiac risk, Howell [/bib_ref]. Of particular importance is defining the patients most vulnerable to complications and the indications for immediate and rapid antihypertensive treatment and/or postponement of surgery to reduce these risks pre-operatively, intra-operatively and postoperatively. Perioperative hypertension often occurs in conjunction with sympathetic nociceptive stimulation during the induction of anaesthesia, during surgery and with acute pain in the early postoperative period. Hypertension may also accompany hypothermia, hypoxia or intravascular volume overload from excessive intraoperative fluid therapy, particularly in the ensuing 24-48 h as fluid is mobilised from the extravascular space [bib_ref] Hypertension, hypertensive heart disease and perioperative cardiac risk, Howell [/bib_ref] [bib_ref] Alpine anesthesia: can pretreatment with clonidine decrease the peaks and valleys?, Longnecker [/bib_ref] [bib_ref] Studies of anaesthesia in relation to hypertension II. Haemodynamic consequences of induction..., Prys-Roberts [/bib_ref]. There are no nationally agreed guidelines for the diagnosis or management of raised blood pressure before elective surgery. The evidence regarding the effect of raised pre-operative blood pressure is very limited. Local guidelines do exist but vary from area to area. Both the AAGBI and the British Hypertension Society recognised the need for a national guideline and consensus statement to address the various issues of concern. We have limited our deliberations to a specific scope. Only the period before planned surgery is covered. Blood pressures which may cause an immediate risk to health are specified, rather than those that may cause risk over the long-term. The best method of taking accurate blood pressure measurements is examined. We considered how long blood pressure should be controlled before surgery is undertaken. Communication between different hospital departments, primary care and the patient are of importance. We hope that by providing national guidance the chances of a patient receiving conflicting advice will be minimised. ## Scope This guideline is aimed at adults presenting for planned surgery. The following groups of patients are specifically not studied, although many of the general points covered in the guideline may apply. ## 328 Emergency/urgent surgery By definition, these patients have no or very limited time for investigation, treatment or postponement. Such surgery must almost always proceed, but all those involved, including the patient, must be aware of any associated increased risk. ## Obstetrics Most cases of hypertension in pregnancy will be directly related to the pregnancy (although with an ageing obstetric population with higher rates of obesity, this may be less so). The monitoring and treatment of blood pressure is a specific and integral part of obstetric care, regardless of the need for surgery, and even for 'elective' Caesarean section there may be very limited opportunity for delay. ## Paediatrics Childhood hypertension is relatively uncommon, and its epidemiology and natural history is relatively unclear and there are no definitive trials on screening. Thus, its diagnosis and management, including preoperatively, is a specialist area beyond the scope of the general guidance in this publication. ## Cardiac surgery Peri-operative hypertension commonly complicates surgery for congenital and acquired cardiac disease. Management will be affected by many other factors including the planned procedure, the use or not of cardiopulmonary bypass and the other indications for vaso-and cardio-active medication. We have thus considered it to be a specialist area beyond the scope of the general guidance in this publication. ## Surgery for blood pressure management This includes surgery for phaeochromocytoma and bariatric surgery; we have excluded this from our guidance for similar reasons to that of cardiac surgery. # Methods We formed a Working Party consisting of four members from each society who were academics and clinicians with varied interests, including vascular anaesthesia, cardiology, elderly care medicine and general practice. We agreed on the scope of the guideline, and then carried out a systematic review with the quality of evidence described using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach [bib_ref] Going from evidence to recommendations, Guyatt [/bib_ref] [bib_ref] for the GRADE Working Group. Rating quality of evidence and strength of..., Guyatt [/bib_ref]. The GRADE approach considers the quality of a body of evidence as high, moderate, low or very low. To achieve a full consensus document was important. Therefore, we consulted 20 general practitioners, including those with a specialist interest in cardiovascular medicine, as well as senior academics. A consultation guideline was then made available to members of both societies for comment. We specifically asked for and received comments from the patient group, Blood Pressure UK. The comments and responses have been made available online. The Council and Executive of the respective societies were given the task of final approval. ## Blood pressure, hypertension and anaesthesia The anaesthetist has two broad considerations in the hypertensive patient who presents for surgery. One is to be cognisant of the effect of chronic hypertension on the individual's peri-operative and long-term cardiovascular risk. The other is to consider whether the blood pressure measured in the primary care setting is associated with adverse peri-operative events and to decide whether this should be reduced before surgery. The association between hypertension and perioperative harm was first reported in the 1950s [bib_ref] Splanchnicectomy for essential hypertension; results in 1,266 cases, Smithwick [/bib_ref] [bib_ref] Surgical measures in hypertension, Thompson [/bib_ref]. Systolic blood pressures in excess of 170 mmHg and diastolic blood pressures in excess of 110 mmHg were associated with complications such as myocardial ischaemia [bib_ref] Multifactorial index of cardiac risk in noncardiac surgical procedures, Goldman [/bib_ref]. Hypertension was the second-most common factor associated with postoperative morbidity [bib_ref] The National Veterans Administration surgical risk study: risk adjustment for the comparative..., Khuri [/bib_ref]. In 2003, Weksler et al. published a 'quasi'randomised controlled study of 989 treated hypertensive patients who had diastolic blood pressures between 110 and 130 mmHg measured in the anaesthetic room [bib_ref] The dilemma of immediate preoperative hypertension: to treat and operate, or to..., Weksler [/bib_ref]. In one group, surgery proceeded after intranasal nifedipine, and in the other group, surgery was delayed while further antihypertensive treatment was pursued in hospital. During the first three postoperative days, the rates of neurological and cardiovascular complications were similar. One might conclude that there was no difference in an infrequent outcome, or that the study had insufficient power to detect a small difference (see section below, treatment for hypertension: extension of evidence from the community to the peri-operative period). The association of hypertension with cardiovascular disease is established, but there is no clear evidence that patients with stage 1 or 2 hypertension [fig_ref] Table 1: Categorisation of the stages of hypertension [/fig_ref] without evidence of target organ damage have increased peri-operative cardiovascular risk [bib_ref] Hypertension and anesthesia, Hanada [/bib_ref]. Patients with stage 3 or 4 hypertension, who are more likely to have target organ damage, have not been subjected to rigorous randomised controlled trials of perioperative interventions. There is evidence that hypertension with target organ damage is associated with a small increased incidence of peri-operative major adverse cardiovascular events [bib_ref] Hypertension, hypertensive heart disease and perioperative cardiac risk, Howell [/bib_ref]. It is not known whether or not reducing blood pressure in these patients during a postponement of planned surgery would reduce this rate of events; there is sparse evidence to guide a decision. Any decision should take into account factors other than blood pressure, namely: age; comorbidity; functional capacity (i.e. functional status and reserve); and the urgency and indication for surgery (see section below, 'The treatment of cardiovascular risk, not hypertension'). The latest guidelines published by the National Institute for Health and Care Excellence (NICE), in conjunction with the British Hypertension Society, recognise the importance of target organ damage in the management of hypertension by targeting a lower threshold for further medical intervention [1]. Whether or not these thresholds and targets should be rigorously applied in the peri-operative setting is not clear. Patients with hypertension (controlled or uncontrolled) demonstrate a more labile haemodynamic profile than their non-hypertensive counterparts [bib_ref] Alpine anesthesia: can pretreatment with clonidine decrease the peaks and valleys?, Longnecker [/bib_ref]. The induction of anaesthesia and airway instrumentation can lead to a pronounced increase in sympathetic activation, which may lead to a significant increase in blood pressure and heart rate. A reduction in systemic vascular resistance soon after the induction of anaesthesia commonly leads to varying degrees of hypotension. Reduction in vascular resistance is multifactorial and may be secondary to loss of the baroreceptor reflex control, central neuraxial blockade, and direct effects of anaesthetic agents. The effect on vascular tone will be exaggerated by 'deep' or excessive anaesthesia and in patients who are fluid-depleted. This, and the often exaggerated haemodynamic response to surgery, pain and emergence from anaesthesia, have also been described as being more common in the hypertensive population [bib_ref] Studies of anaesthesia in relation to hypertension II. Haemodynamic consequences of induction..., Prys-Roberts [/bib_ref]. Some researchers have demonstrated an association between pre-operative hypertension and relatively minor physiological derangements such as intra-operative hypotension, hypertension and arrhythmia, but studies have not conclusively demonstrated that fluctuations in haemodynamic variables cause clinically significant harm [bib_ref] Pre-existing medical conditions as predictors of adverse events in day case surgery, Chung [/bib_ref]. Larger studies to investigate differences between untreated hypertensive patients and those treated (successfully and unsuccessfully) have not demonstrated increased rates of peri-operative cardiovascular events. However, these findings may not be applicable to current practice, as many of these studies were conducted in the late 1970s [bib_ref] Risks of general anesthesia and elective operation in the hypertensive patient, Goldman [/bib_ref]. This appreciation of labile haemodynamics in hypertensive patients has led to a number of anaesthetic techniques designed to achieve a more stable haemodynamic profile during surgery. These techniques include co-induction, invasive arterial monitoring with titrated or prophylactic vasopressor therapy, depth-of-anaesthesia monitoring, beta-blockers and the optimisation of stroke volume with intravascular fluid therapy. The omission of antihypertensive drugs, such as angiotensin-converting enzyme inhibitors and receptor blockers, combined with the careful reintroduction of these drugs after surgery, is commonplace and appears to be associated with fewer significant peri-operative haemodynamic fluctuations [bib_ref] Angiotensin system inhibitors in a general surgical population, Comfere [/bib_ref]. The introduction of peri-operative beta-blockade for high cardiac-risk patients increases postoperative mortality, secondary to hypotension and stroke, albeit with less cardiac injury, as demonstrated in the POISE-1 study [bib_ref] Effects of extended release metoprolol succinate in patients undergoing non-cardiac surgery (POISE..., Devereaux [/bib_ref]. The anaesthetist should be aware that sudden withdrawal of certain antihypertensive agents such as clonidine, alpha-methyldopa and beta-blockers can be associated with adverse events. Withdrawal of beta-blockers may also be associated with myocardial ischaemia that is often silent in the peri-operative period and easily missed without continuous ECG monitoring and serial serum troponin measurements. Best practice: the measurement of blood pressure Blood pressure should be measured in primary care before non-urgent surgical referral Primary care blood pressure assessment of patients before referral for elective surgery. Investigations and treatment should continue to achieve blood pressures < 140/90 mmHg. ABPM and HBPM, ambulatory and home blood pressure measurement; DBP and SBP, diastolic and systolic blood pressure. should be asked to attend their general practice for the concurrent determination of whether primary care hypertension is present. The setting in which blood pressure is measured should be relaxed and temperate in a standardised environment with current calibrated equipment. The seated patient should have their supported arm outstretched for at least one minute before the initial reading. The pulse rate and rhythm should be recorded before the blood pressure is measured by a validated device. Automated sphygmomanometers (www.bhsoc.org/bp-monitors) are inaccurate when the pulse is irregular, when the blood pressure should be measured by auscultation over the brachial artery during manual deflation of an arm cuff. Blood pressure should be measured in both arms in patients scheduled for vascular or renal surgery. If the difference between arms in systolic pressure is greater than 20 mmHg, repeat the measurements; subsequently, measure from the arm with the higher blood pressure. The patient is normotensive if the blood pressure measurement is less than 140/90 mmHg. If the first measurement is equal to or higher than 140/ 90 mmHg, the blood pressure should be measured twice more, with each reading at least one minute apart. The lower of the last two readings is recorded as the blood pressure; if it is less than 140/90 mmHg the patient is normotensive. If the reading is between 140/90 mmHg and 179/ 109 mmHg, the patient may have stage 1 or 2 hypertension. In primary care, the patient would be offered ambulatory (ABPM) or home blood pressure monitoring (HBPM) to establish their true blood pressure (GRADE 1B). If the reading is equal to or higher than 180/110 mmHg in primary care, the patient may have severe hypertension and would be considered for immediate treatment. ## Best practice: the diagnosis of hypertension General practitioners should establish whether blood pressure has been measured and managed in all adults before non-urgent surgical referrals. A blood pressure measurement taken within the preceding 12 months should be detailed in the referral letter. The diagnosis of hypertension in patients referred for investigation of surgical disease that are not treated for hypertension and who have not had a blood pressure measurement in the preceding 12 months follows the same process as any other primary care patient. We recommend that the practice instigates ambulatory or home blood pressure measurements before non-urgent referrals if the standard blood pressure is equal to or greater than 160/ 100 mmHg. If the patient's ABPM/HBPM blood pressure is equal to or greater than 150/95 mmHg (or equal to or greater than 135/85 mmHg with target organ damage), the patient is diagnosed as having hypertension; treatment should be discussed and commenced using the NICE/BHS CG127 algorithm. This process can take place at the same time as urgent surgical referral, but a reduction in blood pressure to less than 160/100 mmHg should precede non-urgent surgical referral. The referral letter should document that an informed discussion has taken place with patients who decline treatment, or detail that all appropriate attempts have been made to reduce blood pressure for patients with persistent hypertension, which might have included specialist investigations. Surgical outpatients should request that general practitioners forward primary care blood pressure measurements if these have not been documented in the referral letter. Pre-operative assessment clinics should measure the blood pressures of patients who present without documentation of primary care blood pressures. If the blood pressure is raised above 180 mmHg systolic or 110 mmHg diastolic, the patient should return to their general practice for primary care assessment and management of their blood pressure, as detailed above . If the blood pressure is above 140 mmHg systolic or 90 mmHg diastolic, but below 180 mmHg systolic and below 110 mmHg diastolic, the GP should be informed, but elective surgery should not be postponed. ## Best practice: the treatment of hypertension This section summarises the recommendations for primary care following the diagnosis of hypertension. There is good evidence (GRADE 1A) for the treatment 332 of hypertension with one or more of the following: diuretics (thiazide, chlorthalidone and indapamide); beta-blockers; calcium channel-blockers (CCB); angiotensin converting enzyme (ACE) inhibitors, or an angiotensin-2 receptor blocker (ARB) [1]. In the future, the threshold for treating high blood pressure might change to cardiovascular risk (see below, the treatment of cardiovascular risk, not hypertension). Step 1 treatment Patients aged less than 55 years should be offered an ACE inhibitor, or a low-cost ARB. If an ACE inhibitor is prescribed but is not tolerated (for example, because of cough), offer a low-cost ARB. Angiotensin-converting enzyme inhibitors and ARBs are not recommended in women of childbearing potential. An ACE inhibitor should not be combined with an ARB. Patients aged over 55 years and Black patients of African or Caribbean family origin of any age should be offered a CCB. If a CCB is not suitable, for example because of oedema or intolerance, or if there is evidence of heart failure or a high risk of heart failure, a thiazide-like diuretic should be offered. If diuretic treatment is to be initiated or changed, offer a thiazide-like diuretic, such as chlorthalidone .0 mg once daily), or indapamide (1.5 mg modified-release once daily or 2.5 mg once daily), in preference to a conventional thiazide diuretic such as bendroflumethiazide or hydrochlorothiazide. For patients who are already having treatment with bendroflumethiazide or hydrochlorothiazide Secondary care blood pressure assessment of patients after referral for elective surgery. The GP should be informed of blood pressure readings in excess of 140 mmHg systolic or 90 mmHg diastolic, so that the diagnosis of hypertension can be refuted or confirmed and investigated and treated as necessary. DBP and SBP, diastolic and systolic blood pressure. and whose blood pressure is stable and well controlled, treatment with the bendroflumethiazide or hydrochlorothiazide should be continued. Beta-blockers are not a preferred initial therapy for hypertension. However, beta-blockers may be considered in younger patients, particularly those with an intolerance or contraindication to ACE inhibitors and ARBs, or women of childbearing potential or patients with evidence of increased sympathetic drive. If beta-blockers are started and a second drug is required, add a CCB rather than a thiazide-like diuretic to reduce the person's risk of developing diabetes. ## Step 2 treatment If blood pressure is not controlled by Step 1 treatment, use a CCB in combination with either an ACE inhibitor or an ARB. If a CCB is not suitable for Step 2 treatment, for example because of oedema or intolerance, or if there is evidence of heart failure or a high risk of heart failure, offer a thiazide-like diuretic. For Black patients of African or Caribbean family origin, consider an ARB in preference to an ACE inhibitor, in combination with a CCB. Step 3 treatment Before considering Step 3 treatment, check that drugs from Step 2 have been prescribed at optimal doses, or at the maximum tolerated doses. If treatment with three drugs is required, the combination of ACE inhibitor or ARB, CCB and thiazide-like diuretic should be used. ## Step 4 treatment If resistant blood pressure exceeds 140/90 mmHg in clinic after treatment with the optimal or highest-tolerated doses of an ACE inhibitor, or an ARB plus a CCB, with a diuretic; adding a fourth antihypertensive drug and expert advice should be considered. Further diuretic therapy with low-dose spironolactone (25 mg once daily) should be considered if the serum potassium concentration < 4.6 mmol.l À1 . Caution is required in patients with reduced estimated glomerular filtration rates because of an increased risk of hyperkalaemia. Increasing the dose of thiazide-like diuretics should be considered if the serum potassium concentration > 4.5 mmol.l À1 . Serum sodium and potassium concentrations and renal function should be checked within 1 month of increasing diuretic dose, and repeated as required thereafter. If further diuretic therapy for resistant hypertension at Step 4 is not tolerated, or is contraindicated or ineffective, consider an alpha-blocker or beta-blocker. If blood pressure remains uncontrolled with the optimal or maximum tolerated doses of four drugs, expert advice should be sought if it has not yet been obtained. As recently as 2008, the HYVET study demonstrated the clinical benefits of treating hypertension in people aged ≥ 80 years, while health economic analysis has confirmed the cost effectiveness of this strategy [bib_ref] Treatment of hypertension in patients 80 years of age or older, Beckett [/bib_ref]. As a result, NICE now recommends that patients aged ≥ 80 years should be offered treatment only if they have stage 2 hypertension. The 2011 Hypertension Guideline also recommends that the decision to treat should be based on standing blood pressure, and should take into account the presence of co-morbidities such as dementia. The guideline also makes a distinction between initiating treatment in the over-80s and continuing long-term and well-tolerated treatment when patients reach this age. In other words, patients who were started on treatment when younger should not have their current therapy back-titrated when they celebrate their 80th birthday. ## The treatment of cardiovascular risk, not hypertension It is likely that treatment for hypertension will no longer be based upon blood pressure [bib_ref] on behalf of the Blood Pressure Lowering Treatment Trialists' Collaboration. Blood pressure-lowering..., Sundstr€ Om [/bib_ref]. This is a surprising statement; the diagnosis of hypertension that merits treatment hasuntil recentlybeen based on patients' blood pressure, irrespective of other cardiovascular risk factors, despite the NICE guidance recognising their importance [1]. This practice conflicts with the treatment of hypercholesterolaemia, which is not based on the cholesterol concentration alone, but instead on the composite 5-or 10-year risk of: stroke; myocardial infarction; heart failure; cardiovascular morbidity; or death, ascribed to these diagnoses. The magnitude by which cardiovascular disease is reduced by treatment for both hypercholesterolaemia 334 and hypertension is dependent on the composite cardiovascular risk, not the concentration of cholesterol or the blood pressure. Anaesthetists should gauge their concern for a hypertensive patient by the calculated five-year rate of cardiovascular events, not by the blood pressure measurement per se. Hypertension is common; this is responsible for the well-publicised reduction in population rates of stroke by antihypertensive treatment. The absolute effect of treatment for the individual, even over a fiveyear period, is smaller than many anaesthetists might realise. presents the effect of five-year antihypertensive treatment for cardiovascular risk in a population quartered by the five-year rate of any cardiovascular event. Planned major surgery temporarily increases mortality. For instance, planned open repair of abdominal aortic aneurysm increases mortal-ity in the first postoperative month ten times, whereas endovascular repair increases mortality four times. If cardiovascular events are similarly increased by major planned surgery, one would anticipate that the preoperative antihypertensive treatment of cardiovascular risk would have a proportionately greater absolute effect on the rates of events while their risk remains elevated. illustrates the absolute effect of established antihypertensive treatment in the month following a planned operation in patients from , assuming two scenarios: that the operation does not affect the rates of cardiovascular events; and that the operation increases the rates of cardiovascular events six times. This guideline has outlined that blood pressure before planned non-urgent surgery is measured in primary care, where the diagnosis of hypertension is The effect of antihypertensive treatment on the five-year rates of events (per 1000) in a population quartered on the basis of the untreated cardiovascular five-year risk: lowest quartile (< 11% risk); next quartile (11-15% risk); next quartile (15-21% risk); highest quartile (> 21% risk). The absolute reduction in event rates per 1000 patients per month by antihypertensive treatment, assuming that the control rate is unaffected by surgery ('same') or increased, in this example sixfold ('9 6'). made, and treatment is managed. The lifelong risk of mortality and morbidity may be unaffected by postponing surgery for the assessment of cardiovascular risk by primary care and possible antihypertensive treatment [bib_ref] Too much blood pressure?, Carlisle [/bib_ref]. For instance, clinicians might like to consider the uncertainty in how long it takes for cardiovascular risk to fall with antihypertensive medication (as opposed to how long it takes for blood pressure to fall), and the 1% relative increase in cardiovascular risk that accompanies each postponed month, due to the patient ageing. Clinicians might also consider that patients who smoke or who have hypercholesterolaemia are not subjected to the summary cancellations justified by blood pressure readings. A further consideration is the absence of a scale of enthusiasm for postponing surgery that matches the continuum of cardiovascular risk, which would result in older smoking hypercholesterolaemic normotensive men having surgery postponed more frequently than younger hypertensive women who do not have any other cardiovascular risk factors. ## Quartile of risk ## Quartile of risk ## Communication Pre-operative assessment clinics should inform general practitioners when they measure raised blood pressures in patients who have not had readings taken in primary care in the preceding 12 months. The letter should request that the general practitioner determine whether the patient has hypertension in primary care. The letter should also state whether or not surgery will proceed without a diagnosis of hypertension being made or treatment commenced. Appendix 1 is an example of a letter explaining that surgery will not proceed until the diagnosis of hypertension has been excluded or confirmed, and in the latter case treated with the patient's consent. It is important that the patient has a copy and is instructed to make an appointment at their surgery with a nurse or a doctor and to take the letter with them. The language used should seek cooperative management rather than demand action. In the first instance, the GP will need to establish that the blood pressure is high and this is not a white coat effect. It must be clearly stated how to re-establish the procedural pathway when the blood pressure has been shown to be satisfactory, treated or not. [table] Table 1: Categorisation of the stages of hypertension. [/table]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/anae.13348	This guideline aims to ensure that patients admitted to hospital for elective surgery are known to have blood pressures below 160 mmHg systolic and 100 mmHg diastolic in primary care. The objective for primary care is to fulfil this criterion before referral to secondary care for elective surgery. The objective for secondary care is to avoid spurious hypertensive measurements. Secondary care should not attempt to diagnose hypertension in patients who are normotensive in primary care. Patients who present to pre‐operative assessment clinics without documented primary care blood pressures should proceed to elective surgery if clinic blood pressures are below 180 mmHg systolic and 110 mmHg diastolic.
55b69309ce294fc3b0cc8a24268c955660286930	pubmed	Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a consensus statement	Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a consensus statement Objectives Janus kinase inhibitors (JAKi) have been approved for use in various immune-mediated inflammatory diseases. With five agents licensed, it was timely to summarise the current understanding of JAKi use based on a systematic literature review (SLR) on efficacy and safety. Methods Existing data were evaluated by a steering committee and subsequently reviewed by a 29 person expert committee leading to the formulation of a consensus statement that may assist the clinicians, patients and other stakeholders once the decision is made to commence a JAKi. The committee included patients, rheumatologists, a gastroenterologist, a haematologist, a dermatologist, an infectious disease specialist and a health professional. The SLR informed the Task Force on controlled and open clinical trials, registry data, phase 4 trials and meta-analyses. In addition, approval of new compounds by, and warnings from regulators that were issued after the end of the SLR search date were taken into consideration. Results The Task Force agreed on and developed four general principles and a total of 26 points for consideration which were grouped into six areas addressing indications, treatment dose and comedication, contraindications, pretreatment screening and risks, laboratory and clinical follow-up examinations, and adverse events. Levels of evidence and strengths of recommendations were determined based on the SLR and levels of agreement were voted on for every point, reaching a range between 8.8 and 9.9 on a 10-point scale.Conclusion The consensus provides an assessment of evidence for efficacy and safety of an important therapeutic class with guidance on issues of practical management. # Introduction The therapeutic options for patients with immunemediated inflammatory diseases (IMIDs), such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis/ankylosing spondylitis (AxSpA/AS), systemic lupus erythematosus (SLE), psoriasis (PsO), atopic dermatitis (AD), Crohn's disease (CD), ulcerative colitis (UC) and others, have significantly improved over the past two decades. This results primarily from the introduction of several novel medications, in particular biological (b) disease-modifying antirheumatic drugs (DMARDs), as reflected in recent management recommendations. [bib_ref] EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological..., Smolen [/bib_ref] [bib_ref] European League against rheumatism (EULAR) recommendations for the management of psoriatic arthritis..., Gossec [/bib_ref] [bib_ref] 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis, Van Der Heijde [/bib_ref] [bib_ref] Joint AAD-NPF guidelines of care for the management and treatment of psoriasis..., Menter [/bib_ref] [bib_ref] Third European evidence-based consensus on diagnosis and management of ulcerative colitis. Part..., Harbord [/bib_ref] [bib_ref] 3rd European evidence-based consensus on the diagnosis and management of crohn's disease..., Gomollón [/bib_ref] Improved strategic utilisation of drugs has similarly impacted positively on outcomes. Among all therapies developed for IMIDs over the last two decades, only tumor necrosis factor (TNF)-inhibitors exhibit a very broad efficacy across many diseases: RA, PsA, axSpA, juvenile idiopathic arthritis, PsO, CD, UC and uveitis. [bib_ref] Updated consensus statement on biological agents for the treatment of rheumatic diseases, Furst [/bib_ref] Even though targeting just a single cytokine, no other treatment modality has yet been approved for such a broad list of indications, suggesting that TNF is pathogenetically involved across a diverse range of IMIDs. All other biological agents are licensed for fewer indications. This will likely change with the advent of Janus kinase (JAK)-inhibitors (JAKi), a new class of targeted synthetic DMARDs (tsDMARDs) that interfere with signal transduction pathways of a variety of cytokines and thereby have the potential to mediate immune modulatory benefits across a broad range of pathologies and their clinical phenotypes. bDMARDs are usually monoclonal antibodies or receptor constructs that target a specific soluble or cell surface molecule, either a cytokine, a cytokine receptor or another cell membrane antigen. They either prevent interaction of the specific ligand with its cognate receptor, destroy a specific cell population, such as B-cells, or inhibit cross talk between particular cell populations. They have to be administered parenterally since they are proteins. They also do not enter the cell but mediate their respective modes of action outside the cell or via the cell surface. ## Recommendation The pathways that mediate cytokine receptor signal transduction have been elucidated in recent years providing novel and rational targets for drug development to modify cytokine effector function. Synthetic chemical agents that interfere with these pathways have been developed for various indications. [bib_ref] 25 years of small molecular weight kinase inhibitors: potentials and limitations, Fabbro [/bib_ref] [bib_ref] Selective JAKinibs: prospects in inflammatory and autoimmune diseases, Virtanen [/bib_ref] [bib_ref] Comparison of Janus kinase inhibitors in the treatment of rheumatoid arthritis: a..., Jegatheeswaran [/bib_ref] Among them, the JAKi represent a series of intracellularly active drugs, some of which have been approved for the treatment of several IMIDs. Five JAKi, tofacitinib, baricitinib, peficitinib, upadacitinib and filgotinib, are currently approved for therapeutic use in one or more IMIDs in a number of geographical regions. Our experience with bDMARDs spans two decades across many diseases with thousands of patient years of experience including in registries in many countries. In contrast, data from registries are quite limited for JAKi and some have only recently been approved by several regulatory authorities; safety data for more than 10 years are derived mainly from long term extensions of randomised clinical trials. Therefore, it was deemed important to develop an evidence-based consensus statement that focuses on practical issues in the use of JAKi. ## Scope and purpose Recommendations for the management of individual IMIDs focus primarily on therapeutic strategies and the general use of individual or groups of agents. While quite comprehensive, they usually address a particular disease and general issues, only rarely accommodating the various, often complex aspects related to the general application of an individual drug or a specific mode of action. Therefore, consensus statements on the more comprehensive use of specific agents or classes of drugs have also been developed. [bib_ref] Updated consensus statement on the use of rituximab in patients with rheumatoid..., Buch [/bib_ref] [bib_ref] Consensus statement on blocking the effects of interleukin-6 and in particular by..., Smolen [/bib_ref] [bib_ref] Pimecrolimus in atopic dermatitis: consensus on safety and the need to allow..., Luger [/bib_ref] [bib_ref] Expert consensus paper on the use of Vedolizumab for the management of..., Armuzzi [/bib_ref] These provide more detailed information on efficacy and safety of a class of drugs than in the traditional broad management recommendations. Such 'points to consider' can provide prescribers, like specialists in specific disease areas, and patients (especially when information is available for laypersons), with an expert opinion on appropriate use of a new drug and its place in treatment algorithms. When a drug is approved for more than one indication, a specific consensus statement can be used across specialties. Thus, the target of the present consensus statement comprises rheumatologists, dermatologists, gastroenterologists, other health professionals involved in these areas, patients with these respective diseases, but also hospital managers and representatives of regulators and social security agencies. These points to consider are not meant to suggest a preferential use of JAKi for any particular disease but rather to provide evidence-based information in conjunction with expert opinion once an agent of this class has been considered for the treatment of a patient with a specific disease for which the drug is indicated. A research agenda will complement these points to drive momentum to search for more evidence where this is insufficient or lacking. Before addressing the methodology related to this document, we will briefly allude to the mode of action and other pharmacological aspects of this class of drugs. ## Mode of action JAKs are non-receptor tyrosine kinases associated with the cytoplasmic domain of type I and II cytokine receptors which are activated when these are engaged by their cognate ligands; once phosphorylated, they phosphorylate signal transducers and activators of transcription (STATs) which then induce gene activation. [bib_ref] The JAK-STAT pathway: impact on human disease and therapeutic intervention, O'shea [/bib_ref] JAKi reversibly inhibit kinase signalling for varying periods of the dosing cycle. They are oral small molecules that act intracellularly and prevent the phosphorylation of JAKs. Many cytokines, such as interleukin (IL)-2, 6, 12, 15 and 23 as well as interferons use the JAK-STAT pathways, while others, such as IL-1, IL-17 and TNF, do not (figure 1). In addition, haematopoietic growth factor receptors, such as those for erythropoietin (EPO), thrombopoietin and granulocyte-macrophage colonystimulating factor, use the JAK-STAT pathway (figure 1). Within the cell usually different JAK molecules are associated with each of these receptor chains, acting in tandem as heterodimers, such as JAK1 and JAK2, JAK1 and JAK3 or JAK1 and TYK2. Only in the case of haematopoietic growth factor receptors both chains carry JAK2. Thus, JAK enzymes -JAK1, 2, 3 and TYK2 -function as dimers and once activated phosphorylate STATs, which subsequently induce gene transcription. The selectivity of JAKs can be determined by using purified enzyme systems and a variety of cellular models. Varying approaches may lead to differing results with respect to perceived selectivity of JAKs, and selectivity is dose-dependent, since at higher doses the compounds lose selectivity. The in vivo selectivity may differ further so that in vivo markers may also be helpful. Reduction of inflammation usually produces an increase in haemoglobin, as exemplified by the rapid normalisation of anaemia in patients receiving monoclonal antibodies to the IL-6 receptor. [bib_ref] Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis..., Smolen [/bib_ref] Since EPO signals through JAK2 homodimers, failing to see an increase in haemoglobin in patients with anaemia of chronic disease who experience clinical improvement on JAKi therapy suggests an important degree of JAK2 inhibition. Of note, failure to increase haemoglobin is not necessarily linked to fatigue and rarely a reason to stop a JAKi. Current views on the selectivity of JAKi, taking all aspects including clinical ones (such as effects on haemoglobin levels) into consideration are provided in figure 1. Of note, the totality of in vivo downstream effects of JAKi is still insufficiently understood, especially in specific disease settings, and an important matter for further research activities. Given that individual JAKs and STATs can be activated by more than one cytokine, upregulation and activation of a single STAT pathway does not implicate any one particular cytokine in a response and as such our understanding of the hierarchical contribution of distinct STATs to effector pathways remains conjectural. Nevertheless, success and failure of therapeutic trials of drugs of known selectivity enable some insights into pathogenesis (figure 1). For example, both IL-6 and IL-23 receptors (R) signal via JAKs; since IL-6R inhibition does not appear efficacious in PsA or PsO, while IL-12 and IL-23 inhibition is, [bib_ref] Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1..., Mcinnes [/bib_ref] [bib_ref] Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab..., Reich [/bib_ref] [bib_ref] Efficacy and safety of guselkumab in patients with active psoriatic arthritis: a..., Deodhar [/bib_ref] this infers that beneficial effects of JAKi may arise by inhibiting IL-23 rather than IL-6 signalling. In contrast, IL-6R antibodies, but not anti-IL-12/23 antibodies, [bib_ref] A randomised phase II study evaluating the efficacy and safety of subcutaneously..., Smolen [/bib_ref] are efficacious in RA and, therefore, JAKi may be assumed to convey efficacy by blocking IL-6 rather than IL-12 or 23 signal transduction. Moreover, neither IL-12, IL-23 nor IL-6R inhibition are efficacious in AS, while JAKi appear to be 28 ; consequently, this effect cannot be explained by interference with IL-6, IL-12 or IL-23 signal transduction, but rather by inhibition of signal transduction of other cytokines captured by JAKi [fig_ref] Figure 1: Depiction of cytokines that activate and drugs that target Janus kinases [/fig_ref]. However, also inhibition of type I (or type II) interferon signal transduction may play a role. Similar deliberations may be made for inflammatory bowel disease, where IL-6R inhibition is not, or only weakly efficacious, 31 while IL-12/23 blockade is efficacious, 32 and for PsO. [bib_ref] Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase..., Bachelez [/bib_ref] On the other hand, while pan JAKi is apparently efficacious in UC but not in CD, more JAK1 selective inhibitors (filgotinib, upadacitinib) showed promising results in CD, implying that differences in the pathogeneses of these two inflammatory bowel diseases manifest in subtle but functionally important variations in the relative contribution of these signalling pathways. [bib_ref] Jak selectivity for inflammatory bowel disease treatment: does it clinically matter?, Danese [/bib_ref] Finally while TNF does not activate the JAK-STAT pathway directly, it might do so indirectly via induction of other cytokines, such as IL-6 or type I interferons. [bib_ref] IRF1 is critical for the TNF-driven interferon response in rheumatoid fibroblast-like synoviocytes..., Bonelli [/bib_ref] This adds further complexity to our understanding of the pathogenesis of IMIDs. Thus, JAKi via its mode of action across signal transduction of multiple cytokines is efficacious across a range of IMIDs. By corollary, this effect has potential safety repercussions (see below). Clinical experience with JAKi will likely provide innovative insights to rewrite our understanding of IMIDs. Among the JAKi currently approved or under study for IMIDs, current information on enzyme assays, cellular assays and in vivo data (see above note on laboratory test results regarding JAK2 inhibition, especially anaemia) suggest that at clinically used doses tofacitinib is preferentially a JAK 1, 3 and 2 inhibitor; baricitinib is primarily a JAK 1 and 2 inhibitor; peficitinib is an inhibitor of JAK3 over JAK 1, 2 and TYK2; upadacitinib is a JAK1 inhibitor with effects on JAK2, and filgotinib is primarily a JAK 1 inhibitor (figure 1). [bib_ref] Emerging topical and systemic JAK inhibitors in dermatology, Solimani [/bib_ref] As mentioned above, the preferential selectivity is dose-dependent and decreases with increasing doses as their common mechanism is to prevent ATP-mediated protein tyrosine kinase phosphorylation (although a specific TYK2 selective inhibitor is also under development that inhibits signal transduction by stabilising the pseudokinase domain of the protein). 41 # Methods The expert committee adhered to the EULAR standard operating procedures for the development of recommendations. [bib_ref] update of the EULAR standardised operating procedures for EULAR-endorsed recommendations, Van Der Heijde [/bib_ref] A steering committee comprising 15 members and an expanded Task Force consisting of 14 additional individuals invited based on their expertise and availability and including two patient research partners (MdW, MV) and a health professional (MS-M) as well as a dermatologist (W-HB), a gastroenterologist (MT), a haematologist/haemostaseologist (KG), an infectious disease specialist (KLW) and a fellow who performed the systematic literature review (SLR) (AK), evaluated the available data. The clinicians were all experienced in the treatment of chronic inflammatory diseases, had participated in clinical trials of JAKi and/or bDMARDs, and several had long-standing experience in patient outcomes research and prior consensus statement development. The patients and health professionals all had experience in consensus activities. There was a broad global representation from European countries, Asia, Australia, Latin America and North America. All task force members declared their potential conflicts of interest and had ongoing opportunity to declare if they felt conflicted throughout the process. Drugs that had not yet undergone regulatory assessment or formal approval but for which evidence from clinical trials was available, could be considered in the recommendations to anticipate potential future uptake in clinical practice, with all Depiction of cytokines that activate and drugs that target Janus kinases (JAKs) presumably involved in the pathogenesis of immunemediated inflammatory diseases (IMIDs). Top: efficacy of agents targeting specific JAK-inducing cytokines in different IMIDs. Centre: cytokines and respective receptors that trigger JAKs, types of JAKs activated and type of STATs (signal transducers and activators of transcription) activated by the respective JAKs. Bottom: JAK-inhibitors which are currently approved for IMIDs and their overall (including clinically derived) selectivity and presumed interference (+ or -) with certain cytokine pathways. axSpA, axial spondyloarthritis; EPO, erythropoietin; GM-CSF, granulocyte-monocyte colony stimulating factor; IBD, inflammatory bowel diseases; IFN, interferon; IL, interleukin; ND, not done; PsA, psoriatic arthritis; PsO, psoriasis; R, receptor; RA, rheumatoid arthritis; TP, thrombopoietin. [bib_ref] Comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine signaling in..., Mcinnes [/bib_ref] Recommendation respective caveats that may emerge during the approval process. Indeed, during the time of writing or revising the manuscript (and thus after the face-to-face meetings), two drugs, upadacitnib and most recently filgotinib, were approved (at least in some regions), confirming the validity of the conclusions drawn on these agents in the course of the process developing the consensus statement. The steering committee and the fellow (AK) initially discussed the research questions for the SLR which was then performed accordingly by searching the totality of the respective clinical trial literature until end of December 2018 in Medline, Embase, Cochrane and 2018 EULAR and ACR abstracts. The details of the SLR are published separately.Cochrane risk of bias tool was used. The SLR addressed RA, PsA, PsO, AS, systemic lupus erythematosus (SLE), UC, CD, alopecia areata (AA)/alopecia universalis, and atopic dermatitis (AD). The results of the SLR were first presented to the steering group which developed a list of proposed recommendations and/or topics to be addressed by the whole task force. The SLR and the list prepared by the steering group were then presented to the task force which met end of March 2019. Efficacy aspects were discussed by the whole task force with input from experts in respective fields. The Task Force was split into four breakout groups. One group addressed screening, the second monitoring, the third contraindications and the fourth adverse effects. Representatives of each breakout group reported the results of the deliberations and presented proposals for the wording of individual points to the whole task force which discussed them in detail before voting took place. For a general principle or point of consideration to be accepted for the final document without further change, a majority of 75% of the votes was required in the first ballot. If this result was not achieved, the respective text was amended and subjected to a second ballot, for which a 67% majority was required. If this ballot was not successful, further changes were proposed until a≥50% majority was attained (or the proposal rejected). The points to consider are presented in the wording they were finally voted on (table 1). The results of the respective last ballot are shown as percentage of present members in table 1. Notes captured the contents of the discussions and the reasoning behind each decision to be presented in the comments accompanying the individual items in the manuscript. Data which emerged after the voting process, such as material made public by regulators, were taken into consideration in the manuscript to provide the readers with up-to-date information. After the face-to-face meeting, the points to consider as agreed by the task force received a final adjudication in terms of level of evidence and strength of recommendation. They were finally subjected to an anonymous vote (by email) on the levels of agreement. Each recommendation received an adjudication on a scale of 0-10, 0 meaning no agreement whatsoever and 10 absolute agreement. The draft of the manuscript was sent to all task force members for their comments which were all considered for the final version prior to submission of the manuscript. # Results ## General principles The task force agreed on four general principles (table 1). The first of these refers to the importance of shared decision making between the patient and the specialist, including information on the benefits and risks of JAKi which is highlighted as principle A. This is in line with various management recommendations but needs to receive special emphasis when a drug or class of medicines is new and long-term experience is still lacking. The task force further recommends to use these points-toconsider together with general management recommendations for the individual diseases which are usually provided by the respective international or national societies (item B) and also to refer to the product information related to the specific disease to be treated (see below item D). At outset, the task force decided not to provide 'recommendations' for the use of JAKi in treatment algorithms, but rather 'points to consider' assisting the clinician when thinking of starting, or having decided to start treatment with a JAKi (principle C). Recommendations may be seen as too directive and would have to be brought into the context of other medications and general treatment strategies and adjusted as new information comes to hand in a rapidly evolving therapeutic area. In contrast, the task force saw its role in elucidating important aspects that should be taken into account when thinking of the prescription of a JAKi. To this end, general principles as well as specific considerations are highlighted as an adjunct to product information (principle D). ## Individual points Six major groups of consideration are highlighted (table 1): indications; dosage and comedications; contraindications; pretreatment screening and risks; adverse events; and laboratory and clinical follow-up. The order within these groups does not relate to any ranking by importance but occurred either by chance or some rationale-based approach to therapies in general. ## I. indications JAKi have proven efficacious with acceptable safety in patients with a variety of IMIDs. They have received regulatory approval for patients with RA, PsA and UC who have failed prior conventional synthetic DMARD (csDMARD) or bDMARD therapy, and an approval is being sought in further indications, such as dermatological, and interferonopathies. Approval of additional JAKi for IMIDs is expected. At present, individual JAKi have been approved for different diseases and at varying doses, as detailed below. ## Treatment dose and comedications in different imids Treatment doses and comedications may differ between indications (see below) and may have to be adjusted with higher age and organ (hepatic, renal) function impairment. Once the therapeutic target (such as remission) is reached, dose reduction or increase of intervals between doses may be considered; this dose adjustment is not within the label of the JAKi, but similar dose changes outside the label have been suggested for bDMARDs in various recommendations. In the following, we will address these aspects for the individual IMIDs for which JAKi are approved or may be licensed in the future. ## Rheumatoid arthritis Addition of a JAKi to continued methotrexate (MTX) or other csDMARDs should be considered if the patient tolerates the csDMARD, [bib_ref] EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological..., Smolen [/bib_ref] since-just like for all bDMARDs-there is evidence for better efficacy of combination compared with monotherapy, clinically and/or structurally. Monotherapy of JAKi compared with MTX monotherapy in MTX naïve RA patients failed to show significant structural (though not clinical) superiority for baricitinib [bib_ref] Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or..., Fleischmann [/bib_ref] and-for the primary endpointfailed to show clinical (though not structural) superiority for filgotinib, [bib_ref] Effi CACY and safety of Filgotinib for patients with rheumatoid arthritis naïve..., Westhovens [/bib_ref] while combination therapy achieved significant superiority across all outcomes. On the other hand, monotherapy of tofacitinib and upadacitinib in MTX naïve patients had significantly better clinical and structural efficacy than MTX monotherapy, but neither was investigated in 3-arm trials with an additional combination arm. In contrast, filgotinib was Points to consider for the treatment of patients with immune mediated inflammatory diseases with Janus kinase (JAK) inhibitors ## Item Wording LoE SoR Vote (%) LoA ## General principles* A Initiation of JAK-inhibitor therapy and the treatment target to be achieved should be based on a shared decision between the patient and the medical specialist, which requires full information of the patient on the potential benefit and risks of this therapy. n.a. n.a. 100 10 B Therapeutic approaches to treating patients with chronic inflammatory conditions should be in line with international and national recommendations (algorithms) for the management of the respective disease. n.a. n.a. [bib_ref] Jak inhibitor therapy in a child with inherited USP18 deficiency, Alsohime [/bib_ref] 9.5 C The points to consider when initiating JAK-inhibitor therapy do not provide information on when JAK-inhibitors should be used in the treatment algorithm, but rather attempt to assist the clinician once the decision to prescribe a JAK inhibitor has been made. n.a. n.a. 92 9.8 D These points to consider address specific (but not all) aspects related to the application of JAK-inhibitor therapy and the clinician should additionally refer to the disease-specific product information. n.a. n.a. Evaluate response using validated, disease-specific measures of disease activity; for evaluation and definition of response, be aware that CRP and ESR may be reduced independently of reduction of disease activity and possibly even in infections. 2b/5 B/D 95 9.8 These bullet points have been agreed on as abbreviated summaries of the discussions and the explanatory text to each of these items should be regarded as an integral part of these points. *These points are a short abbreviation of the items discussed and presented in detail in the body of the text. They should not be applied independently of the information provided there in more detail, but present only an overview of the general scope of the consensus statement. The percentages shown reflect the proportion of participants who approved the respective bullet point during the voting at the task force meeting. Some items carry two levels of evidence, because part of the respective points have only the level of expert opinion (level 5), namely II/2: comorbidities not studied, since most excluded from trials; III/1: patients with chronic infections (even if mild) were not studied; IV/2and VI/1: proposed intervals not studied; VI/3 blunting of the acute phase response during infections not sufficiently studied. bDMARD, biological disease-modifying antirheumatic drug; CDAI, Crohn's Disease Activity Index; CPK, creatine phosphokinase; CRP, C reactive protein; csDMARD, conventional synthetic diseasemodifying antirheumatic drug; HBV, hepatitis B virus; HCV, hepatitis C virus; LoA, levels of agreement; LoE, level of evidence; n.a., not available; NMSC, non-melanoma skin cancer; SoR, strength of recommendation; TB, tuberculosis; VTE, venous thromboembolism. Recommendation assessed in a 3-arm trial in MTX-naive RA patients; while at both the 100 mg and 200 mg dose filgotinib plus MTX attained the primary endpoint of superiority against MTX monotherapy, filgotinib monotherapy at 200 mg failed to show statistical superiority compared with MTX monotherapy (filgotinib 100mg as monotherapy was not tested), None of the JAKi has ever been compared with MTX plus glucocorticoids, the standard therapy recommended by EULAR for over a decade [bib_ref] EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological..., Smolen [/bib_ref] which has not been shown to be inferior to bDMARDs plus MTX. However, a JAKi can be given as monotherapy in case of intolerance or contraindications to MTX and other csDMARDs. The recommended dose of tofacitinib for RA is 5 mg two times a day in most countries; at this dose tofacitinib was superior to placebo in patients with active disease despite MTX or prior bDMARD therapy, and in a head to head study tofacitinib 5 mg two times a day combined with MTX was non-inferior (but not superior) to adalimumab combined with MTX while monotherapy of tofacitinib 5 mg two times a day failed to show noninferiority to either combination therapy with tofacitinib plus MTX or adalimumab plus MTX. [bib_ref] Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with..., Fleischmann [/bib_ref] Of note, according to information by regulatory authorities tofacitinib at 10 mg two times a day was associated with an increased venous thromboembolism (VTE) and pulmonary embolism (PE) rate in patients with RA enriched for cardiovascular risk factors, and a similar warning was also issued for 5 mg two times a day 55 (see also below). In addition, the dose should be reduced in patients with a creatinine clearance (CrCl) of <30 mL/min and is contraindicated in patients with severe hepatic impairment (Child Pugh C). The recommended dose of baricitinib in RA is 4 mg once daily (except for some countries such as USA, Canada and China, where it is 2 mg daily). At the 4 mg dose in combination with MTX, it showed superior efficacy to placebo (or de novo MTX) in all RA patient populations, MTX/csDMARD-insufficient responders (IR), bDMARD-IR or MTX-naïve, respectively; in most countries the approval is for these populations apart from MTX-naïve patients, as combination therapy or monotherapy. A dose of 2 mg once daily is appropriate for patients aged ≥75 years, those with a CrCl of 30-60 mL/min and may be appropriate for patients with a history of chronic or recurrent infections. In a head to head study baricitinib 4 mg per day combined with MTX had superior efficacy compared with adalimumab 40 mg combined with MTX. [bib_ref] Baricitinib versus placebo or adalimumab in rheumatoid arthritis, Taylor [/bib_ref] Subanalyses revealed that this superiority was primarily seen for patient reported outcomes, but not for joint counts. In a tapering study patients in long-term low disease activity or remission after 15 months therapy could reduce baricitinib to 2 mg per day; low disease activity (LDA) was maintained at 12 weeks after step down in 83% of patients; 90% of those who flared regained their original response after dose increase. [bib_ref] Dose reduction of baricitinib in patients with rheumatoid arthritis achieving sustained disease..., Takeuchi [/bib_ref] Combination of baricitinib with MTX had significantly better structural outcomes compared with MTX alone, but-while monotherapy was similar to combination therapy in terms of clinical and functional outcomes-structural benefit was not significant for baricitinib monotherapy. [bib_ref] Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or..., Fleischmann [/bib_ref] Since the date of the SLR, upadactinib has been approved by FDA and EMA at 15 mg daily. At this dose, it showed superior efficacy to placebo (or de novo MTX) in all RA patient populations, MTX-IR, bDMARD-IR or MTX-naïve, respectively. In most countries, the approval is for these populations except for MTX-naïve, as combination therapy or monotherapy. A upadacitinib monotherapy study in patients with IR to MTX had high response rates but lacked a comparator group of upadacitinib combined with MTX. [bib_ref] Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response..., Smolen [/bib_ref] In combination with MTX, upadacitinib 15 mg provided superior efficacy compared with adalimumab plus MTX in a head to head study. [bib_ref] Upadacitinib versus placebo or adalimumab in patients with rheumatoid arthritis and an..., Fleischmann [/bib_ref] As in the study of baricitinib versus adalimumab, subanalyses revealed that this superiority was primarily seen for patient-reported outcomes, but not for joint counts. [bib_ref] Upadacitinib versus placebo or adalimumab in patients with rheumatoid arthritis and an..., Fleischmann [/bib_ref] No dose adjustment is needed for renal impairment, but with severe hepatic impairment the drug is contraindicated. More recently, filgotinib was approved at 100 mg and 200 mg doses in Europe 59 and in Japan. In contrast, FDA did not approve filgotinib wishing to await data from spermatogenesis safety studies and raising concern about the safety of the 200 mg dose.Filgotinib has completed phase 3 clinical trials at 100 mg and 200 mg daily. Data of a study comparing filgotinib plus MTX head to head with adalimumab plus MTX recently became available and revealed non-inferiority for DAS28-C reactive protein (CRP) <3.2 for the 200 mg, but not the 100 mg dose; it was not possible to claim superiority versus adalimumab plus MTX due to the statistical plan. [bib_ref] Efficacy and safety of filgotinib for patients with rheumatoid arthritis with inadequate..., Combe [/bib_ref] Filgotinib has also been studied as monotherapy (see above). Peficitinib showed significant efficacy on symptoms, signs and structural outcomes of RA in randomised trials including monotherapy and concomitant MTX treatment, in patients with an IR to TNFi and an open label study with etanercept as a safety control. These studies included a majority of Japanese, Korean and Taiwanese patients, while the difference to placebo was small in a global study where very high placebo response rates were seen. [bib_ref] Peficitinib, a JAK inhibitor, in combination with limited conventional synthetic disease-modifying antirheumatic..., Genovese [/bib_ref] Peficitinib is approved in Japan and Korea at 100 and 150 mg daily. The dose of JAKi should be modified according to patientspecific demographics, comorbidities and/or concomitant medications as per product monograph inserts (see also section on contraindications). There is no evidence at present that one JAKi is more efficacious clinically, functionally or structurally or safer than another JAKi. While two studies have shown superior efficacy of a JAKi plus MTX compared with an anti-TNF plus MTX, two other trials have failed to show such effect ; moreover, in the trials showing superiority of a JAKi plus MTX to adalimumab plus MTX, the significantly better efficacy was seen for most outcomes, but not for tender and swollen joint counts. Thus, the relevance of this finding is currently limited; moreover, as of now, no study compared one JAKi with another. On the other hand, several of the above cited studies clearly revealed that JAKi have superior efficacy than TNFi for pain and fatigue, an aspect that deserves further investigation, as it may relate to a hitherto insufficiently recognised and specific mode of action for this drug class. No studies are yet available in JAKi IR or intolerant patients switching from one JAKi to another JAKi. However, a recent study showed efficacy of anti-TNF therapy after IR to a JAKi, [bib_ref] Safety and effectiveness of upadacitinib or adalimumab plus methotrexate in patients with..., Fleischmann [/bib_ref] and safety regarding switch from a bDMARD to a JAKi without washout, information that was missing hitherto. Regarding dose reduction in patients with RA in sustained Clinical Disease Activity Index (CDAI) or Boolean remission on background csDMARD, trial evidence is currently confined to dose reduction for baricitinib. [bib_ref] Dose reduction of baricitinib in patients with rheumatoid arthritis achieving sustained disease..., Takeuchi [/bib_ref] ## Psoriatic arthritis Currently, only tofacitinib is approved for PsA; the licensed dose is 5 mg two times a day. The clinical trials demonstrated efficacy in patients with prior IR to csDMARDs [bib_ref] Tofacitinib or adalimumab versus placebo for psoriatic arthritis, Mease [/bib_ref] and TNFi. [bib_ref] Tofacitinib for psoriatic arthritis in patients with an inadequate response to TNF..., Gladman [/bib_ref] The efficacy in PsO is described below. Since the closing date of the SLR, two phase 3 trials of upadacitinib were completed successfully, showing efficacy regarding main outcomes of PsA, also when compared with adalimumab (non-inferiority for the ACR20 response with the 15 mg and superiority with the 30 mg dose). Filgotinib at 200 mg daily showed efficacy in a phase 2 trial 70 and phase 3 data are awaited. ## Ankylosing spondylitis Tofacitinib demonstrated significant efficacy at 12 weeks for signs and symptoms in patients with highly active AS (by modified New York criteria) refractory to NSAIDs in a phase 2 doseranging placebo-controlled RCT. The highest Assessment of SpondyloArthritis international Society (ASAS) 20 response was observed at 5 mg two times a day, especially in patients with both elevated CRP and evidence of MRI inflammation in the sacroiliac joints. [bib_ref] Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled,..., Van Der Heijde [/bib_ref] A dose-dependent effect for clinical response was not evident. Separation from placebo was observed at 4-8 weeks suggesting a slower onset of response than seen with TNFi. Filgotinib at 200 mg once daily has been assessed in patients with active AS refractory to NSAIDs and TNFi (10%) in a 12 week phase 2 placebo-controlled RCT. [bib_ref] Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in..., Van Der Heijde [/bib_ref] Significant benefit for disease activity, assessed by the AS Disease Activity Score (ASDAS), was evident by week 1 and major improvement in ASDAS was noted in 33% versus 2% of patients on filgotinib and placebo, respectively, at 12 weeks. For most outcomes separation from placebo was observed at 4-8 weeks. Upadacitinib at 15 mg daily was assessed in a 12-week phase 2/3 placebo-controlled trial that recruited patients with active AS refractory to NSAIDs. [bib_ref] Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis (SELECT-AXIS..., Van Der Heijde [/bib_ref] Significantly more patients had an ASAS 40 response at week 14 in the upadacitinib versus the placebo group (52% vs 26%) and this was observed at the first postbaseline visit at week 2. Other outcomes including MRI spine and sacroiliac joint inflammation, were also superior for upadacitinib, just like for tofacitinib and filgotinib. Overall, the 12-week phase 2 data support the efficacy of JAKi for a variety of disease outcomes relevant to AS to a degree comparable to TNFi while the pattern of AEs and changes in laboratory outcomes were similar to those reported in previous studies in other indications. ## Dermatological diseases including pso Nine different JAKi and three selective TYK2 inhibitor have been evaluated in PsO; none of them has been approved for this indication to date except for occasional individual countries, such as Russia (tofacitinib). Tofacitinib was tested in one phase II, four phase III and one long-term extension study, the results of which were recently summarised. [bib_ref] Benefit-risk profile of tofacitinib in patients with moderate-to-severe chronic plaque psoriasis: pooled..., Strober [/bib_ref] Tofacitinib 5 and 10 mg two times a day showed superiority over placebo for all efficacy endpoints at week 16, with response maintained for 52 weeks of continued treatment. The Psoriasis Area and Severity Score (PASI) response, however, appeared numerically lower than that typically seen for bDMARDs such as IL-12/23 or IL-17 inhibitors. Tofacitinib improved patients' quality of life and was well tolerated. With the exception of herpes zoster, rates of safety events of interest were similar to those in the published literature and healthcare databases for other systemic PsO therapies. Tofacitinib 10 mg two times a day demonstrated greater efficacy (PASI75 at 12 weeks: 43% in MTX-IR and 21% in TNFi patients) than 5 mg two times a day. An additional phase IIa study evaluating topical application of tofacitinib in mild-to-moderate PsO found significant clinical improvement over placebo treatment after 4 weeks. [bib_ref] A randomized phase 2A efficacy and safety trial of the topical Janus..., Ports [/bib_ref] Baricitinib was studied in a phase IIa dose-ranging study, using once daily dosing over 12 weeks. A statistically significant difference among patients exhibiting at least a 75% improvement in their PASI (PASI75) when compared with placebo was observed for patients receiving 8 or 10 mg daily (43% and 54% vs 17%), 75 a much higher dose than approved for RA and, again even at this dose the skin response is numerically lower than reported for several of the more recently approved bDMARDs; for example, for IL-12/23 inhibitors the PASI75 amounted to about 70% and 80% for ustekinumab and guselkumab, respectively,. and to 89% on IL-17 inhibition. [bib_ref] Phase 3 trials of ixekizumab in moderate-tosevere plaque psoriasis, Gordon [/bib_ref] For the JAK1 inhibitors abrocitinib, itacitinib and GSK2586184 as well as the JAK1/3 inhibitor peficitinib, data in the public domain are equally available from one phase II study each. 60% of patients receiving the most effective dose regimen (200 mg twice daily) of abrocitinib experienced a 75% improvement of the PASI. [bib_ref] Efficacy and safety of the Janus kinase 1 inhibitor PF-04965842 in patients..., Schmieder [/bib_ref] Itacitinib showed significant improvement in the Physician Global Assessment (PGA) after 4 weeks of treatment with 600 mg once daily versus placebo, [bib_ref] A randomized, double-blind, placebocontrolled, dose-escalation study of the safety and efficacy of..., Bissonnette [/bib_ref] while GSK2586184 at 400 mg once daily yielded a 75% PASI improvement in 57% of patients after 12 weeks, [bib_ref] Investigation of selective JAK1 inhibitor GSK2586184 for the treatment of psoriasis in..., Ludbrook [/bib_ref] and patients treated with 50 mg of peficitinib once daily benefitted from improved PASI, PGA and reduced body surface area affected. [bib_ref] A phase 2A randomized, double-blind, placebocontrolled, sequential dose-escalation study to evaluate the..., Papp [/bib_ref] Another JAKi, ruxolitinib, was tested in two topical formulations containing 1% and 1.5% of ruxolitinib, respectively, versus placebo and two active comparators, namely calcipotriene 0.005% cream and betamethasone doproprionate 0.05% cream. A statistically significant difference versus the vehicle was observed after 4 weeks of treatment for the ruxolitinib 1% group, with comparable efficacy of ruxolitinib formulations with the active comparators. [bib_ref] Preliminary clinical activity of a topical JAK1/2 inhibitor in the treatment of..., Punwani [/bib_ref] For two additional JAKi, no peer-reviewed publicly available data have been published so far. Finally, a phase II study evaluating the TYK2 inhibitor BMS-986165 was recently published. [bib_ref] Phase 2 trial of selective tyrosine kinase 2 inhibition in psoriasis, Papp [/bib_ref] Doses ranging from 3 mg every other day up to 12 mg daily were studied and compared with placebo. BMS-986165 at doses of 3 mg daily and higher was found to result in greater clearing of PsO than did placebo over a period of 12 weeks, with PASI75 responses up to 75% in the highest dose group. Data for two additional TYK2 inhibitors await peer-reviewed publication. Evidence for therapeutic efficacy of JAK-inhibitors or TYK2inhibitors has also been suggested in several other immunemediated inflammatory dermatoses, including atopic dermatitis, alopecia areata, vitiligo, 84 palmoplantar pustulosis and a case of a mucocutaneous disease called idiopathic erythema multiforme associated with a mutation in TRPS1 and JAK-STAT activation. [bib_ref] Jak inhibition as a therapeutic strategy for immune and inflammatory diseases, Schwartz [/bib_ref] Taken together, PsO belongs to a group of chronic inflammatory skin diseases for which inhibition of JAKs or TYK2 has shown clinical efficacy. However, the extent of efficacy observed and the safety profile of the JAKi has so far not led to drug authorisation by EMA or FDA, but there is considerable interest around TYK2 inhibition, given the absence of some safety issues linked to non-selective JAKi, as well as regarding indications other than PsO, namely AD, where there are still far less options available for systemic therapies. ## Inflammatory bowel disease Tofacitinib is indicated for the treatment of adult patients with moderately to severely active UC who have had an inadequate response, lost response or were intolerant to either conventional therapy or a biologic agent. [bib_ref] Tofacitinib as induction and maintenance therapy for ulcerative colitis, Sandborn [/bib_ref] Tofacitinib 5, 10 and 15 mg two times a day showed significant efficacy for remission (Mayo score) in patients who were cs-and bDMARD-IR. [bib_ref] an oral Janus kinase inhibitor, in active ulcerative colitis, Sandborn [/bib_ref] The recommended dose is 10 mg given orally twice daily for induction for 8 Recommendation weeks (or 16 weeks if adequate benefit is not achieved) and 5 mg given twice daily for maintenance (in TNFi-IR patients 10 mg two times a day maintenance may be used). The 10 mg two times a day dose was associated with VTEs and PEs in patients with RA 53 (see also below). Upadacitinib and peficitinib similarly have shown efficacy in phase 2 trials in csDMARD and bDMARD-IR patients in doseranging studies of UC. In CD, tofacitinib at 5-15 mg two times a day has shown no significant efficacy in induction and maintenance of Crohn's disease activity index remission (<150) compared with placebo. [bib_ref] Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two..., Panés [/bib_ref] However, selective JAK1 inhibition by filgotinib showed increased remission rates in patients with moderate to severe CD. [bib_ref] Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the..., Vermeire [/bib_ref] Moreover, upadacitinib also showed promising results in a phase II trial in CD 37 and larger phase III trials have been initiated. Collectively, these findings hold promise for these agents as clinical therapeutics in IBD which await corroboration in ongoing phase III trials. ## Other diseases Baricitinib was investigated in a phase 2 trial of systemic lupus erythematosus and demonstrated significant efficacy at 4 mg but not 2 mg compared with placebo. [bib_ref] Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial, Wallace [/bib_ref] Other indications for which JAKi are being evaluated include non-infectious uveitis, CANDLE syndrome and other interferonopathies, including USP18 deficiency. [bib_ref] Pharmacokinetics, pharmacodynamics, and proposed dosing of the oral JAK1 and JAK2 inhibitor..., Kim [/bib_ref] [bib_ref] JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies, Sanchez [/bib_ref] [bib_ref] Jak inhibitor therapy in a child with inherited USP18 deficiency, Alsohime [/bib_ref] The reader is referred to the SLR manuscript. ## Ii. treatment dose and comedication ## Use the dose recommended for the specific disease. The dosing of individual JAKi in the various diseases has been addressed in the previous section (see above). ## Dose adjustments due to drug interactions Tofacitinib is metabolised by the hepatic cytochrome P (CYP) 450 pathway which leads to drug interactions with inhibitors such as ketoconazole and promoters such as rifampicin, necessitating dosage adjustments, although it is also 30% renally excreted. In contrast, baricitinib is 70% renally excreted. Filgotinib is metabolised by hepatic carboxylesterases and has a major metabolite GS-829845 which is a pharmacologically active, selective inhibitor of JAK1, but is 10-20 times less potent than the parent compound. Upadacitinib predominantly undergoes hepatic oxidation with minor CYP metabolism and peficitinib undergoes hepatic conjugation. Organic anion transporter 3 inhibitors, such as probenecid, interact with baricitinib requiring a dose reduction to 2 mg per day (with normal renal function). Rifampicin when used in latent tuberculosis (TB) prophylaxis or therapy for active TB increases hepatic metabolism of tofacitinib and upadacitinib so that a dose increase of the latter has to be considered. Ketoconazole has the opposite effect, inhibiting tofacitinib and upadacitinib metabolism so a dose reduction is suggested. Dose adjustments due to hepatic or renal impairment are discussed below. The dosing of the individual agents and their metabolisation are summarised in table 2. ## Comedication Comedication has been addressed in the previous section, including addition of JAKi to pre-existing csDMARDs as combination therapy. ## Consider dose reduction in sustained remission on background therapy This aspect has also been addressed in the previous section. For dose adjustments due to impaired organ function see below. ## Iii. contraindications that should be considered Contraindications are primarily related to the adverse event and the pharmacokinetic/pharmacodynamic profile of the various JAKi. 1. Severe active infections, acute or chronic, including latent TB and opportunistic: these infections can be seen in patients treated with JAKi. [bib_ref] Analysis of infections and all-cause mortality in phase II, phase III, and..., Cohen [/bib_ref] Serious infection rates in RA and PsA studies of tofacitinib, baricitinib and upadacitinib were comparable to adalimumab with higher rates occurring at higher doses. Tofacitinib treated RA patients above 65 years (with cardiovascular risk factors) exhibited a higher rate of serious infections compared with TNFi treated patients and according to EMA tofacitinib should be used in these patients only if there is no other alternative.A recently published post hoc analysis of RA trial data that included an adalimumab comparator found similarly increased risks for serious infections among the elderly, particularly among those using 10 mg two times a day tofacitinib. Risk elevations as compared with younger patients were similar for those using adalimumab and tofacitinib 5 mg two times a day, but several fold higher for those using 10 mg two times a day. [bib_ref] Age-based (<65 vs ≥65 years) incidence of infections and serious infections with..., Winthrop [/bib_ref] 4. Pregnancy and lactation: Limited data are available and contraception while taking JAKi is advised for both female and male patients in the absence of adequate data. Tofacitinib has been shown to be teratogenic in rats and rabbits, and to affect parturition and peri/postnatal development. [bib_ref] A pharmacological approach to managing inflammatory bowel disease during conception, pregnancy and..., Picardo [/bib_ref] Filgotinib reduces spermatogenesis in a dose-dependent manner in animal studies; to date, this has not been observed in humans, but a definitive study evaluating this question is currently underway 97 so this can then be taken into account appropriately in male patients. These agents have short plasma half-lives but a gap of 4 weeks is recommended after the last dose if future pregnancy is being contemplated. It is not known whether tofacitinib is secreted in human milk, but it is secreted in the milk of lactating rats. A risk to the breast-fed child therefore cannot be excluded. As a precautionary measure, the use of tofacitinib during breast-feeding is contraindicated. A study of a small number of patients with UC taking tofacitinib observed healthy newborns, no foetal deaths or congenital malformations and spontaneous abortions appeared consistent with background risks in the USA. [bib_ref] Outcomes of pregnancies with Maternal/ Paternal exposure in the tofacitinib safety databases..., Mahadevan [/bib_ref] Similar data exist for RA and PsO. [bib_ref] Pregnancy outcomes in the tofacitinib safety databases for rheumatoid arthritis and psoriasis, Clowse [/bib_ref] ## History of vte events: in patients with a history of throm- boembolic events initiation of a JAKi should be carefully evaluated based on the increased rates of VTEs in patients at risk for these events (see below under risks and adverse events). Increased VTEs, especially PE, have been observed in patients with cardiovascular risk factors treated with 10 mg tofacitinib two times a day indicating that also these (arterial) risks require consideration. Patients with recurrent thromboembolic events will usually receive anticoagulation treatment likely counteracting the risk. The safety and efficacy of JAKi is under investigation in juvenile patients but has not yet been established in persons <18 years of age. For restrictions regarding patients >65 years of age see below. Finally, JAKi have not been studied and, therefore, are not recommended in combination with bDMARDs or potent immunosuppressive agents such as cyclosporine or tacrolimus because of the possibility of increased immunosuppression and increased risk of infection or lymphoma. IV. Pretreatment screening and risk assessments 1. History and physical examination: Important patient details to obtain before starting therapy include a history and risk estimation of VTE, infections, TB, risk factors for hepatitis B and C, as well as usual medical considerations such as comorbidities, cardiovascular risk factors and concomitant medications of relevance, for example, Cox 2 inhibitors, prednisone doses >7.5 mg daily or oral contraceptives. The recommendation for patients over 70 years of age is a baricitinib dose reduction to 2 mg daily due to age-related reductions in renal function. Moreover, EMA has restricted the use of tofacitinib in people older than 65 years also due to an increased risk of serious infections.No dose reduction is recommended for modest renal impairment with upadacitinib and filgotinib therapy. Baseline skin check for non-melanoma skin cancer (NMSC) in patients at risk and chest X-ray is also recommended, unless recently performed. 2. Routine laboratory testing that includes a full blood count (including a differential white cell count), liver enzymes (in particular transaminases), and renal function tests are recommended before starting JAKi. Baseline lipid levels are sug-gested unless recently checked. No creatine phosphokinase (CPK) testing is needed. ## Hepatitis b virus (hbv) testing for anti-hbs, anti-hbc, and HBsAg is recommended in all patients. Patients with evidence of chronic HBV infection (ie, positive HBsAg) should avoid JAKi or treatment with biologics if possible. If not possible, then concomitant treatment or prophylaxis with an anti-viral (eg, entecavir, tenofovir or tenofovir alafenamide) should be undertaken alongside consultation with a hepatologist. [bib_ref] clinical practice guidelines on the management of hepatitis B virus infection, Lampertico [/bib_ref] For patients with evidence of prior HBV exposure (positive HBc antibody) and no evidence of active viral replication (ie, negative HBsAg), a baseline HBV DNA should be obtained to rule out occult active HBV infection. If positive, then patients have active HBV and should be managed according to the above. The main virological event of concern in these anti-HBc positive patients is HBsAg reappearance (seroreversion), consistently associated with hepatitis flare; HBV DNA detection (without HbsAg) leads to seroreversion and hepatitis in 50% of cases. [bib_ref] clinical practice guidelines on the management of hepatitis B virus infection, Lampertico [/bib_ref] If HBV-DNA negative, then such patients can start JAKi and should be routinely monitored for HBV DNA and HBsAg reappearance (seroreversion) in line with respective national recommendations for TNFi. If HBV DNA or HBsAg subsequently turns positive during monitoring, then the patient should be managed as above with referral to a hepatologist for treatment. The JAKi should be temporarily stopped until full evaluation can be made. Concurrent treatment with an antiviral is possible, and the JAKi can be reinstituted once anti-viral therapy has been started. [bib_ref] Evaluation of hepatitis B virus in clinical trials of baricitinib in rheumatoid..., Harigai [/bib_ref] Hepatitis C virus (HCV) antibody testing is recommended and should be further assessed if positive, that is, HCV RNA testing. If positive, then the patient has active HCV and should be referred for treatment. In such case, JAKi should be withheld until HCV treatment has been completed. 4. HIV testing is recommended for those with HIV risk factors. 5. As the risk for TB-reactivation with JAKi is similar to that for TNFi, screening for TB is recommended, unless already done prior to bDMARD commencement without a risk of exposure since then. All patients in JAKi phase 3 studies were screened for TB and patients with active TB excluded while patients with latent TB were commenced on anti-TB therapy and included. Cases of TB were noted with JAKi more commonly than with placebo in pivotal trials, with at least some cases occurring in endemic areas likely representing newly acquired infection rather than reactivation of prior infection. . Vaccination status should be sought. Country and regional vaccination guidelines should be followed. EULAR has recently updated its vaccination recommendations for patients with autoimmune diseases. [bib_ref] 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune..., Furer [/bib_ref] In addition to Herpes zoster reactivation, Herpes simplex and cytomegalovirus reactivation may also occur. HPV reactivation is not known to occur, but has not been evaluated systematically. Herpes zoster reactivation: A history of varicella or zoster infection or immunisation should be obtained. Herpes zoster reactivation is clearly increased under JAKi with incidence rates (IRs) between 3-4 (Western Europe, USA, Australia) and 9 (Japan, Korea) per 100 patient-years compared with 2-3 per 100 patient-years for TNFi. Risk factors include age, female gender, prednisolone >7.5 mg per day, infection and hospitalisation. 11 As for serious infections, there is also a dose response for Herpes zoster reactivation. The reactivation is likely based on the mode of action of JAKi blocking interferon pathways. If a patient develops Herpes zoster, ## Recommendation JAKi treatment should be temporarily interrupted until the episode resolves. A small proportion of patients can develop recurrent zoster. Antiviral prophylaxis could be considered in such individuals. Evidence for the efficacy of the live Zostavax vaccine is questionable and as a live attenuated vaccine it necessitates a delay of 3-4 weeks postvaccination before starting a JAKi; further, a single missed dose of MTX could be considered, since MTX may blunt the antibody response, 107 but this approach is not evidence based. In a live zoster vaccination study, zoster IRs at follow-up were numerically similar in the tofacitinib 5 mg and adalimumab and MTX arms but higher rates were seen for the combination of tofacitinib 5 mg two times a day with MTX. [bib_ref] Live zoster vaccine in patients with rheumatoid arthritis treated with tofacitinib with..., Calabrese [/bib_ref] Notably, zoster rates at follow-up were generally similar in vaccinated versus non-vaccinated patients, but further studies are clearly needed. While the vaccination resulted in reasonable immune responses, 1 patient developed zoster infection having had no prior immunity. [bib_ref] The safety and immunogenicity of live zoster vaccination in patients with rheumatoid..., Winthrop [/bib_ref] A new zoster vaccine has been more recently approved; being a nonlive vaccine, it is not contraindicated in patients receiving immunosuppressive or immunomodulating agents, but currently there are no data on safety and protective immunogenicity of this vaccine in patients treated with JAKi. As studies are underway, these questions should be resolved soon. The safety of the inactivated zoster vaccine (Shingrix) has been suggested by a small open label study of 400 patients with RA (no zoster activation, 6.7% disease flares, mostly mild, self-limiting, and not requiring therapeutic change), but efficacy and immunogenicity of the vaccine in this setting is unknown. [bib_ref] Safety of the zoster recombinant adjuvanted vaccine in rheumatoid arthritis patients: a..., Stevens [/bib_ref] should be considered by history and a potential clotting abnormality should be pondered in patients with a history of VTEs in whom such assessments have not yet been done. While these events are rare, the risks are increased in patients with prior VTEs; with increasing age (patients older than 65 years are at higher risk for having VTEs with tofacitinib); obesity (people with obesity have two times the risk of VTEs as people with normal weight, and the higher the weight, the higher the risk); prolonged immobility (ie, long travel, lower-extremity paralysis due to spinal cord injury, trauma with reduced mobility); hereditary (ie, factor V Leiden, prothrombin mutation 20210, etc) and acquired (ie, antiphospholipid syndrome, malignancy) thrombophilia; Cox 2 inhibitor therapy ; prednisolone of ≥7.5 mg/d and above; major surgical interventions, such as neurosurgic, urologic, gynaecologic and orthopedic surgery. Interestingly, a recent study from Sweden suggested that VTEs are significantly related to disease activity with an adjusted RR of 1.99 during high, 1.45 during moderate and 1.11 with low RA activity compared with remission. This potential relation between VTE rates and RA disease activity remains to be fully elucidated. For more details regarding VTEs and PEs see below under adverse events. ## Risk factors for vtes ## V. adverse events Adverse events are mainly related to the inhibition of cellular pathways and include those already mentioned above under risks. However, several other adverse events need more detailed consideration. 1. Serious infections including opportunistic infections such as TB and others, as well as reactivation of Herpes zoster and other viruses can occur. The IR of Herpes zoster reactivation amounts to about 3-4 compared with placebo (IR=1). Their frequency is dose and co-medication dependent and the reactivation of Herpes zoster is more frequent than on bDMARDs and especially frequent in Japan and Korea. Moreover, EMA (but not FDA) has restricted the use of tofacitinib in people older than 65 years due to an increased risk of serious infections.Herpes zoster was also seen with baricitinib and less commonly with upadacitinib. It is also listed as an important potential risk for filgotinib by EMA, and while they state that no signal for varicella zoster infection has been detected in the filgotinib RA clinical trial program, the agency requests further evaluation by additional pharmacovigilance activities. 117 2. Malignancy: The overall rates are not increased except for the risk of NMSC which might be elevated and, therefore, the task force recommends regular skin examinations, especially in countries with increased risk of NMSC, such as Australia. The task force also felt that current malignancy (except NMSC and cervical carcinoma in situ undergoing treatment) may be a contraindication for JAKi, but as stated previouly, this should be a shared decision making with the patient. 3. Anaemia and cytopenias: Anaemia of chronic disease, as usually seen in most IMIDs, does not improve on the group level with all JAKi except for filgotinib, and in some patients the pre-existing anaemia may deteriorate, presumably due to JAK 2 inhibition; JAK 2 is involved in EPO signalling (see [fig_ref] Figure 1: Depiction of cytokines that activate and drugs that target Janus kinases [/fig_ref]. Cytopenias may occur but were not more frequent than on placebo, [bib_ref] Safety profile of Baricitinib in patients with active rheumatoid arthritis with over..., Smolen [/bib_ref] although with all JAKi a few patients may exhibit neutropenia and/or lymphopenia. 4. VTE/pulmonary embolism (PE). Across indications, in randomised controlled trials and long term extensions of tofacitinib followed for up to 9.5 years, no increased risk of VTE for the 5 mg bd dose has been seen. However, in a still ongoing safety study of patients with RA enriched for cardiovascular risk factors, a statistically significant PE imbalance for tofacitinib 10 mg bd as compared with 5 mg two times a day was demonstrated with an absolute IR of 0.5 for 10 mg and 0.3 for 5 mg 53-55 ; compared with TNFi (absolute IR of 0.1) which were investigated as a control arm, the PE risk thus being about threefold higher for the 5 mg dose and about sixfold higher for the 10 mg dose. In this same study, as reported by the EMA, VTE without PE were somewhat numerically higher with tofacitinib than TNFi but the difference was not statistically significant. Since this is an ongoing study, the full data for the 5 mg dose will have to be awaited for a full assessment of the VTE risk, but the 10 mg two times a day dose was discontinued in this study. A recent analysis of VTE/PE in clinical trials of UC in which most of the patients had been treated with a dose of 10 mg two times a day reported that during the placebo controlled period no UC patient had a VTE or PE and 1 VTE and 1 PE each were seen in placebo treated patients. [bib_ref] Venous thromboembolic events in the tofacitinib ulcerative colitis clinical development programme, Sandborn [/bib_ref] During the long term, open-label extension comprising about 2400 patient-years of exposure, 1 patient had a VTE and 4 had PEs, all with risk factors for these events. [bib_ref] Venous thromboembolic events in the tofacitinib ulcerative colitis clinical development programme, Sandborn [/bib_ref] The recent EMA assessment provided evidence for an increased PE risk at the 5 mg and especially the 10 mg two times a day dose of tofacitinib.The FDA has not made a final determination and is awaiting the final, adjudicated results of the study. Baricitinib at 4 mg had an imbalance in VTEs compared with the control arms (placebo or adalimumab) in the controlled period of RA trials; this has not been observed with the 2 mg dose. [bib_ref] Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response..., Smolen [/bib_ref] the risk may be up to 10-fold for patients with a history of VTEs and twofold for those patients taking Cox2 inhibitors. [bib_ref] Cardiovascular safety during treatment with Baricitinib in rheumatoid arthritis, Taylor [/bib_ref] Subsequently, there was no increase in risk when patients were transitioned from placebo or MTX to baricitinib as well as across long-term extension studies over 6 years but VTEs in the LTE were observed equally with 2 and 4 mg. Numerically increased rates of VTEs have also been observed in the double blind phases of upadacitinib trials, primarily with the 15 mg once a day dose, although not in the head-tohead trial against adalimumab. With respect to filgotinib, EMA regards VTE as a potential risk, but the agency also concluded that no increase in reports of VTEs was seen for filgotinib (100 mg and 200 mg doses) compared to placebo or comparators (MTX, ADA). Importantly, however, additional data by pharmacovigilance activities have been required by EMA. Taken together, these observations elicited warnings (in some countries "black box" warnings) for VTE in the labels of all approved JAKi, plus additional warnings issued by the regulators (see above). In particular, the EMA recommends the use of tofacitinib in patients with RA 'above the age of 65 only when there is no alternative treatment'. Such age considerations have not been set in place for other JAKi that have similar VTE warnings in their label; however, data on outcomes studies in patients with cardiovascular risk factors are not available for those other agents. VTEs on baricitinib also occurred in patients with risk factors, such as obesity, and several continued therapy, although mostly under anticoagulation. [bib_ref] Cardiovascular safety during treatment with Baricitinib in rheumatoid arthritis, Taylor [/bib_ref] While the overall risk of VTE is age dependent and in the order of 1:100-1:1000 (occurrence rate 0.25/100 patient years), this risk is about doubled in patients with RA.Further research is needed to delineate the mechanisms how JAKi increases VTE rates (and how this compares to patients with RA in general), while we also lack understanding how glucocorticoids, Cox2 inhibitors, oral contraceptives, tamoxifen, thalidomide, antipsychotics elevate VTE risk. In any event, careful consideration should be given as whether or not to start a JAKi in any patient who may be at risk for a VTE. With respect to major adverse cardiovascular events (MACE) across indications, in randomised controlled trials and longterm extensions no increased risks have been observed. As indicated above, a long-term study of tofacitinib in RA patients with cardiovascular risks is ongoing and has hitherto not shown evidence for an increase in MACE (regarding increase in VTEs see above). 5. Laboratory abnormalities without clinical sequelae in the majority of patients: CPK elevations are occasionally seen without weakness, thus far with occasional myalgia, but usually without clinical repercussions, although one patient has had rhabdomyolysis.Thus, in the rare event of symptoms, CPK should be tested, although in general this is not necessary. While the underlying cause is unknown and there have been suggestions this may be due to a renal tubular effect, there are some data suggesting this effect might be due to restoration of muscle development with associated CPK elevations (an event that is suppressed by oncostatin M whose signalling depends on JAKs). Creatinine increases have also been observed but without organ dysfunction or other clinical sequelae, such as hypertension. Finally, gastrointestinal perforation has been reported in clinical trials and may be a risk of bariticitinb and tofacitinib 126 (and possibly other JAKi). Thus, JAKi should be used with caution in patients who may be at increased risk for gastrointestinal perforation (eg, patients with a history of diverticulitis and taking concomitant NSAIDs or glucocorticoids). Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of gastrointestinal perforation knowing fever and elevation of acute phase reactants may be blunted by JAKi therapy. VI. Laboratory and clinical monitoring during follow-up 1. As a minimal laboratory monitoring during follow-up, the task force recommends measurement of full blood count and differential, transaminases, renal function, at 1 month and 3 months and then periodically such as every 3 months plus lipid levels just at 3 months. Blood count: Haemoglobin change of less than or equal to 20g/L decrease and haemoglobin levels greater than or equal to 90g/L do not require dose adjustment. Greater than a 20g/L decrease or a haemoglobin of less than 80g/L (confirmed by repeat testing) should lead to dose interruption until haemoglobin values have normalised. Filgotinib leads to small dose dependent average increase in haemoglobin levels, compared with all other JAKi. Absolute neutrophil counts over 1000/mm 3 require no dose adjustment, however, a count of 500-1000/mm 3 on two sequential measures suggest dose reduction or temporary cessation until count above 1000/mm 3 when JAKi can be recommenced. Absolute lymphocyte counts over 750/mm 3 require no dose adjustment, a count of 500-750/mm 3 on two sequential measures suggests a dose reduction or temporary cessation until the count is greater than 750/mm 3 to allow recommencement. There is some evidence that lymphocyte counts below 500/mm [bib_ref] 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis, Van Der Heijde [/bib_ref] ## Recommendation (treat-to-target), in line with current management recommendations for RA and PsA, and in line with recommendations for other IMIDs, respectively. It should be borne in mind that acute phase reactant levels may be reduced by JAKi independent of clinical improvement and, therefore, scores that are heavily weighted on acute phase reactants, such as the DAS28, should not be used for follow-up. [bib_ref] Remission in rheumatoid arthritis: missing objectives by using inadequate DAS28 targets, Aletaha [/bib_ref] ## Consideration of patient preferences In rheumatology, there is still a substantial number of patients with suboptimal outcomes or who are faced with uncontrollable disease symptoms. They fail to respond adequately to existing DMARDs. Therefore, the advent of DMARDs with a new mode of action is welcome. The oral route may enable some patients to become more independent from hospital or health professionals compared with subcutaneous injections or infusions and also appeals to those with a needle phobia; on the other hand, some biological agents are only administered monthly or even less frequently and this may be seen as an advantage compared with taking a drug once or twice daily. Cost considerations are an overarching principle in RA treatment recommendations and thus part of treatment decisions; while the costs of JAKi are currently usually higher than those for biosimilars, this may change once these drugs become generic. Careful consideration of initiation and open communication with the patient are warranted. The prescription of JAKi may not be at the expense of attention to safety risks and must be in line with existing specialty guidelines for management and good clinical practice which also includes the need for regular laboratory monitoring even in patients receiving JAKi monotherapy. These points to consider contain important information for patients. A patient version or a decision tool will support patients to weigh potential benefits, harms and their personal goals and preferences, and subsequently strengthen their role in the decision-making process. ## Research agenda The committee felt that many questions remained open and needed to be addressed in future research in both adult and paediatric populations. These questions are pertinent to all JAKi and are presented in box 1. # Discussion Similar to the situation with bDMARDs 15-20 years ago, realworld experience with JAKi is limited. Therefore, this task force was formed which consisted of experienced clinical trialists and people involved in treating patients with IMIDs across several medical areas and across nations and continents as well as patients and a health professional. The task force set out to provide the readers with comprehensive guidance on the use of this novel class of targeted therapies regarding efficacy and safety, based on evidence and complemented by expert opinion. In this consensus statement points to consider are provided for the use of JAKi across IMIDs for which they are approved or may be approved in the near future. The consensus statement is designed to support physicians and other health professionals treating patients with IMIDs as well as patients themselves and other stakeholders, such as hospital administrators and payers, with an up-to-date summary on the thoughtful application of JAKi. Where there is occasional redundancy in the paper, it derives from the fact that certain pieces of information relate to more than one chapter of this consensus statement, thus allowing readers who only focus on selected portions to obtain pertinent information. Currently baricitinib, filgotinib (in Europe and Japan), peficitinib (in Japan), tofacitinib and upadacitinib are licensed for one or more autoimmune inflammatory diseases. The consensus statement is primarily based on the evidence derived by an SLRfrom clinical trials and some observational studies, whereby safety aspects can currently be primarily or solely derived from information of the controlled and extended trial periods of the drugs. Indeed, efficacy data from comprehensive clinical trial programmes but hardly any long-term registry data from clinical practice are available on safety aspects . However, trial efficacy and safety data are constantly being expanded, as are the indications. At present five available JAKi are approved for use in RA patients, but tofacitinib is already licensed for PsA and UC and other compounds will also likely receive approval for a range of indications. Thus, JAKi may arrive at a similarly broad or even broader list of indications across IMIDs as TNFblockers. However, their broad efficacy is unrelated to inhibition of TNF signalling, but rather due to the fact that the intracellular blockade of JAKs relates to cytokines that are distinctly involved in different IMIDs, such as IL-6 in RA, IL-23 in PsA, PsO and IBD, or interferons in other diseases. Moreover, even if none of the cytokines activating the JAK-STAT pathway is known to be of significance in the pathogenesis of a particular disease, such as axial spondyloarthritis, it is possible that there are synergistic inhibitory effects by interfering with signalling of several cytokines that individually are only minimally pathogenetically relevant, culminating in clinical efficacy. Moreover, JAKi also interfere with the consequences of JAK activation induced by cytokines that do not directly use the JAK-STAT pathway for signalling, such as TNF, which can activate IL-6 and interferons downstream of their primary effects, thus affecting various pathogenic pathways. [bib_ref] IRF1 is critical for the TNF-driven interferon response in rheumatoid fibroblast-like synoviocytes..., Bonelli [/bib_ref] There are some differences between the drugs which are due to different selectivities regarding JAKi when looking at both in vivo and in vitro data, spanning from predominant JAK1 inhibition (filgotinib) to pan-JAKi (peficitinib, tofacitinib); these may translate into differences in reversible cytokine inhibition over the dosing period. These differences will be dose dependent [bib_ref] Comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine signaling in..., Mcinnes [/bib_ref] and may be reflected in variability in safety but also aspects of efficacy. Recommendations on indications and dosages can easily be derived from the clinical trials and labels of the respective drugs as stipulated by regulators, but the presumably more important items within this consensus statement relate to contraindications, pretreatment screening, safety and risks as well as monitoring and follow-up examinations. All these items have been addressed. The recommendations may change once further pharmacovigilance and registry data become available. They may also change once more information becomes known regarding pathways to disease or pathways leading to adverse events. Of note, the task force was informed by, and developed its recommendations based on, a detailed SLR evaluating studies that were published until the end of 2018; however, since then additional safety aspects became known from information provided by regulators, but the trial(s) on which this new safety information is based have not yet been published. Thus, the task force went beyond the data provided in the SLR and addressed publications and regulatory communications that appeared after the end of the SLR period to provide readers with the most up-to-date material. Among the adverse events, some have been expected from knowledge regarding blockade of cytokines that use JAK-STATs for signalling, such as an increased risk of serious (including opportunistic) infections. Others go beyond expectations but are explained by the pharmacologic effects of the drugs, such as the increase in herpes zoster rates. The failure to reverse anaemia of chronic disease would also be in line with expectations based on inhibition of JAK2, and this conclusion is confirmed by the improvement of anaemia when a more selective JAK1 inhibitor is applied. [bib_ref] Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with..., Westhovens [/bib_ref] However, even if relatively rare and associated with known risk factors, the occurrence of VTEs and PEs is an unexpected and hitherto unexplained event requiring further information and elucidation. It is not clear if idiosyncratic platelet activation, changes in procoagulant or fibrinolytic activity, or abnormal endothelial activation might be involved. However, other tyrosine kinase inhibitors may activate procoagulant activity 132 which might be related to changes in lipids or lipoprotein levels. [bib_ref] CETP activity: a link between lipid metabolism and coagulation system, Hatakeyama [/bib_ref] During the deliberations of the task force, comments arose that the control arms of some pivotal studies had an unusually low IR of VTEs; nonetheless, it is the nature of randomised controlled trials that the risk should be balanced across study arms and if one arm differs, one may conclude that the results are a consequence of the respective treatment. Further research activities in this area are urgently needed. Since the time of the SLR, the task force meetings and the start of preparing this manuscript, the COVID-19 pandemic has struck the world. Many patients with IMIDs who are treated with bDMARDs or JAKi have contracted this viral disease. Currently, there is insufficient knowledge about the risks (or potential benefits) of immunomodulating drugs in these patients in either altering susceptibility to infection, or in determining disease progression once infected with SRAS-CoV2. Case reports and individual centre's experiences do not yet suggest that these patients are at increased risk of having an adverse outcome of COVID-19. However, as yet no systematic analyses have been performed to inform physicians whether JAKi therapy may be continued or should be stopped prior to or during infection. Regardless, since these patients may be at an increased risk, primary prevention should be stressed with rigorous application of recommended public health and behavioural measures applied, including physical distancing, wearing masks and hygienic measures as recommended by most governments worldwide. Prophylactic discontinuation of an effective anti-inflammatory or immune modulatory therapy is not recommended at this time. [bib_ref] Inflammatory bowel disease care in the COVID-19 pandemic era: the Humanitas, Milan,..., Fiorino [/bib_ref] [bib_ref] Clinical course of COVID-19 in a series of patients with chronic arthritis..., Monti [/bib_ref] [bib_ref] Should biologics for psoriasis be interrupted in the era of COVID-19?, Lebwohl [/bib_ref] However, if therapy has been temporarily ceased in IMID patients with proven COVID-19 infection, when to safely recommence therapy is also not known for patients that have recovered. It is suggested that when oropharyngeal PCR swabs are negative virus shed after a further 7 days may be non-viable. [bib_ref] Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore, Young [/bib_ref] To better understand the consequences of COVID-19 on IMID patients with and without specific therapies, it is critical to enter patients infected with SARS-CoV2 into relevant registries and several exist. [bib_ref] SECURE-Psoriasis: a de-identified registry of psoriasis patients diagnosed with COVID-19, Balogh [/bib_ref] Of note, JAKi has been suggested to be potentially beneficial against COVID-19, particularly in the context of the cytokine release syndrome like hyperinflammation which occurs in a small subset of patients, and several trials are currently ongoing to learn whether this approach has positive, negative or neutral effects.A rationale for the potential efficacy of baricitinib has been recently provided by Stebbing et al and based on predicted interference with viral trafficking. [bib_ref] COVID-19: combining antiviral and antiinflammatory treatments, Stebbing [/bib_ref] However, answers to the clinical validity of these hypotheses must come from observational studies as well as properly performed clinical trials. In summary, JAKi are a new class of agents for the treatment of a variety of IMIDs with efficacy in many indications that is at least as good as that of bDMARDs and with an acceptable safety profile. Given their non-protein nature, antidrug antibodies and thus a potential secondary loss of efficacy would not occur. It is anticipated that based on these qualities and on the fact that they can be taken by the oral route their use will significantly increase over time. The presented consensus statement may be particularly helpful to those prescribing these drugs who aim to achieve the most appropriate and optimal use of these therapies. [fig] Figure 1: Depiction of cytokines that activate and drugs that target Janus kinases (JAKs) presumably involved in the pathogenesis of immunemediated inflammatory diseases (IMIDs). Top: efficacy of agents targeting specific JAK-inducing cytokines in different IMIDs. Centre: cytokines and respective receptors that trigger JAKs, types of JAKs activated and type of STATs (signal transducers and activators of transcription) activated by the respective JAKs. Bottom: JAK-inhibitors which are currently approved for IMIDs and their overall (including clinically derived) selectivity and presumed interference (+ or -) with certain cytokine pathways. axSpA, axial spondyloarthritis; EPO, erythropoietin; GM-CSF, granulocyte-monocyte colony stimulating factor; IBD, inflammatory bowel diseases; IFN, interferon; IL, interleukin; ND, not done; PsA, psoriatic arthritis; PsO, psoriasis; R, receptor; RA, rheumatoid arthritis; TP, thrombopoietin. 19 40 146 147 [/fig] [fig] II: immune mediated inflammatory diseases (IMIDs) who have failed prior conventional and/or biological therapies; as of 2019, these include rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ulcerative colitis (UC). there is no direct evidence of superiority regarding efficacy or safety of one JAK-inhibitor over another one. Treatment dose and comedications in different IMIDs [/fig] [table] 2: Malignancy: using a JAKi in this situation should be a shared [/table]	None	https://ard.bmj.com/content/annrheumdis/80/1/71.full.pdf	Objectives Janus kinase inhibitors (JAKi) have been approved for use in various immune-mediated inflammatory diseases. With five agents licensed, it was timely to summarise the current understanding of JAKi use based on a systematic literature review (SLR) on efficacy and safety. Methods Existing data were evaluated by a steering committee and subsequently reviewed by a 29 person expert committee leading to the formulation of a consensus statement that may assist the clinicians, patients and other stakeholders once the decision is made to commence a JAKi. The committee included patients, rheumatologists, a gastroenterologist, a haematologist, a dermatologist, an infectious disease specialist and a health professional. The SLR informed the Task Force on controlled and open clinical trials, registry data, phase 4 trials and meta-analyses. In addition, approval of new compounds by, and warnings from regulators that were issued after the end of the SLR search date were taken into consideration. Results The Task Force agreed on and developed four general principles and a total of 26 points for consideration which were grouped into six areas addressing indications, treatment dose and comedication, contraindications, pretreatment screening and risks, laboratory and clinical follow-up examinations, and adverse events. Levels of evidence and strengths of recommendations were determined based on the SLR and levels of agreement were voted on for every point, reaching a range between 8.8 and 9.9 on a 10-point scale. Conclusion The consensus provides an assessment of evidence for efficacy and safety of an important therapeutic class with guidance on issues of practical management.
8091b69a204839cb1684776a41ee6993cb86bc90	pubmed	Development of patient-centred standards of care for osteoarthritis in Europe: the eumusc.net-project	Development of patient-centred standards of care for osteoarthritis in Europe: the eumusc.net-project Objective The eumusc.net project is an initiative founded by the European Community and the European League Against Rheumatism. One aim of the project was to facilitate equal standards for musculoskeletal health across Europe. The aim of this work-package was to develop patient-centred and consensus based standards of care (SOC) for osteoarthritis (OA), which should be available in a professional and a patient version. Methods A systematic review concerning guidelines dealing with OA was conducted. Furthermore, experts in musculoskeletal diseases were contacted to ensure that 'grey' literature was not excluded. Documents that fulfilled predefined inclusion/exclusion criteria were included and all interventions for OA were extracted and categorised. Based on this list of interventions, a three round Delphi exercise with an international and multidisciplinary expert panel, including patient research partners, was performed to achieve expert consensus. Results Six documents were included and used for further analysis. Out of them, 46 interventions have been extracted and 10 consensus based SOC were formulated. In addition, a patient version, written in a layunderstandable wording and in the format of checklist questions was developed. An example is SOC 5: "People with OA should achieve optimal pain control using pharmacological and non-pharmacological means." The matching patient-centred checklist question reads: "Do I know how to control pain associated with OA?" Conclusions The SOC for OA will be available in the 23 languages of the European Union to enhance unified information to patients and professionals and to further harmonise the treatment/care of OA within Europe. # Introduction Osteoarthritis (OA) is a highly prevalent, progressive, degenerative joint disorder leading to pain, stiffness, disability, reduction in quality of life and limitations in the activities of daily living; it is characterised by loss of cartilage, changes in subchondral bone and abnormalities in other joint tissues, such as the synovial membrane and ligaments. Mechanical, biochemical and genetic factors are well known risk factors. [bib_ref] Development of criteria for the classification and reporting of osteoarthritis. Classification of..., Altman [/bib_ref] [bib_ref] The prevalence and burden of arthritis, Reginster [/bib_ref] [bib_ref] Obesity and osteoarthritis: more complex than predicted! Ann, Pottie [/bib_ref] OA is one of the most prevalent musculoskeletal conditions. Its incidence increases in both genders with age and its impact on quality of life can be very high. [bib_ref] The prevalence and burden of arthritis, Reginster [/bib_ref] Since the occurrence of OA will increase in the future with the demographic development and aging of the society it constitutes a large and rising economic factor for the health system with high direct and indirect costs. Even though currently no disease modifying therapies are known, availability and application of consensus based, cost conscious, effective treatment is highly desirable. This can be partly achieved through guidelines, which can then improve healthcare delivery. [bib_ref] Educational interventions for implementation of arthritis clinical practice guidelines in primary care:..., Lineker [/bib_ref] Clinical Practice Guidelines are systematically developed statements assisting in decisions about appropriate healthcare for specific clinical circumstances.Standards of care (SOC) are defined as 'standards of quality' that are authoritative statements of minimum and/or excellent levels of performance or results. The use of the expression 'standard' creates a doubt between minimum or optimal care. Therefore this should be explicitly described as an attribute of the SOC. The aim of the guidelines is to support decision making; in contrast, the intention of SOC is evaluating practice. Therefore the terms should not be used synonymously.In this project the aim was to develop a SOC as a minimum SOC acceptable in European countries but not to develop a guideline. Patients with a chronic disease indicate the need for information about their disease. [bib_ref] Patient education, disease activity and physical function: can we be more targeted?..., Drăgoi [/bib_ref] At the moment little is known about the impact of guidelines and SOC and their accessibility (as regards obtainment and comprehensibility) for patients. It is recommended that authors of guidelines develop a version that can be understood by the average patient. However, this requirement is not universally realised. In the European Musculoskeletal Conditions Surveillance and Information Network (eumusc. net) clinical practice guidelines are identified and appraised. Such activity has already been finalised for rheumatoid arthritis. [bib_ref] Development of patient-centred standards of care for rheumatoid arthritis in Europe: the..., Stoffer [/bib_ref] Using an expert panel of patients and clinicians from across Europe, we have developed a SOC for OA and additionally a layfriendly version of the SOC is provided. # Subjects and methods A literature search, including a critical appraisal of guidelines, was performed, followed by a three round Delphi exercise with European experts in the field of OA, in order to develop a SOC for OA that is applicable and acceptable in the whole of Europe. ## Identification of guidelines A systematic literature review was performed in various databases: Guideline registers, Medline, CINAHL and the Internet (Google), between February 2010 and August 2010, using the following keywords: "clinical practice guideline", "guideline", "guidance", "recommendation", "standard of care", "osteoarthritis", and all names of European countries. The reference lists were searched for further relevant publications. 'Grey literature' (American English 'gray literature'), is also known as 'fugitive literature' aimed to produce nonconventional publications. Therefore, these sources are rarely included in bibliographical retrieval systems and it is not mandatory for them to have undergone a peer review process. Nevertheless, these documents could contribute new findings and important information in the context of our study.In order not to exclude possible 'grey' literature, national societies, health professional associations and patient organisations in 44 countries were contacted and asked to provide relevant national documents for this study. ## Inclusion and exclusion criteria In this study, guidelines published after January 2002 and until August 2010 dealing with hand, hip and knee OA, or dealing with OA in general, denoted as guidelines or recommendations, with full text written in English or German, were included. Guidelines on non-pharmacological and pharmacological treatment were reviewed in their current version. Because of the European perspective in this study and considering the differences between healthcare systems in Europe and the USA, only European guidelines with a full text version were considered for the analysis. The decision to focus on European guidelines was reconfirmed by the fact that in different healthcare systems the roles of health professionals vary substantially. It was a consensual agreement of the working group to develop a SOC for hand, hip and knee OA and to exclude the management of OA of the spine. Therefore, guidelines for the management of back pain and/or OA of the spine were not taken into account. ## Assessment of methodological quality Documents obtained in their full version and fulfilling the above inclusion and exclusion criteria were evaluated using the Appraisal of Guidelines for Research and Evaluation instrument (AGREE) II criteria 8 to assess the methodological quality. Only guidelines receiving a high score in the overall assessment (4-7 on a 7-point scale) of the AGREE II criteria were used for further analysis to ensure that only high-quality guidelines could influence the content of the SOC. ## Data extraction All interventions and recommendations to treat OA mentioned in the included documents were extracted. ## Delphi exercise Based on the information retrieved from the guidelines, the relevance and availability in different European countries of the extracted interventions were discussed and grouped in a 1-day meeting in Vienna. The expert panel consisted of 4 patient research partners and 22 health professional experts with extensive experience in clinical and/or scientific work from a total of 17 expert centres for musculoskeletal diseases in 10 European countries. All experts and patient partners are authors of this article. After the meeting a first draft of SOC was developed and sent to the expert panel via email. Each comment of a working group member had the same weight. Panel members were asked for their agreement with the proposed wording of the SOC and in case of disagreement to suggest an alternative formulation. The comments of the expert group were built into the next version of the SOC that was circulated again. Furthermore, in this round the experts were asked to score each SOC using a scale of 1-3: 1="A must have for the final set of SOC"; 2="Would be nice to have in the final set of SOC"; 3="Is not important in a final set of SOC". [bib_ref] American College of Surgeons Guidelines Program: a process for using existing guidelines..., Freel [/bib_ref] After including the comments provided by the panel members, the final set of SOC was sent to the expert panel to obtain the level of agreement within the group. Each panel member was asked to score each SOC on a scale from 0 (0='I totally disagree') to 10 (10='I agree completely'). Based on the expert-SOC, we formulated questions for the patient-centred checklist (for each item) aiming for a comprehensive and lay-understandable wording. Each member of the working group could comment on the draft. The final approval of the wording of the patient-centred checklist was made by the patient partners. The aim of this checklist is to enable patients with OA to clarify if they have all the required information. The checklist can also be the basis for the conversation with health professionals. ## Literature search update To assure that the SOC are up to date at the time of publication, the literature search was repeated in August 2014 using the same keywords and searching the same databases. # Results References were identified from Medline (n=697), CINAHL (n=45), guideline registers (n=10) and the internet (the first 150 Google hits, without paid hits). A total of 902 references were obtained. Eighty-seven national scientific societies, patient organisations and health professional associations in 44 countries were contacted and after sending up to three reminder emails, we achieved a response rate of 63%. Excluding duplicates, the European organisations provided 14 documents. Among the documents provided by the national societies, health professional associations and patient organisations, 12 documents have been excluded because they were written in the national language and there was no translation available (Croatia n=1, Estonia n=1, Finland n=1, Hungary n=1, Israel n=1, Italy n=1, Moldavia n=2, Netherlands n=1, Poland n=1, Slovakia n=1, Sweden n=1). The titles and/or abstracts of the 916 documents were reviewed. Of these, 873 were excluded for not being a guideline or a recommendation. Full texts of 43 documents were reviewed. Thereafter, additional 37 documents were excluded because of non-European origin, failing to fulfil methodical requirements, or in a language different from English or German. Ultimately, six documents 12-17 fulfilled the inclusion/exclusion criteria and were used for the final analysis. From these guidelines 46 interventions, such as exercise or appropriate pain control, could be extracted. All recommendations presented in the retrieved guidelines have been excerpted and accordingly linked with the interventions found in the previous step. ## Results delphi round 1 The working group meeting was held in September 2010 in Vienna and was attended by 16 (62%) experts from the expert panel. In this meeting, the 46 interventions and/or methods were critically revised and classified into four groups (representing the main treatment modalities in OA): (1) Education, information and self-management (2) Pharmacological treatment (3) Non-pharmacological treatments (rehabilitative interventions and lifestyle interventions) (4) Surgical treatment. During the meeting, the relevance and availability of some interventions recommended in the various guidelines were discussed. For example, we categorised the interventions "application of heat, appliance of paraffin wax, use of local heat or cold" under the term "thermotherapy". Thereafter, we agreed that this intervention is relevant for the treatment of OA and in a second step we determined if the respective intervention is generally deliverable in the countries represented in the working group. The first proposed scheme was visualised on a mind map and each working group member had the option to propose statements in the form of one sentence to summarise the content. During the whole development process the working group was instructed to focus on clear and easy statements. A draft of 8 SOC in the format of short sentences was formulated. This draft version was sent to the whole expert panel. ## Results delphi round 2 In the second Delphi round, we received feedback from 18 (69%) experts, consisting of 60 comments. These were used to formulate the second draft of the SOC. The rearrangement of the SOC led to a version consisting of 10 SOC. ## Results delphi round 3 We then received 34 comments from 14 (54%) experts in the third Delphi round. The importance of each SOC was rated by 18 (69%) experts. The inclusion of the comments from the third Delphi round resulted in the final version of the SOC [fig_ref] Table 1: Standards of care for people with osteoarthritis [/fig_ref]. Based on the 'expert-SOC', a patient version in the format of a checklist was formulated with the intention that it should be easy to understand for lay people [fig_ref] Table 2: What this means for you and your osteoarthritis… 1 Was my OA... [/fig_ref]. The Level of Agreement of the SOC was rated by 21 (81%) experts and was between 9.3 and 9.9 on a scale 0-10, as shown in the last column of table 1. While the search focused on the English and German literature for practical reasons, the SOC and the patient version will be available in all 23 languages of the European Union online and will also be distributed widely with the support of the patient organisations aiming to spread the information and to overcome language barriers. People with symptoms of OA should have access to a health professional competent in making a (differential) diagnosis. 9.9 SOC 2 People with symptoms of OA should be assessed at diagnosis and upon significant worsening for ▸ Pain ▸ Function ▸ Physical activity ▸ BMI ▸ Ability to do their tasks and work 9.5 ## Soc 3 People with OA should receive a treatment plan with a shared treatment target set between them and a health professional. 9.3 SOC 4 People with OA should have access to different health professionals such as occupational therapist and physiotherapist if needed to treat their symptoms and achieve optimal possible functioning in daily life and participation in social roles (including paid work). ## 9.4 SOC 5 People with OA should achieve optimal pain control using pharmacological and non-pharmacological means. 9.7 SOC 6 People with OA should achieve optimal function using pharmacological and non-pharmacological means. 9.7 SOC 7 People with OA receiving NSAID or aspirin therapy should be assessed for GI bleeding risk, CVD risks and renal risks. 9.6 SOC 8 People with OA should receive information tailored to their needs within 3 months of diagnosis by health professionals about ▸ their disease and all aspects of living with and managing their OA, in written form and in a format suited and tailored to the individual, in a timely fashion appropriate to their needs; ▸ the benefit of exercises and physical activity and should be instructed to exercise appropriately; ▸ aids, devices and other products for environmental adaptations; ▸ ergonomic principles and activity-based methods to enhance functioning in daily life and participation in social roles; ▸ the importance of an ideal body weight; ▸ the role of analgesics-their potential benefits and risks; ▸ a healthy lifestyle (such as discontinuation of all types of tobacco use, balanced use of alcohol, physical activity, healthy diet, management of sleep disturbance if necessary); ▸ prevention of accidents and injuries; ▸ support groups and patient organisations; ▸ when to think about surgery; ▸ additional treatment options provided some people might find useful; 9.5 ## Soc 9 People with OA should receive information about weight reduction if necessary. 9.8 SOC 10 People with OA failing to respond to pharmacological and non-pharmacological therapy should be considered for surgical intervention. If referred, they should be seen by an orthopaedic surgeon within a reasonable time. # Discussion To our knowledge, this is the first study that brought together existing OA guidelines to develop an expert and patient-centred SOC for OA. We did not expect that for the large field of OA only a few European guidelines existed. The extent of the available documents also differed largely. In 1966, Donabedian proposed that healthcare quality could be measured by considering the structure, the process and the outcomes of care. [bib_ref] Evaluating the quality of medical care, Donabedian [/bib_ref] Based on that principle, there has been a trend towards developing national SOC and good practice in many different specialties across the world to raise and harmonise quality of care and enable equity of care. The number of initiatives to define and implement SOC, though increasing, is still low. The aim of this initiative was to develop accepted, consensus-based and patient-centred SOC for persons with OA, to obtain the best quality of care within the resources available, especially in the current context of economic crisis. This document is intended to help and support health professionals involved in OA care as well as patients by providing a statement of SOC requirements. It can also act as the formal record of SOC as part of the clinical governance process of any rheumatology unit and health system. In addition to pharmacological treatment, nonpharmacological methods delivered by health professionals such as physiotherapists, occupational therapists and specialists for physical medicine and rehabilitation are necessary. However, while the importance given to non-pharmacological treatment is reflected in the guidelines, high-quality evidence, except for knee OA, is scarce. This could be a result of the difficulty of conducting and funding high-quality randomised controlled trials for non-pharmacological treatments and because OA might not be seen as a high priority in funding institutions. Thus, further research in this area is urgently required to assess the evidence for these interventions. The focus of the eumusc.net project was to investigate the musculoskeletal health status in Europe (in work-package 4), to develop SOC (in work-package 5), Quality Indicators (in workpackage 6) and to identify "facilitators and barriers" for implementing the SOC (in work-package 7). [bib_ref] Facilitators to implement standards of care for rheumatoid arthritis and osteoarthritis: the..., Moe [/bib_ref] To help implementation of the SOC, they will be presented at the eumusc.net homepage with a link from the European League Against Rheumatism homepage and the national societies will be informed accordingly, asking them to convey the SOC to their members. In addition, a project is planned to bridge the gap between evidence and practice, including an audit of rheumatology centres that agree to participate. The aim of the audit is to evaluate if the SOC are implemented in the daily routine. The SOC for OA have been developed according to the process that was used for the development of the SOC for rheumatoid arthritis. [bib_ref] Development of patient-centred standards of care for rheumatoid arthritis in Europe: the..., Stoffer [/bib_ref] The aim of this initiative was to provide a set of questions that patients could use in the consultation of health professionals to facilitate the discussion of the treatment. While a strength of our study is the provision of consensus based information concerning OA worded in a way that can be easily understood by lay persons including patients, our study also has several limitations: we restricted the included guidelines to those available in English and German language only, we did not conduct an empirical testing and we did not re-evaluate the evidence base of the guidelines. Even if the interventions were retrieved from the guidelines, the wording of the SOC was a consensus within the expert group including the expertise of the patient partners. Also, we did not address OA of the spine, as back pain is different from peripheral joint OA and has a different diagnosis and therapy. It was not the scope of the project to examine the economical feasibility and the validity of the SOC. Further research is suggested to explore these areas. Finally, implementation could not yet be assessed so far. To evaluate this implementation, in another work package, Health Care Quality Indicators have been developed.The SOC should be a minimum standard for all European countries and, ideally, ought to be implemented as soon as Clinical and epidemiological research possible, but not later than by the year 2020 according to the aims of this European Union project. Furthermore, they are meant to be a resource for interested persons. The checklist presented should give persons without a professional background the ability to clarify what appropriate care is and to facilitate the discussion of the treatment options with their health professionals. With this work, we hope to promote more unification of the treatment of OA throughout Europe. In summary, in order to improve quality of care in patients with OA, service providers, support groups, policy-makers, patients and health professionals themselves should work together to develop a framework for managing OA. This framework should take account of the chronicity of this disorder and the current changing environment for the delivery of healthcare. This set of SOC will help achieve this goal. [fig] 9. 5 BMI: body mass index; CVD, cardiovascular disease; GI, gastrointestinal; NSAID, nonsteroidal anti-inflammatory drugs; OA, osteoarthritis; SOC, standards of care.Clinical and epidemiological research Literature search update The second literature search provided three additional documents 18-20 fulfilling the inclusion and exclusion criteria. The recommendations presented in the three documents retrieved in the literature update have been extracted. In the next step, all recommendations given in the guidelines have been linked to the SOC to investigate if they are up to date. This led to a change in the wording of one SOC (SOC number 4). The new wording was checked by the working group and was approved. [/fig] [table] Table 1: Standards of care for people with osteoarthritis [/table] [table] Table 2: What this means for you and your osteoarthritis… 1 Was my OA diagnosed by a health professional? 2 Do I have regular assessment concerning my symptoms and functioning in daily life? 3 Do I have a treatment target and a corresponding treatment plan? 4 Do I have the opportunity to receive support if needed from health professionals such as rheumatologist, dietician, general practitioner, nurse, occupational therapist, physiotherapist, psychologist and social worker? 5 Do I know how to control pain associated with OA? 6 Do I know how to maximise my physical function despite having OA? 7 Have I been assessed for any risks associated with my treatment? 8 Do I understand my disease and my role in its management? ▸ Have I been offered information in different formats and/or education about my disease? ▸ Have I been informed about living with and managing my OA? ▸ Have I been informed about a healthy lifestyle? ▸ Have I been informed about exercises specific for me? ▸ Have I been informed about pain relieving medication-the benefits and potential risks? ▸ Do I know what benefit I can have from my exercise program? ▸ Have I been informed and did I receive advice and training on aids, devices and ergonomic principles to enhance function in daily life and participation in social roles? 9 If my BMI is >27, have I been informed about weight reduction? 10 Have I been informed about when surgery should be considered, what it involves, its benefits and risks? BMI, body mass index; OA, osteoarthritis. [/table]	None	http://www.oarsijournal.com/article/S1063458414008668/pdf	Objective The eumusc.net project is an initiative founded by the European Community and the European League Against Rheumatism. One aim of the project was to facilitate equal standards for musculoskeletal health across Europe. The aim of this work-package was to develop patient-centred and consensus based standards of care (SOC) for osteoarthritis (OA), which should be available in a professional and a patient version. Methods A systematic review concerning guidelines dealing with OA was conducted. Furthermore, experts in musculoskeletal diseases were contacted to ensure that ‘grey’ literature was not excluded. Documents that fulfilled predefined inclusion/exclusion criteria were included and all interventions for OA were extracted and categorised. Based on this list of interventions, a three round Delphi exercise with an international and multidisciplinary expert panel, including patient research partners, was performed to achieve expert consensus. Results Six documents were included and used for further analysis. Out of them, 46 interventions have been extracted and 10 consensus based SOC were formulated. In addition, a patient version, written in a lay-understandable wording and in the format of checklist questions was developed. An example is SOC 5: “People with OA should achieve optimal pain control using pharmacological and non-pharmacological means.” The matching patient-centred checklist question reads: “Do I know how to control pain associated with OA?” Conclusions The SOC for OA will be available in the 23 languages of the European Union to enhance unified information to patients and professionals and to further harmonise the treatment/care of OA within Europe.
677a55a2777a53afe76c8cfb847597cc5454c92e	pubmed	Consensus for prevention and management of coronavirus disease 2019 (COVID-19) for neurologists	Consensus for prevention and management of coronavirus disease 2019 (COVID-19) for neurologists # Introduction The 2019-novel coronavirus (2019-nCoV) has been declared a world pandemic by WHO on 11 March 2020. [bib_ref] Covid-19: WHO declares pandemic because of "alarming levels" of spread, severity, and..., Mahase [/bib_ref] Clinical symptoms of 2019-nCoV have mostly resembled that of severe acute respiratory syndrome coronavirus (SARS-CoV) of 2003. Both shared the same receptor, angiotensin converting enzyme 2 (ACE2). 2 Therefore, this virus was named SARS-CoV-2. By 28 March 2020, a total of 593 735 SARS-CoV-2 infected cases have been confirmed in 200 countries worldwide. In addition to the respiratory system involvement, recent evidence has shown that SARS-CoV-2 can affect other organ systems including nervous, vascular, digestive, urinary, haematological and so on. The pathological findings confirmed the nature of multiorgan damaged by SARS-CoV-2, which include pulmonary lesion and cerebral oedema, microvascular steatosis and thrombosis. [bib_ref] Pathological findings of COVID-19 associated with acute respiratory distress syndrome, Xu [/bib_ref] Neurological symptoms can be trivial or non-specific at the early stage of the COVID-19 infected patients, which have often been delayed and misdiagnosed and led to inappropriate management. These patients then become silent contagious sources or 'virus spreaders'. Although neurological involvement is uncommon in patients with COVID-19, it can be seen in those with severe infection and the patients may manifest as acute cerebrovascular diseases, impaired consciousness or encephalopathy, and skeletal muscle injury. [bib_ref] Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: a retrospective..., Mao [/bib_ref] In order to help neurologists to understand the occurrence, development and outcome of this disease and be familiar with its diagnosis and treatment process, we present this 'Consensus for prevention and management of coronavirus disease 2019 (COVID-19) for neurologists'. In this consensus, we summarised the current clinical guidelines and research progress on the management of COVID-19 and emphasised on its neurological manifestations. We hope that this consensus statement can help all recognise the infection early and protect the providers and healthcare environment. ## Overview of the novel coronavirus coronaviruses (covs) CoVs are enveloped viruses with a singlestrand, positive-sense RNA genome, which are separated into four genera based on phylogeny: alpha-CoV (group 1), beta-CoV (group 2), gamma-CoV (group 3) and delta-CoV (group 4). CoVs was first isolated from domestic animals in 1937. The first human coronavirus was isolated from the nasal discharge of patients in 1965. In humans, CoVs infections primarily involve the upper respiratory and gastrointestinal tracts. Under the electronic microscope, there are many evenly arranged protrusions on the surface of viral particles. The entire virus particle resembles a 'crown' of a medieval European emperor. Hence, it was given the name of 'coronavirus'. A coronavirus particle is usually enclosed by an envelope, and its membrane surface has three proteins: spike (S), envelope (E) and membrane (M). Protein spike (S), projecting from the virus membrane and resembling a crown, is the key structure for its infectivity and pathogenicity. These spikes Open access can recognise and bind to receptors on the surface of host cells and subsequently invade the host cells. [bib_ref] Epidemiology, genetic recombination, and pathogenesis of coronaviruses, Su [/bib_ref] severe acute respiratory syndrome coronavirus 2 SARS-CoV-2, the β-type novel coronavirus, is one of the viruses that exists in the form of RNA with a total of 29 000 nucleotide bases. These bases preserve the genetic information for its reproduction. Genomic sequence analysis of SARS-CoV-2 has been published on virological. org, nextstrain. org, bioRxiv and other academic journals. In early February of 2020, Chinese researchers shared the total sequences of this new type of virus so they can be used by other researches around the world. SARS-CoV-2 virus sequence is highly homologous to that of bat coronavirus (96.2% similarity). The entire bat coronavirus genomic sequence has 79.5% homology to SARS coronavirus. [bib_ref] A pneumonia outbreak associated with a new coronavirus of probable bat origin, Zhou [/bib_ref] SARS-CoV-2 spike protein and HIV gp120 protein are both recognition proteins on the membrane surface, but their pathogenic mechanisms are quite different. The spike protein enables SARS-CoV-2 to identify ACE2 receptors in the mucosal epithelium and invade. However, the gp120 protein in HIV allows HIV to recognise the CD4 receptor and invade CD4 + T cells.There is currently no evidence indicating that SARS-CoV-2 is capable of invading T cells, any cells that express CD4 or any cells that do not express ACE2. SARS-CoV-2 does not invade cells that are not prone to infection by other known coronaviruses. So far, the reported SARS-CoV-2 sequences in Global Initiative of Sharing All Influenza Data and GenBank database have a maximum of 10 nucleotide differences from the earliest SARS-CoV-2 sequence in Wuhan 9 to the latest sequence worldwide including Europe, USA and so on, suggesting that SARS-CoV-2 entered human body recently. ## Route of transmission Although SARS-CoV-2, SARS and Middle East respiratory syndrome coronaviruses belong to the same large family of coronaviruses, their genetic characteristics are significantly different. For COVID-19, transmission through respiratory droplets and contact are the main routes of transmission. It has also been confirmed that live virus and virus nucleic acid can be detected in human stool. [bib_ref] Notes from the field: isolation of 2019-nCoV from a stool specimen of..., Yong [/bib_ref] Thus, we speculated that the digestive tract might be another transmission route. Moreover, SARS-CoV-2 can be transmitted through aerosols under a prolonged exposure in a relatively closed environment. ClInICAl ChArACTerIsTICs And mAnIfesTATIons COVID-19 is highly contagious and has a long latency period. The incubation period is generally 3-14 days, but the most extended period was reported to be 24 days. Local news in Wuhan has reported a case of asymptomatic SARS-CoV-2 infection that had a 38-day incubation period. People who have visited the epidemic area or have a contact history with patients or suspected cases should consider self-quarantine and closely monitor body temperature and related symptoms. systemic and respiratory symptoms Patients with COVID-19 often have a fever, dry cough and fatigue as the primary manifestations, and in some patients, pharyngeal pain, abdominal pain, diarrhoea and conjunctivitis are common. Therefore, if a patient has any of these symptoms, even if the symptoms are mild, testing for COVID-19 is recommended. neurological symptoms and signs Neurological symptoms have been observed in patients with COVID-19. [bib_ref] Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: a retrospective..., Mao [/bib_ref] It has been reported that more than onethird of patients experienced various neurological symptoms including the involvement of central nervous system (dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia and epilepsy), peripheral nervous system (taste impairment, smell impairment, vision impairment and neuralgia) and skeletal muscular damage. Skeletal muscle injury was defined when a patient had skeletal muscle pain and elevated serum creatine kinase level above 200 U/L. In patients with central nervous system manifestations, the most common complaints were dizziness and headache. In patients with peripheral nervous system manifestations, the most common complaints were taste and smell impairment. The nervous system manifestations were significantly more common in patients with severe infection, manifested as ischaemic stroke and cerebral haemorrhage diagnosed by clinical symptoms and head CT, impaired consciousness and skeletal muscle injury. [bib_ref] Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: a retrospective..., Mao [/bib_ref] Rapid clinical deterioration or worsening could be from a neurological event such as stroke, which may have contributed to its high mortality rate. The main reason of clinical worsening is the hyperactivation of inflammatory factors that eventually causes a fatal inflammatory storm as the disease progresses. In addition, coagulation system is damaged causing the D-dimer and platelet abnormalities, which increases the risk of cerebrovascular disease. During the epidemic period of COVID-19, when seeing patients with above neurological manifestations especially more develop nervous system manifestations, doctors should consider SARS-CoV-2 infection as a differential diagnosis so to avoid misdiagnosis and seize the opportunity of stopping it from infecting the others. ## Issues require special attention in laboratory inspection Most patients with COVID-19 have a low grade fever, but a few would have high temperature. It is worth noting that some patients may have difficulty breathing. In some patients, their lung CT scans may have signs of severe damage from the infection, but their temperature remain within normal limit. In these patients, feeling weak or exhaustion was their main complaint. In other patients, their temperature may drop, but their pneumonia actually progressed. Therefore, to judge the progression of the disease, lung CT is essential (figure 1). In laboratory examinations, their premorbid routine blood test may show lymphopaenia. Recently, some companies have developed a SARS-CoV-2 antibody test, and its use for clinical monitoring is being studied. These laboratory findings and parameters may serve as a biomarker bearing a value relevant to the prognostic perspective. ## Open access At present, nucleic acid testing for SARS-COV-2 is still the essential criterion and gold standard for confirming the diagnosis. However, its sensitivity is low and repeated tests may often be needed. Therefore, the current consensus is that a COVID-19 infected individual may present asymptomatically or symptomatically with or without abnormal laboratory findings and lung changes on CT and an unrevealing nucleic acid test. . During this period, increased inflammatory response and blood coagulation abnormalities could be the main causes of clinical worsening. These patients are more likely to convert into critical stage. Someone has tried to use the immune modulation treatment, including small doses of methylprednisolone, gamma globulin, haemodialysis and anticoagulation, and found that was effective. ## A few weeks later and if the infection is still progress- ing, the treatment of these critically ill patients would become difficult and the mortality rate becomes high. ## Possible causes of neurological symptoms and precautions for neurologists Symptoms related to the development of acute cerebrovascular diseases Among patients with SARS-CoV-2 infection, middle-aged and elderly people accounted for the majority of strokes, especially in critically ill patients. Serum D-dimer level is generally increased, which could be the source of embolic vascular events. Many of these patients may already have other cerebrovascular risk factors, such as hypertension, diabetes mellitus, hyperlipidaemia, smoking or previous stroke history. Some may develop their firstever acute ischaemic stroke. [bib_ref] Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: a retrospective..., Mao [/bib_ref] Therefore, medical staff should pay close attention to the manifestation of neurological symptoms. If an acute ischaemic stroke patient with suspected or confirmed diagnosis of COVID-19 are admitted, emergency treatment should be jointly offered by neurologists and infectious disease specialists. For ischaemic stroke patients with a high D-dimer level, preventive anticoagulation is recommended. These Open access patients should be transferred to the isolation ward, and neurologists would assist in the management. Since SARS-CoV-2 specifically binds to ACE2 receptors, 2 patients with hypertension may encounter blood pressure fluctuations following SARS-CoV-2 infection, which may increase the risk of intracranial haemorrhage. Furthermore, some critically ill patients with SARS-CoV-2 infection have severe thrombocytopaenia, another highrisk factor for cerebral haemorrhage. For hypertensive patients with SARS-CoV-2 infection, it is recommended to stop using ACE inhibitors or angiotensin ΙΙ receptor blockers (ARBs) as antihypertensive drugs, and consider calcium channel blockers, diuretics and other classes of antihypertensive drugs. ## Symptoms related to intracranial infection Based on the previous discovery, coronavirus may invade the central nervous system. Researchers have detected SARS coronavirus nucleic acid in patients' cerebrospinal fluid, and SARS coronavirus was also verified in brain tissue on autopsy. For this SARS-CoV-2 outbreak, some patients have had symptoms similar to those with intracranial infections such as headache, seizure and disturbance of consciousness. Few patients had central nervous system symptoms before having pulmonary symptoms. [bib_ref] Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: a retrospective..., Mao [/bib_ref] Therefore, neurologists should be vigilant when seeing COVID-19 infected patients and look for any signs suspicious for intracranial infection, and if possible, MRI of head with and without contrast should be performed. A lumbar puncture to look for SARS-CoV-2 nucleic acid by using PCR is recommended. For these COVID-19 patients with intracranial infection, treatment strategies such as controlling cerebral oedema, treating and preventing seizures and treating psychotic symptoms should be considered and the guidelines should be followed. Symptoms related to muscle damage Historically, SARS coronavirus was involved in the myocardial inflammation. [bib_ref] Sars-Coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS, Oudit [/bib_ref] In clinical observation, some patients with COVID-19 may experience symptoms of skeletal muscle damage, such as fatigue or limb aches, and mild elevation of serum creatine kinase level. [bib_ref] Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: a retrospective..., Mao [/bib_ref] They are due to inflammatory reaction caused by the SARS-CoV-2 infection or direct muscle damage by the virus. For patients with muscle damage symptoms, screening for SARS-CoV-2 infection is recommended. In addition to active treatment of COVID-19, strengthening nutritional support is recommended. ## Precautions for neurologists In this outbreak, patients with COVID-19 can begin with neurological symptoms or develop neurological complications during the treatment. Neurologists may see these patients in the clinic, emergency room and in-patient ward. According to the 'Technical guidelines for prevention and control of new coronavirus infection in medical institutions (First Edition)'developed by General Office of the National Health Commission of the People's Republic of China and clinical characteristics of these patients, we propose the following precautions for neurologists, especially for those who are working in high-risk areas. Cautions in neurology clinic 1. Neurologists need to wear disposable work caps, medical protective masks, work clothes such as scrubs, disposable latex gloves and carry hand sanitiser that contains ethanol, hydrogen peroxide or sodium hypochlorite. 2. Patients and their companions must have temperature measured in triage routinely before entering the consulting room. To reduce cross-infection, companions should avoid entering the room. Everyone must wear disposable medical masks. 3. For patients with neurological symptoms but also highly suspicious of COVID-19, it is recommended that the patient go to a fever clinic first and consult a neurologist later. 4. After work, doctors should remove the protective gear step by step according to the decontamination protocol. It is forbidden to leave the contaminated area wearing personal protective equipment for the purpose of preventing cross-infections. Management in neurological emergency and staffing acute stroke green pathway1. The protection level in the emergency room and stroke green pathway should be at least at level 2: wearing working clothes and caps, medical protective masks, goggles/face shields and disposable isolation gown. When treating suspected or confirmed cases of COVID-19 or patients with close contact history, the protection level should be appropriately raised: wearing medical protective masks, goggles/face shields, disposable medical protective clothing, disposable latex gloves and long shoe covers. 2. Neurological emergency and stroke green pathway (including consultation rooms, CT/MRI rooms, interventional operating rooms and so on) should be strictly separated from routine emergency and fever clinics to ensure no direct interaction with a patient with fever. 3. Doctors should ask patients and their companions whether they have typical symptoms of COVID-19, such as fever, sore throat and so on, within 14 days of exposure or a contact history with suspected or confirmed cases. Patients should have a chest CT at the same time of having a head CT. In any suspected conditions, a specialised medical staff should accompany the patient to the fever clinic and carry out stroke triage/emergency treatment in the fever clinic. The patient should be admitted to an isolation ward after treatment. Patients without suspected situations can be admitted to a buffer ward to receive the next treatment and do further screening for COVID-19 at the same time. A neurologist should round on these patients regularly. Patients will be transferred to the general ward of neurology only when COVID-19 has been definitely ruled out. 4. Patients who receive thrombolysis or thrombectomy should avoid entering the neurological intensive care unit and should be treated in a private room first. Medical staff should pay close attention to those in isolation. If the body temperature (monitoring at least for 3 days), blood routine, chest CT and SARS-CoV-2 nucleic acid tests are negative, the patient can be transferred to a semiprivate or multiperson ward. 5. Medical staff treating neurological emergency and responsible for acute stroke green pathway must have a good work/life balance, avoid long working hours and sleep deprivation. Appropriate exercises and nutritional support are also very important to fend off infections. Management in neurology wards 1. During the epidemic period or working in areas with high risk of COVID-19, medical staff in general wards should wear disposable work caps, medical protective masks and work clothes. It is recommended that to assess and treat those with severe infection in an intensive care unit (ICU), a team of two should be organised to enter the areas and depart together. Forming such partnership can help healthcare providers to look out for and assist each other. In case one healthcare provider feels ill, which make him unable to continue to work in the ICU, the other one can help evaluate and evacuate. 2. Only one family companion is permitted for each patient, and the companion must have had the same screening tests to exclude COVID-19 before entering the ward. A guard at the entrance of the ward is needed to take the temperature of anyone entering the ward. All people in the ward must wear disposable medical masks to avoid cross infection. [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, Huang [/bib_ref]. Everyone in the ward should monitor body temperature regularly. Patients and their companions should have COVID-19 screening test every few days until discharge. Once a person with fever has been identified, medical staff should notify the prevention and control team of the hospital immediately, then assist the treatment, examination, isolation and disinfection of wards. 4. If a highly suspected case has been identified during the monitoring, doctors should notify the prevention and control team and arrange for an in-hospital COVID-19 specialist consultation immediately. Other patients, their companions and medical staff who came in contact with should be separated. The temperature and COVID-19 related symptoms of all contacts should be closely monitored. The patient should be temporarily taken to a separate room and then quickly transferred to the isolation ward or a designated hospital once the diagnosis has been confirmed. The space where the patient stayed must be disinfected strictly. # Conclusion COVID-19 is a highly contagious disease that has become a worldwide pandemic. Patients infected may show neurological symptoms first. Healthcare providers and neurologists should pay close attention to these symptoms and have a high index of suspicion when evaluating patients in an endemic area. Early recognition may help initiate treatment and isolation early so to prevent clinical worsening and spreading of virus. [fig] Figure 1: Pulmonary progress on axial chest CT. (A) During the first few days, a single lesion; (B) during the first week, multiple lesions; (C) during the first and second week, nearly 50% involvement of bilateral lungs; (D) after the second week, diffuse lesion of bilateral lungs. Arrows indicate the infected area. [/fig] [fig] Figure 2: Brain CT and chest CT images from a critically ill patient with COVID-19. (A) Brain CT showing cerebral infarction. Arrows indicate the infarction area. (B) Diffuse lesion of bilateral lungs from the same patient. [/fig]	None	https://svn.bmj.com/content/svnbmj/5/2/146.full.pdf	Coronavirus disease 2019 (COVID‐19) has become a pandemic disease globally. Although COVID-19 directly invades lungs, it also involves the nervous system. Therefore, patients with nervous system involvement as the presenting symptoms in the early stage of infection may easily be misdiagnosed and their treatment delayed. They become silent contagious sources or ‘virus spreaders’. In order to help neurologists to better understand the occurrence, development and prognosis, we have developed this consensus of prevention and management of COVID‐19. It can also assist other healthcare providers to be familiar with and recognise COVID-19 in their evaluation of patients in the clinic and hospital environment.
d5fa61b22afb2ab09ed2c0e6eeb9a64a63577749	pubmed	Gastro-oesophageal reflux disease in children: NICE guidance	Gastro-oesophageal reflux disease in children: NICE guidance ## Diagnosing and investigating gastro-oesophageal reflux disease - Recognise regurgitation of feeds as a common and normal occurrence in infants and that it: -Is caused by gastro-oesophageal reflux-a normal physiological process in infancy (the box outlines the definitions of gastro-oesophageal reflux and GORD used in this guideline) -Does not usually need any investigation or treatment -Is managed by advising and reassuring parents and carers. [Based on high, moderate, and low quality evidence from observational studies and on the experience and opinion of the Guideline Development Group .] - Be aware that in a small proportion of infants, gastro-oesophageal reflux may be associated with signs of distress or may lead to certain recognised complications that need clinical management. This is known as gastro-oesophageal reflux disease. [Based on the experience and opinion of the - Give advice about gastro-oesophageal reflux, and reassure parents and carers that in well infants effortless regurgitation of feeds: -Is common (affects at least 40% of infants) -Usually begins before the infant is 8 weeks old -May be frequent (5% of those affected have six or more episodes a day) The bottom line - Frequent, effortless regurgitation of feeds is common during early infancy. Although worrying for parents, it usually resolves by the age of 1 year and usually does not need investigation or specific treatment. Effective management requires detailed, repeated, and confident reassurance - For infants and children who present with regurgitation or vomiting, actively look out for "red flags" (such as projectile vomiting, bile stained vomiting, haematemesis, blood in stool, abdominal distension, or systemic features) that may suggest more serious conditions - Consider simple cheap interventions, such as minor feed modifications or thickening agents, when possible and avoid acid suppressing drugs in isolated overt regurgitation - Do not use upper gastrointestinal contrast radiology to diagnose or assess the severity of gastro-oesophageal reflux disease. This test is indicated for other reasons such as dysphagia or unexplained bile stained vomiting ## Definitions used in the guideline Gastro-oesophageal reflux: The passage of gastric contents into the oesophagus. It is a common physiological event that can happen at all ages from infancy to old age and is often asymptomatic. It is more common after feeds or meals. In many infants it is associated with a tendency to "overt regurgitation"-the visible regurgitation of feeds. Gastro-oesophageal reflux disease: Gastro-oesophageal reflux that causes symptoms (for example, discomfort or pain) severe enough to merit medical treatment or that has associated complications (such as oesophagitis or pulmonary aspiration). In adults, the term is often used more narrowly, referring specifically to reflux oesophagitis. ## Marked distress: There is limited evidence, and no objective or widely accepted clinical definition, for what constitutes marked distress in infants and children who cannot adequately communicate their sensory emotions. In this guideline, marked distress refers to an outward demonstration of pain or unhappiness outside of that considered to be the normal range by an appropriately trained competent healthcare professional on the basis of a thorough assessment. This assessment should include a careful analysis of the description offered by the parents or carers of the individual child. [Based on high, moderate, and low quality evidence from observational studies.] - When reassuring parents and carers about regurgitation, advise them that they should return for review if any of the following occur: -Regurgitation becomes persistently projectile -There is bile stained (green or yellow-green) vomiting or haematemesis (blood in vomit) -There are new concerns, such as signs of marked distress (box), feeding difficulties, or faltering growth -There is persistent frequent regurgitation beyond the first year of life. [Based on moderate and low quality evidence from observational studies and on the experience and opinion of the GDG.] - In infants, children, and young people with vomiting or regurgitation, look out for "red flag" symptoms (table⇓) that may suggest disorders other than gastro-oesophageal reflux. - Arrange an urgent specialist hospital assessment to take place on the same day for infants younger than 2 months with progressively worsening or forceful vomiting of feeds to assess them for possible hypertrophic pyloric stenosis. [Based on the experience and opinion of the GDG.] - For recommendations relating to the indications for endoscopy and oesophageal pH study or impedance monitoring, see the further information box. - Investigate the possibility of a urinary tract infection in infants with regurgitation if there is: -Faltering growth -Late onset of regurgitation (after age 8 weeks) -Frequent regurgitation and marked distress. [Based on the experience and opinion of the Initial management of gastro-oesophageal reflux and GORD - For further recommendations on enteral tube feeding and surgery see the further information box. ## Overcoming barriers It can be difficult to persuade families that distressing and disabling symptoms (such as frequent and severe vomiting in thriving infants) will almost certainly improve with time but can be helped by relatively minor interventions, rather than referral for unnecessary tests or the use of drugs with no confirmed effect. This guideline offers clear direction as to when and how families can be appropriately reassured and provides links to downloadable information for parents. However, for different clinical presentations or evolving symptoms, especially potentially serious red flag presentations, the guideline recommends actions that are clearly necessary by way of investigation, treatment, and referral. ## Further information on the guidance A gastro-oesophageal reflux disease (GORD) pathway that visually represents all of the recommendations is available on the National Institute for Health and Care Excellence (NICE) pathways website (http://pathways.nice.org.uk/pathways/dyspepsia-and-gastro-oesophageal-reflux-disease). NICE pathways are for health and social care professionals, public health experts, commissioners or providers of health and social care services, and members of the public. Audit and costing tools to support implementation are also available (www.nice.org.uk/guidance/NG1/resources). Parents, children, and young people can also be directed to corresponding NICE information for the public (www.nice.org.uk/guidance/NG1/informationforpublic). # Methods This guidance was developed by the National Collaborating Centre for Women's and Children's Health in accordance with NICE guideline development methods (www.nice.org.uk/guidelinesmanual). The Guideline Development Group (GDG) comprised two paediatric gastroenterologists (including the chair); a paediatrician; a neonatologist; a consultant in paediatric neurodisability; a paediatric surgeon; two general practitioners; an advanced paediatric nurse practitioner; a paediatric dietitian; a health visitor; lay members with experience of caring for such infants, children, or young people; and experts in guideline methodology. There was also a pharmacist as an "invited expert." The GDG identified relevant clinical questions, collected and appraised clinical evidence, and where possible evaluated the cost effectiveness of proposed interventions. The draft guideline underwent a public consultation and a validation process in which stakeholder organisations were invited to comment; all comments were considered when producing the final version of the guideline. NICE has produced four different versions of the guideline: a full version containing all the evidence, the process undertaken to develop the recommendations, and all the recommendations; a version containing a list of all the recommendations, known as the "NICE guideline"; a version for patients and the public (www.nice.org. uk/guidance/NG1/informationforpublic); and a web version of the care pathway (the "NICE pathway"). All these versions are available from the NICE website (www. nice.org.uk/guidance/NG1). Implementation tools will also be available from the NICE website. The guideline will be reviewed for update in two years' time as part of the NICE guideline development programme. # Future research A prospective cohort study to evaluate the diagnostic accuracy of symptoms associated with GORD in infants, children, and young people with complex severe neurodisability to detect GORD (diagnosed as reflux oesophagitis identified by endoscopy and oesophageal pH monitoring). A randomised controlled trial in formula fed infants with suspected GORD that compares the effects of an extensively hydrolysed formula feed versus a placebo milk substitute on clinical symptoms and the results of objective measurements (endoscopy and oesophageal pH monitoring). A prospective evaluation of objective symptom profiles, oesophageal pH monitoring, and upper gastrointestinal endoscopy before and after fundoplication surgery in children with GORD. ## Further recommendations Gastrointestinal contrast study [Based on high, moderate, and low quality evidence from observational studies and on the experience and opinion of the GDG.] - Consider performing an oesophageal pH study without impedance monitoring in infants, children, and young people if, using clinical judgment, this is thought necessary to ensure effective acid suppression. [Based on the experience and opinion of the Enteral tube feeding for GORD - Consider enteral tube feeding to promote weight gain in infants and children with overt regurgitation and faltering growth only if: -Other explanations for poor weight gain have been explored or -Recommended feeding and medical management of overt regurgitation is unsuccessful. - Before starting enteral tube feeding for infants and children with faltering growth associated with overt regurgitation, agree in advance: -A specific individualised nutrition plan -A strategy to reduce enteral tube feeding as soon as possible -An exit strategy, if appropriate, to stop enteral tube feeding as soon as possible. [Based on the experience and opinion of the GDG.] - In infants and children receiving enteral tube feeding for faltering growth associated with overt regurgitation: -Provide oral stimulation, continuing oral feeding as tolerated -Follow the nutrition plan, ensuring that the intended target weight is achieved and that appropriate weight gain is sustained -Reduce and stop enteral tube feeding as soon as possible. [Based on the experience and opinion of the GDG.] - Consider jejunal feeding for infants, children, and young people: -Who need enteral tube feeding but who cannot tolerate intragastric feeds because of regurgitation or -If reflux related pulmonary aspiration is a concern. [Based on the experience and opinion of the Investigations before surgery Haematemesis (blood in vomit) with the exception of obviously swallowed blood (for example, after a nose bleed or ingested blood from a cracked nipple in breastfed infants) Urine microbiology investigation 2 Late onset suggests a cause other than reflux, such as a urinary tract infection (also see National Institute for Health and Care Excellence (NICE) clinical guideline on urinary tract infection in children 2 ). Persistence suggests an alternative diagnosis Onset of regurgitation or vomiting (or both) after age 6 months or persisting after age 1 year Stool microbiological investigation and specialist referral 3 May suggest a variety of conditions, including bacterial gastroenteritis, infant cows' milk protein allergy (also see NICE clinical guideline on food allergy in children and young people 3 ), or an acute surgical condition ## Suggested action* possible diagnostic implication symptom or sign Specialist referral May suggest raised intracranial pressure-for example, owing to hydrocephalus or a brain tumour Rapidly increasing head circumference (more than 1 cm/week); persistent morning headache and vomiting worse in the morning Specialist referral 5 May suggest raised intracranial pressure-for example, owing to meningitis (also see NICE clinical guideline on bacterial meningitis and meningococcal septicaemia 5 ) Altered responsiveness-for example, lethargy or irritability Trial of cows' milk exclusion and specialist referral 3 May suggest cows' milk protein allergy (also see NICE clinical guideline on food allergy in children and young people 3 ) Infants and children with, or at high risk of, atopy Specialist refers to a paediatrician with the skills, experience, and competency necessary to deal with the particular clinical concern that has been identified by the referring healthcare professional, usually a consultant general paediatrician. Depending on the clinical circumstances, specialist may also refer to a paediatric surgeon, paediatric gastroenterologist, or a doctor with the equivalent skills and competency. For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe [fig] •: Do not offer an upper gastrointestinal contrast study to diagnose or assess the severity of GORD in infants, children, and young people. [Based on the experience and opinion of theGDG.] Perform an urgent (same day) upper gastrointestinal contrast study for infants with unexplained bile stained vomiting. Explain to the parents and carers that this is needed to rule out serious disorders such as intestinal obstruction caused by midgut volvulus.[Based on the experience and opinion of the GDG.] Consider an upper gastrointestinal contrast study for children and young people with a history of bile stained vomiting, particularly if it is persistent or recurrent. [Based on the experience and opinion of the GDG.] Offer an upper gastrointestinal contrast study for children and young people with a history of GORD who present with dysphagia. [Based on the experience and opinion of the GDG.] Endoscopy and oesophageal pH or impedance monitoring Refer infants, children, and young people to a specialist for a possible upper gastrointestinal endoscopy with biopsies if there is: -Haematemesis (blood stained vomit) not caused by swallowed blood (assessment to take place on the same day if clinically indicated; also see table 1) -Melaena (black, foul smelling stool) (assessment to take place on the same day if clinically indicated; also see table 1) -Dysphagia (assessment to take place on the same day if clinically indicated) -No improvement in regurgitation after age 1 year -Persistent faltering growth associated with overt regurgitation -Unexplained distress in children and young people with communication difficulties -Retrosternal, epigastric, or upper abdominal pain that needs ongoing medical treatment or is refractory to medical treatment -Feeding aversion and a history of regurgitation -Unexplained iron deficiency anaemia -A referral for fundoplication -Back arching or features of Sandifer's syndrome.[Based on high, moderate, and low quality evidence from observational studies and on the experience and opinion of the GDG.] Consider performing an oesophageal pH study (or combined oesophageal pH and impedance monitoring if available) in infants, children, possible need for fundoplication (see second point under "Investigations for surgery") -A suspected diagnosis of Sandifer's syndrome. [/fig] [table] Table Table 1\|: "Red flag" symptoms suggesting conditions other than gastro-oesophageal reflux in infants and children Suggested action Possible diagnostic implication Symptom or sign Gastrointestinal Paediatric surgery referral May suggest hypertrophic pyloric stenosis in infants up to 2 months old Frequent, forceful (projectile) vomiting Paediatric surgery referral May suggest intestinal obstruction Bile stained (green or yellow-green) vomit Specialist referral for investigation May suggest an important and potentially serious bleed from the oesophagus, stomach, or upper gut [/table]	None	None	#### The bottom line Gastro-oesophageal reflux is a normal physiological event, whereas gastro-oesophageal reflux disease (GORD) occurs when this process causes symptoms severe enough to merit medical treatment or when there are associated complications. In infants and children it is particularly difficult to differentiate between the two conditions because of the wide variety of potential symptoms and the lack of a simple, reliable, and widely available diagnostic test. The true burden of the problem is therefore difficult to quantify, and it is accepted that clinical practice varies greatly. Children affected by the disease include premature and term neonates, otherwise well infants and children, and those with known risk factors, such as repaired diaphragmatic hernia and other congenital anomalies or severe neurodisabilities. This last group of children may have complex comorbidities and the underlying pathophysiology may have important differences. This article summarises the most recent guidance from the National Institute for Health and Care Excellence (NICE) on how to recognise, diagnose, and manage gastro-oesophageal reflux disease in infants, children, and young people. …
789026239664246ef8f62fae10af7b0903c92e79	pubmed	Clinical practice guidelines for the diagnosis and treatment of patients with soft tissue sarcoma by the Spanish group for research in sarcomas (GEIS)	Clinical practice guidelines for the diagnosis and treatment of patients with soft tissue sarcoma by the Spanish group for research in sarcomas (GEIS) # Introduction Soft tissue sarcomas (STS) constitute an uncommon and heterogeneous group of tumours of mesenchymal cell origin, with an estimated incidence averaging five cases per 100,000 per year in Europe. STS can arise anywhere in the body, but most originate in the extremities, less frequently in the trunk, retroperitoneum, head and neck and viscera. They can occur at any age, and although more common in middle aged and older adults, they are also seen in children and young adults. Although STS comprise of more than 50 different histopathological subtypes, they share several clinicopathological features and are usually considered as a group for diagnostic and therapeutic purposes, with the exception of specific particularities of some subtypes such as rhabdomyosarcoma, gastrointestinal stromal tumour (GIST), extraskeletal osteosarcoma and Ewing sarcoma. STS require a multidisciplinary and complex therapeutic approach, involving pathologists, radiologists, surgeons, Abstract Soft tissue sarcomas (STS) constitute an uncommon and heterogeneous group of tumours, which require a complex and specialized multidisciplinary management. The diagnostic approach should include imaging studies and core needle biopsy performed prior to undertaking surgery. Wide excision is the mainstay of treatment for localized sarcoma, and associated preoperative or postoperative radiotherapy should be administered in high-risk patients. Adjuvant chemotherapy was associated with a modest improvement in survival in a meta-analysis and constitutes a standard option in selected patients with high-risk STS. In metastatic patients, surgery must be evaluated in selected cases. In the rest of patients, chemotherapy and, in some subtypes, targeted therapy often used in a sequential strategy constitutes the treatment of election. Despite important advances in the understanding of and radiation and medical oncologists, and should preferably be done in specialist centres. In the recent years, there have been important advances in the understanding of the pathology and molecular biology of this disease. However, the advances in therapeutic results have been quite moderate. Moreover, due mainly to the rarity and complexity of the disease, the results in clinical practice are not always optimal. For this reason, the Spanish Group for Research on Sarcoma (GEIS) has updated its multidisciplinary clinical practice guidelines, with the aim of facilitating the diagnosis and treatment of these patients [bib_ref] Guía de Práctica Clínica en los Sarcomas de Partes Blandas, García Del Muro [/bib_ref]. These guidelines have been developed by a multidisciplinary group of specialists in the different fields involved in sarcoma diagnosis and therapy. A bibliographic search of published articles was performed in the MEDLINE database (PubMed) and the Cochrane Library. Searches were limited to human studies, clinical trials, meta-analyses, clinical guidelines and consensus statements. Additionally, a review of abstracts of relevant, still to be published, phase III studies focused on STS therapy presented at relevant international oncology meetings like the American Society of Clinical Oncology (ASCO) meeting and European Society of Medical Oncology (ESMO) meeting, in the recent years, was performed. In a face-toface consensus meeting, the different sections, written by different responsible experts, were presented to the entire group. The members then discussed the results and determined the level of evidence and the grade for each recommendation according to the ASCO guidelines [bib_ref] American society of clinical oncology guideline on the role of bisphosphonates in..., Hillner [/bib_ref]. The main objective of this document consists of providing clear practical recommendations about the different aspects involved in the management of this group of diseases, intended to help in the therapeutic decision-making processes and therefore contribute to improve STS patient's care in Spain. ## Warning signs and indications for referral to specialist sarcoma centres The symptoms of presentation of benign and malignant soft tissue tumours can frequently overlap, but there are clinical warning signs that may help to distinguish between both situations: tumour size >5 cm and recent increase in tumour size and depth location or pain. In almost three out of four of cases, patients who will be diagnosed with STS have at least one of the four warning signs. However, delays of several months from the first symptom/sign until the final diagnosis are not uncommon [bib_ref] Early symptoms of bone and soft tissue sarcomas: could they be diagnosed..., George [/bib_ref]. For this reason, any programme of early reference to expert centres must take into account these warning signs and should design efficient access from primary clinical centres to sarcoma specialized ones [bib_ref] Why do patients with soft tissue sarcoma present so late?, Johnson [/bib_ref]. There is much evidence to support that early recognition and referral to a specialist center that provides a multidisciplinary diagnosis and therapeutic approach and treats a high number of cases annually, could improve outcome in patients with STS. A lot of data support that the first diagnostic approach is critical for functional results and disease control in patients with sarcoma. It is recommended that patients in which a STS is suspected should be referred to a specialized center before the biopsy is performed because complications and mistakes are more frequent in non specialized ones. The most frequent fault is the practice of excisional biopsies of deep tumours or superficial larger than 5 cm. There is a correlation between these procedures and the presence of affected surgical margins in the oncologic surgery (data from GEIS STS registry). The impact of affected surgical margins in primary surgery implies a poorer local control of the disease and also enhances the probability of amputation [bib_ref] Consequences of local recurrence of soft tissue sarcoma: 205 patients from the..., Trovik [/bib_ref]. Regarding the definition of a sarcoma referral center, the most widely accepted is a center with a multidisciplinary specialist team who holds regular committee sessions, which is composed of surgeons, pathologists, radiologists, radiation and medical oncologists with wide experience in STS management [bib_ref] Conformity to clinical practice guidelines, multidisciplinary management and outcome of treatment for..., Ray-Coquard [/bib_ref]. However, there are no reliable data indicating the minimum number of cases per year that should be treated in a hospital to be considered as a reference center [bib_ref] Conformity to clinical practice guidelines, multidisciplinary management and outcome of treatment for..., Ray-Coquard [/bib_ref]. Several studies suggest better results in terms of local control, morbidity, and probably even in survival when patients are treated in specialized centres [bib_ref] Conformity to clinical practice guidelines, multidisciplinary management and outcome of treatment for..., Ray-Coquard [/bib_ref] [bib_ref] Monitoring referral and treatment in soft tissue sarcoma: study based on 1,851..., Bauer [/bib_ref] [bib_ref] Should Soft Tissue Sarcomas be Treated at a Specialist Centre?, Bhangu [/bib_ref]. Therefore, centralized referral should preferably be done from the time of a sarcoma is suspected (III, B). ## Diagnostic approach to sts: imaging and pathology ## Local staging Magnetic resonance imaging (MRI) is the modality of choice in the diagnosis and local staging of soft tissue sarcomas. MRI should be performed with intravenous contrast administration, and it is mandatory to obtain images in at least two planes. When MRI is contraindicated, contrastenhanced multislice computed tomography (CT) should be performed, preferably with sagittal and coronal reconstructions. CT can also be appropriate as a modality of choice in retroperitoneal soft tissue sarcomas. MRI signs that suggest the diagnosis of sarcoma in a soft tissue mass includes: location deep to the fascia, size larger than 5 cm, and heterogeneity of signal intensity and contrast enhancement [bib_ref] Magnetic resonance imaging of malignant soft tissue neoplasms in the adult, Walker [/bib_ref]. As there is some overlap in the MRI characteristics between soft tissue sarcomas and some benign soft tissue tumours, it is important to keep in mind that any lesion that cannot be unequivocally characterized by MRI as benign should be considered indeterminate, and requires biopsy. In a patient presenting a soft tissue mass suggestive of sarcoma, the MRI report should provide the following information of the tumour: - Size. - Location (superficial or deep; compartment or extracompartmental). - Anatomical limits. - Relationship with neurovascular structures. - Extension of perilesional oedema. - Pattern of contrast enhancement. - Suggestions of areas for biopsy. The extent of perilesional oedema detected on MRI is important for treatment planning because the presence of viable tumour cells in this area has been demonstrated [bib_ref] Histologic assessment of peritumoural edema in soft tissue sarcoma, White [/bib_ref]. Local tumour staging should be performed prior to the biopsy to prevent bleeding and inflammatory changes caused by the biopsy that can distort the characteristics and extent of the tumour on MRI. It is recommended to obtain radiographs of the affected region to assess the existence of possible calcification within soft tissue tumour, evaluate possible bone erosion and exclude a bone tumour. ## Distant staging Chest radiographs (frontal and lateral) and multislice chest CT are indicated in all cases of STS to rule out pulmonary metastases. Abdominal CT is indicated in the cases of myxoid liposarcoma of the extremities, given the high frequency of synchronous distant lesions in this histological subtype. The clinical benefit of performing an abdominal CT scan in cases of epithelioid sarcoma, synovial sarcoma, angiosarcoma and leiomyosarcoma should be assessed individually in each case. MRI study of the spine may be necessary in cases of myxoid liposarcoma due to its tendency to develop extrapulmonary metastases, and the limitations of bone scan or even positron emission tomography (PET) in the detection of spinal metastases in this histological subtype [bib_ref] Unusual skeletal metastases from myxoid liposarcoma only detectable by MR imaging, Ishii [/bib_ref]. PET usefulness is limited to the detection of malignant transformation of neurofibromas in patients with neurofibromatosis type 1 [bib_ref] Evaluation of intratumoural heterogeneity on 18F-FDG PET/CT for characterization of peripheral nerve..., Salamon [/bib_ref] , and in distant staging for cases of local recurrence of STS in which aggressive salvage surgery is considered. ## Biopsy Percutaneous core needle biopsy (CNB), also known as "tru-cut biopsy", is currently recommended for STS diagnosis [bib_ref] The role of core needle biopsy in the diagnosis of suspected soft..., Strauss [/bib_ref] , because it is minimally invasive and will not limit subsequent surgical interventions. Its accuracy is similar to that of the incisional biopsy, with the added benefit that it does not require hospitalization. In the largest series of patients, CNB had a sensitivity of 99.4 % and a specificity of 98.7 % in the diagnosis of malignancy (sarcoma versus benign mesenchymal tumour) [bib_ref] The role of core needle biopsy in the diagnosis of suspected soft..., Strauss [/bib_ref]. These percentages are very similar to those achieved with the incisional biopsy. In the same way, CNB may properly identify histological subtype and grade in 80 % of the cases [bib_ref] The role of core needle biopsy in the diagnosis of suspected soft..., Strauss [/bib_ref]. It is recommended to perform the biopsy in the same hospital where the patient is treated, either by radiologists or surgeons trained in the practice of these procedures. Close cooperation with the pathologist is mandatory. The use of radiological techniques to guide the CNB, mainly ultrasound and CT, has substantially improved diagnostic procedures. Image guidance allows more precise tumour location and helps to guide the biopsy to those areas of viable tumour. In selecting the areas for biopsy, it is essential to avoid cystic, necrotic or hemorrhagic tumour areas. Imaging studies should also be carefully evaluated to identify more aggressive areas (which usually show a higher degree of contrast enhancement) in order to define the tumour grade more accurately. The most commonly used CNB are between 14 and 18 G. In a recent review, the accuracy of this type of biopsy was not influenced by the gauge of the needle used [bib_ref] Bone and soft-tissue lesions: what factors affect diagnostic yield of image-guided core-needle..., Wu [/bib_ref]. In contrast, the number of biopsy passes (equal or above 4) and the length of the biopsy specimen obtained are factors that increase the diagnostic yield of CNB [bib_ref] Bone and soft-tissue lesions: what factors affect diagnostic yield of image-guided core-needle..., Wu [/bib_ref]. When planning a percutaneous biopsy, it is mandatory to avoid non-involved anatomical compartments, and it should be noted that the path of the biopsy and the scar should be resected by definite surgery. Hemostatic problems also must be corrected prior to the biopsy, due to the risk of tissue contamination caused by post-biopsy hematomas. STS are heterogeneous tumours, and a small sample obtained by this type of biopsy may underestimate the histological grade. Thus, unless a high degree appears in the percutaneous biopsy, definitive histological grade will be established in the surgical specimen. Due to the limitation on the size of the sample obtained by percutaneous biopsy, sometimes it is not possible to establish with certainty the histological diagnosis. In these situations, it may be necessary to perform incisional biopsy (III, B). ## Pathology and molecular pathology Appropriate clinical information should be available for a correct interpretation of the initial biopsy. It is advisable in patients referred from other hospitals to ask for the biopsy material and/or surgical specimen for histological review and confirmation. In general, the core needle biopsy (trucut) is the diagnostic method of choice. Fine-needle aspiration cytology (FNA) is not recommended as the initial diagnostic procedure except in some centres with extensive experience. FNA is, however, suitable to confirm the presence of recurrence or metastasis of a sarcoma already known, and can be useful in some cases of round cell sarcoma, since molecular techniques may be performed on tumour imprints (touch preps). Whenever possible and when it does not interfere with the diagnosis, it is recommended to freeze and preserve tumour fragments, and samples for cytogenetics (tumour imprints on slides pre-treated for immunohistochemistry), as well as liquid samples (plasma, serum) in biobanks. To avoid degradation of the tissue, the interval between biopsy and freezing should not exceed 30 min. The availability of a blood sample could add to the value of tumour tissues. Informed consent for biobanking should be obtained, enabling later analyses and research, as long as this is allowed by local and international rules. ## Pathological diagnosis of soft tissue sarcomas It is mainly based on morphology and immunohistochemistry. It must be in accordance with the 2013 World Health Organisation sarcoma classification. This integrates morphological and immunohistochemical data, together with molecular cytogenetics. The histological tumour grade should be determined when possible; we recommend the system of the Fédération Nationale des Centres de Lutte Contre le Cance (FNCLCC), which is based on the evaluation of three histological parameters (tumour differentiation, mitotic index and percentage of necrosis), and defines three histological grades. In some sarcomas, histological type itself determines the aggressiveness of the tumour, and the histological grade does not provide additional prognostic information. Immunohistochemical study is useful to determine the type of tumour differentiation (muscle, neural, etc.), and, in turn, to rule out non-mesenchymal tumour types (carcinoma, melanoma, lymphoma…); but it does not provide information about the classification of the tumour as benign or malignant. ## Indication of molecular studies Use of molecular techniques is not necessary for the diagnosis of all cases of sarcomas. Molecular studies should be performed especially when: - specific histological diagnosis is doubtful - clinicopathologic presentation is unusual - it may have prognostic/predictive relevance. In the case of STS, the aim of the molecular study is to detect the presence of chromosomal translocations and gene fusions/gene rearrangements by the reverse-transcriptase polymerase chain reaction (RT-PCR) or fluorescence in situ hybridization (FISH). ## Pathology report Regarding the tru-cut (core needle) biopsy, in most cases it allows classification of the tumour (histology) and provides the degree of malignancy. The pathology report of a tru-cut biopsy should include histological type (when not possible it may be useful to try to classify in the categories of spindle cell, pleomorphic, myxoid, epithelioid or round cell), histological grade and the results of any additional tests that have been made (immunohistochemistry and/or molecular biology) [bib_ref] Protocol for the examination of specimens from patients with tumours of soft..., Rubin [/bib_ref]. One limitation of the core biopsy is that it can miss a small high-grade region in a heterogeneous tumour. Therefore, when preoperative treatment is an option, radiological imaging may be useful in addition to pathology, in providing the clinician with information that helps to estimate the tumour grade (i.e. necrosis). The pathology report of a resected specimen of sarcoma should include, in addition to the histological type and tumour grade, tumour description (size, location, percentage of necrosis and hemorrhage and relationship to adjacent structures), status of resection margins, satellite nodules and lymph nodes. An appropriate sampling of the tumour should be made; it is generally recommended to select a section for each centimetre of tumour diameter. In very large tumours, 10-12 blocks can be enough. The sections on the margins should be at right angles. The report should also include the result of the immunohistochemical and molecular studies, if performed. ## Treatment of localized disease surgery Surgery is the mainstay of treatment in localized STS. Although they are a heterogeneous group of neoplasms, the main principles of surgery are common to them all. Surgical treatment should be performed by expert surgeons and should be based on consensus decisions taken on a multidisciplinary board. Wide excision of the tumour is the base of surgical treatment of STS, which implies en bloc resection of all the neoplasm, the neocapsule (or reactive peritumoural tissue) and a variable layer of surrounding healthy tissue, called surgical margin. It is not possible to define the standard surgical margin, because it depends on several factors: tumour size, tumour location (intra or extracompartmental), the anatomical compartment implied, histological grade, proximity to neurovascular structures and the previous treatments performed. Depending of the characteristics of surgical margin, surgery can be classified into: - Intralesional only accepted as a diagnostic biopsy (incisional biopsy). - Marginal includes peritumoural reactive tissue, but not healthy tissue margins. - Wide includes an appropriate margin of healthy tissue free of tumour. However, the presence of the fascia, perineurium, periosteum and vascular adventitia free of tumour are considered as adequate margins. - Radical includes all the anatomical compartment in which STS has grown. - Contaminated a surgical procedure of STS should be considered contaminated if sarcomatous tissue remains exposed during surgery. In these cases, local spread of malignancy could occur. In bloc surgery with wide or radical margin is the right treatment, but marginal surgery could also be accepted in some cases of low-grade STS with extracompartmental location (for example, atypical lipoma). Enneking, Spanier and Goodman have contributed to the improvement of the knowledge and efficacy of surgical procedures in STS by defining the concept of anatomical compartments as a close unit where the tumour is confined, allowing surgeons to plan the surgery better from oncological point of view [bib_ref] A system for the surgical staging of musculoskeletal sarcoma, Enneking [/bib_ref]. The following list defines compartmental and extracompartmental locations of STS [fig_ref] Table 1: Soft tissue sarcoma [/fig_ref]. Surgery of STS must be carefully planned, taking into account the results of imaging and biopsy (STS subtype and grade). Unplanned surgery is unacceptable, and it is one of the main causes of local failure. Surgical procedure can be performed through ischaemia technique, but pneumatic cuff should be far from the tumour, and sanguinea expression should be avoided. Elevation of extremity for 10 or 15 min will provide sufficient blood emptying. Regarding skin incision, it should always be performed on the direction of longitudinal axis of the member affected and should also include biopsy or aspiration cytology scar and previous drainage path. Once tumour excision is completed, the ischaemia system is removed, and two important technical aspects should be carried out: complete hemostasis (which reduces the risk of hematoma appearance and healing delays) and placement of suction drain system (following the longitudinal axis of the incision and as much closer to it as possible). Thorough washing of the tumour bed is mandatory to minimize infectious complications, mainly because these kinds of surgeries tend to be long and harmful for tissues. Inserting metal clips (titanium is preferred) before closing is recommended, in order to properly localize the surgical tumour bed. After that, closing of the defect can be performed trying to avoid empty spaces in the surgical bed, and a weak pressure bandage can also be placed to ensure a good tissue recovery. Moreover, surgical specimen has to be marked to help pathologist to identify surgical margins properly. However, if contamination of the surgical field occurs during surgery, some procedures have to be done: close the gap opened in the tumour by suture, change surgical instruments, expand surgical margins and report it because it will be taken account at the time of planning adjuvant treatments. ## Salvage surgery and amputation Adequate surgery with extremity preservation is usually possible in the vast majority of STS. However, amputation or disarticulation should be planned for the following scenarios: - When free margins cannot be ensured with conservative surgery and they are tried to be obtained with more radical surgery. - When wide infiltration of neurovascular bundles exists. - When properly functional reconstruction is not feasible or the result is, at least, the same as conservative surgery. If after STS surgery margins are not free, this initial surgery is considered suboptimal and, as a consequence and if it is possible, re-surgery should be planned in order to expand margins. Surgery for expanding margins must be more radical, and therefore, reconstruction procedures tend to be more complex [bib_ref] The role of plastic surgery in sarcoma treatment, Viñals [/bib_ref] [bib_ref] Soft-tissue sarcomas and reconstruction options: twenty-two years of experience, Papadopoulos [/bib_ref] [bib_ref] The prognostic significance of margin width for extremity and trunk sarcoma, Liu [/bib_ref]. If after an initial STS treatment a local recurrence occurs, salvage surgery can be performed. However, before planning it, it is important to properly evaluate the existence of a possible multicentric recurrence and/or metastatic disease. In general terms, recurrence surgery is more complicated and more aggressive (and the resection must include drain path drainage of previous surgery). In this situation, the percentage of amputations increases and reconstruction procedures are more often needed [bib_ref] High-grade extremity soft tissue sarcomas: factors predictive of local recurrence and its..., Eilber [/bib_ref]. ## Radiotherapy Adjuvant radiotherapy (RT) is offered in addition to conservative surgery to optimize local control. There are two prospective randomized trials, one using brachytherapy (BRT) ant the other postoperative external beam RT (EBRT), which demonstrated the local control advantage of adjuvant RT over surgery alone in sarcomas [bib_ref] Randomized prospective study of the benefit of adjuvant radiation therapy in the..., Yang [/bib_ref] [bib_ref] Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft..., Pisters [/bib_ref]. The study used EBRT, randomized 141 patients (91 with high-grade tumours, 38/91 < 5 cm, 50 with low-grade tumours, 16/50 < 5 cm) to receive or not receive postoperative RT [bib_ref] Randomized prospective study of the benefit of adjuvant radiation therapy in the..., Yang [/bib_ref]. In this prospective randomized trial, adjuvant postoperative EBRT was shown to result in a statistically significant reduction in local recurrences in patients with either high-grade or low-grade extremity tumours, without significant differences in overall survival. The conclusions of this study are pertinent only to patients who undergo a satisfactory local excision with negative or minimal microscopically positive resection margins. A second study evaluated post-operative BRT, randomizing 164 patients to BRT or no further treatment [bib_ref] Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft..., Pisters [/bib_ref]. The improvement in local control was limited to patients with high-grade lesions and was not associated with a significant reduction in distant metastasis or improvement in disease-specific survival. Post-operative and pre-operative EBRT have also been compared with each other in a randomized manner. The National Cancer Institute of Canada (NCIC) trial compared 50 Gy in 25 fractions pre-operatively and 66 Gy in 33 fractions post-operatively [bib_ref] Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised..., O'sullivan [/bib_ref]. They accrued 182 evaluable patients (31 low-grade STS, 151 high-grade STS) for which eligibility criteria was the need for combined radiotherapy and surgery, that is, if tumour could not be excised with a minimum of 2 cm of healthy tissue or an intact fascial plane. The primary endpoint was the presence or absence of a major wound complication. Of the pre-operatively irradiated patients, 35 % showed wound complications compared with 17 % in the post-operative RT group (p = .01). No difference was found between the two groups in local control, progression-free or overall survival, although the study was not powered to evaluate these end points. Interstitial BRT has been demonstrated to be an effective method of delivering adjuvant RT, within a considerably shorter treatment time than EBRT, and with potentially smaller treatment volumes [bib_ref] Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft..., Pisters [/bib_ref]. However, its relatively limited use could be attributed to lack of effectiveness in low-grade histology, and it is a complex and labour-intensive technique. Regarding some specific technical issues, preoperative RT is delivered in once-daily 1.8-to 2-Gy fractions to a total dose of 50-50.4 Gy. The entire dose is prescribed to a single planning target volume (PTV). In the case of postoperative RT, a portion of the dose is ordinarily applied to a larger volume encompassing the surgical bed with appropriately safe margins. A careful review of the surgical and pathology reports is essential to optimally define the target volume and the dose level to be administered. Commonly applied doses are Gy in once-daily 1.8-to 2-Gy fractions. This is followed by a smaller volume boost to the tumour bed. Typically, doses of 14-18 Gy are applied, resulting in a total dose of 63-66 Gy. The guidelines to construct the RT volumes are available [bib_ref] RTOG Sarcoma Radiation Oncologists Reach Consensus on Gross Tumour Volume and Clinical..., Dian [/bib_ref] [bib_ref] Radiotherapy for Management of Extremity Soft Tissue Sarcomas: Why, When, and Where?, Haas Rick [/bib_ref]. When RT can be administered with minimal toxicity, its significant contribution to local sarcoma control following limited resection is of value. When the expected toxicity of RT is high and the risk of local recurrence is predicted to be low (based on surgical margins, tumour size), surgery without adjuvant RT may be the treatment of choice. Specific recommendations are: wide excision is followed by radiation therapy as standard treatment of deep and high-grade (G2-3) STS (II, B). Radiation therapy is added in selected cases in the case of high-grade, superficial lesions or in the case of low-grade, deep, >5 cm lesions. Radiation therapy is added in selected cases in the case of low-grade, superficial, >5 cm and low-grade, deep, <5 cm lesions (II, B). Radiotherapy may be carried out pre-operatively or postoperatively (I, A). ## Adjuvant chemotherapy The use of adjuvant chemotherapy has been studied in several clinical trials because of the risk of metastasis which is close to 50 % in the group of patients with high-risk STS. These studies, however, often provide conflictive results. Variations in the chemotherapy schedules and the selection criteria used in the different studies could partially explain the disparity in the results. A recent meta-analysis included a total of 18 phase III trials comparing adjuvant chemotherapy versus observation in resected localized STS. The regimens used included doxorubicin or epirubicin, associated with ifosfamide in five trials. The results showed that chemotherapy was associated with a risk reduction in overall recurrence of 10 % and an improvement in overall survival of 6 %. Moreover, the results suggested that the association of anthracyclines and ifosfamide is associated with an improved benefit [bib_ref] A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized..., Pervaiz [/bib_ref]. A previous meta-analysis, including 14 trials, showed a greater benefit in the group of patients with extremity sarcomas. A recent trial focused on patients with highrisk STS (high-grade, deep location and >5 cm) located in the extremities and girdles. The chemotherapy schedule included high doses of epirubicin and ifosfamide. After a median follow-up of 5 years, overall survival was significantly higher for patients treated with adjuvant chemotherapy [bib_ref] Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles:..., Frustaci [/bib_ref] , although that difference decreased after a longer follow-up [bib_ref] Ifosfamide in the adjuvant therapy of soft tissue sarcomas, Frustaci [/bib_ref]. Another trial, performed by the European Organization for Research and Treatment of Cancer (EORTC) not included in the above-mentioned meta-analysis, involved patients with high-and intermediate-grade STS at any site. The adjuvant chemotherapy consisted of doxorubicin and ifosfamide versus placebo. No differences in survival between both arms were found [bib_ref] Adjuvant chemotherapy with doxorubicin and ifosfamide for resected soft tissue sarcoma (EORTC..., Woll [/bib_ref]. Nevertheless, an update of the meta-analysis including this study showed a difference in overall survival favouring adjuvant chemotherapy with a hazard ratio of 0.86 (95 % CI 0.79-0.97) [bib_ref] Adjuvant chemotherapy with doxorubicin and ifosfamide for resected soft tissue sarcoma (EORTC..., Woll [/bib_ref]. Consequently, data from meta-analysis indicate that adjuvant chemotherapy using anthracycline-based regimens provides a significant, although limited, improvement in relapse and survival in patients with high-risk STS. For this reason, it constitutes a standard option of treatment in selected patients (IA). Its administration should be only considered in those patients with high-grade, deep and >5 cm tumours, especially if they are located in the extremities (IIA). However, close observation without chemotherapy administration is also a standard option, given its limited benefit and the risk of associated toxicity (IA). The decision of whether to treat or not should be made in each individual case, after discussion with the patient of potential benefits and risks. If chemotherapy is administered, a regimen including doxorubicin and ifosfamide is recommended (IIA). For patients younger than 65 years, the Frustaci and col. regimen [bib_ref] Ifosfamide in the adjuvant therapy of soft tissue sarcomas, Frustaci [/bib_ref] is recommended (IIB). The standard recommendation consists of five cycles, but the results of a recent randomized trial of neoadjuvant chemotherapy suggest that, in a perioperative setting, a total of three cycles could be enough [bib_ref] Short, full-dose adjuvant chemotherapy in high-risk adult soft tissue sarcomas: a randomized..., Gronchi [/bib_ref] (IIB). Adjuvant therapy is particularly not recommended for the low-grade sarcomas, those <5 cm, retroperitoneal and visceral sarcomas and subtypes not sensitive to chemotherapy (IIB). In the absence of further data, the EORTC 62931 trial suggests that delaying the administration of radiotherapy until completion of adjuvant chemotherapy is not associated with a worse local control [bib_ref] Adjuvant chemotherapy with doxorubicin and ifosfamide for resected soft tissue sarcoma (EORTC..., Woll [/bib_ref] but has the potential advantage of not compromising the optimal chemotherapy administration (IIB). ## Neoadjuvant chemotherapy with or without radiotherapy and response assessment The number of studies regarding neoadjuvant chemotherapy in STS is limited, and most of them are small series and phase II trials. A randomized phase II trial compared three cycles of neoadjuvant chemotherapy with doxorubicin and ifosfamide versus surgery alone in high-risk STS. The study did not demonstrate any benefit of neoadjuvant chemotherapy in terms of survival or in relapse-free survival [bib_ref] A randomised phase II study on neo-adjuvant chemotherapy for 'high-risk' adult softtissue..., Gortzak [/bib_ref]. Recently, a randomized non-inferiority phase III study compared three cycles of pre-operative chemotherapy with epirubicin and ifosfamide versus the same regimen plus two additional adjuvant cycles of treatment after surgery. The results showed that three cycles were not inferior to five cycles in terms of recurrence and survival [bib_ref] Short, full-dose adjuvant chemotherapy in high-risk adult soft tissue sarcomas: a randomized..., Gronchi [/bib_ref]. Additionally, several non-comparative phase II trials showed the feasibility of concurrent neoadjuvant chemoradiotherapy with different regimens and provided promising results [bib_ref] Phase II study of neoadjuvant high-dose ifosfamide with concurrent radiotherapy followed by..., Del Muro [/bib_ref]. This strategy, giving the demonstrated activity of preoperative radiation [bib_ref] Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised..., O'sullivan [/bib_ref] , is being widely studied at present. Therefore, despite the current setting of shortage of evidence, some practical recommendations regarding neoadjuvant therapy in STS may be made. It could be considered as an option in those cases with large STS that are marginally resectable or require very aggressive surgery without assuring clean margins (III B). In those cases, probably the combination of pre-operative radiation and chemotherapy might have advantages over either modality alone (IVB). Additionally, potential benefits of neoadjuvant chemoradiotherapy in patients with high-risk STS could be early treatment of micrometastases, shrinking the tumour, facilitating surgery and testing in vivo tumour chemosensitivity. Nevertheless, in this population neoadjuvant chemotherapy with or without radiotherapy remains investigational. Concerning radiological and pathological response assessment to neoadjuvant therapy, some specific considerations should be addressed. MRI is the imaging modality of choice in the assessment of response in these patients. The assessments of the volume or the signal intensity of the tumour by MRI are not reliable criteria of response to neoadjuvant therapy since the tumour volume increase may be due to oedema and hemorrhage changes in cases of good response, whereas a reduction in tumour volume is usually not obtained even in cases with good response. Contrastenhanced dynamic MRI is a technique that is being actively studied in the assessment of response to neoadjuvant therapy. However, at present its use remains experimental. On the other hand, pathological response to neoadjuvant therapy could be evaluated in the resected specimen. Percentage of necrosis of 95 % at least (similar to that used in bone 1 3 sarcomas) is usually recommended, but data regarding this issue are controversial [bib_ref] Treatment-induced pathologic necrosis: a predictor of local recurrence and survival in patients..., Eilber [/bib_ref]. Nevertheless, decreased cellularity and fibrosis also should be taken into account together with necrosis. ## Role of isolated limb perfusion Hyperthermic isolated limb perfusion (ILP) is a therapeutic approach that can be planned in STS when optimal conservative surgical procedure is not feasible, either due to tumour or patient comorbidity. It allows the administration of much higher doses of chemotherapy avoiding the systemic toxicity. ILP in hyperthermia is a technique in which the circulation of the limb where STS is located is cut off from the rest of the organism through an extracorporeal circuit and treated with biocytotoxic agents. The liquid administered is at a higher temperature than the rest of the body (39 °C), intensifying its effect. The administration of tumour necrosis factor alpha (TNF-α) and melphalan has improved the responses [bib_ref] Outcome and prognostic factor analysis of 217 consecutive isolated limb perfusions with..., Grunhagen [/bib_ref] [bib_ref] Isolated limb infusion for advanced soft tissue sarcoma of the extremity, Moncrieff [/bib_ref]. Two recent reviews have analysed the results of several studies including 518 patients with STS treated with ILP. The overall response rate was 70 %, and the rate of patients in whom limb-sparing surgery was possible was also 70 %, although the number of local and systemic relapses was high. However, these reviews showed that an improved standardization of methodology in studies that evaluate ILP is needed [bib_ref] Hyperthermic isolated limb perfusion for extremity soft tissue sarcomas: systematic review of..., Trabulsi [/bib_ref] [bib_ref] Outcomes of isolated limb perfusion in the treatment of extremity soft tissue..., Bhangu [/bib_ref]. Therefore, hyperthermic ILP with TNF-α and melphalan constitutes an option. It may be considered in patients with limb STS where conservative surgery is not feasible, in order to carry out subsequent surgery preserving limb function (III, B) and patients with disseminated STS in whom local surgery is contraindicated, but local palliative control is necessary (III, B). ## Treatment of metastatic disease With current appropriate management, local control of STS is achieved in around 80-90 % of patients. However, approximately half of all patients with high-grade tumours will develop metastatic disease and most of them will die from it. ## Surgery Patients with exclusive pulmonary metastasis should be evaluated for surgery. The decision of metastasectomy should be based on disease-free period following primary surgery (ideally greater than one year) and total number of lesions (III, B). Complete resection of pulmonary metastases in the group of selected patients with these favourable prognostic features achieves up to 20 % long-term survival [bib_ref] Resection of pulmonary and extrapulmonary sarcomatous metastases is associated with long term..., Blackmon [/bib_ref] [bib_ref] Surgical resection of pulmonary metastases, Mccormack [/bib_ref] [bib_ref] Resection of pulmonary metastases from sarcoma: can some patients benefit from a..., Gossot [/bib_ref] [bib_ref] Survival after pulmonary metastasectomy in soft tissue sarcoma. Prognostic factors in 214..., Choong [/bib_ref] [bib_ref] Soft tissue sarcoma presenting with metastatic disease: outcome with primary surgical resection, Ferguson [/bib_ref]. Prior restaging should be performed to rule out local recurrence or other sites of metastases. There is no clear evidence of benefit associated with the administration of adjuvant chemotherapy after resection of metastases in STS. In contrast, in patients with synchronous lung metastases, short disease-free interval or high number of lesions, chemotherapy should be the initial treatment. Subsequent surgery if benefit is achieved from chemotherapy, however, could be an option (IV, C). ## Chemotherapy and targeted agents ## First-line treatment (doxorubicin and ifosfamide) Doxorubicin and ifosfamide are the most active drugs and, given sequentially or in combination, constitute the standard treatment for advanced STS [bib_ref] Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma:..., Van Glabbeke [/bib_ref]. The association of doxorubicin and ifosfamide increased the response rate and toxicity but did not improve survival in randomized trials [bib_ref] An intergroup phase III randomized study of doxorubicin and dacarbazine with or..., Antman [/bib_ref] [bib_ref] Randomized phase III study comparing conventional-dose doxorubicin plus ifosfamide versus high-dose doxorubicin..., Cesne [/bib_ref] (I, A). High doses of ifosfamide (>10 g/m 2 ) and doxorubicin regimens with GCSF support are also associated with increased response and toxicity but did not show improvement in survival in randomized trials [bib_ref] Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced..., Verweij [/bib_ref] [bib_ref] Efficacy of sequential high-dose doxorubicin and ifosfamide compared with standard-dose doxorubicin in..., Maurel [/bib_ref] (I, A). Therefore, the recommended first-line treatment is doxorubicin at 75 mg/m 2 . Epirubicin could also be an alternative to doxorubicin. Ifosfamide constitutes an alternative for contraindication of doxorubicin or a second-line treatment after doxorubicin failure. Ifosfamide in monotherapy is used at doses of 5-9 g/m 2 , although some data suggest that the higher doses are the most active. However, the use of a combination regime of both drugs could be justified when obtaining an objective response to improve symptoms or when performing surgery is important (III, B). Interestingly, some data suggest these could be some differences in the sensitivity to chemotherapy according to the different histological subtypes. For this reason, at present several studies are being performed on specific subtypes. ## Second-line chemotherapy and beyond Second-line therapy for advanced or metastatic unresectable disease is always palliative. Thus, close clinical observation may be an option for asymptomatic patients, especially for those with low-grade tumours or known low responsive entities. For symptomatic patients with poor performance status, radiotherapy or best supportive care alone is appropriate options. Symptomatic patients with good performance status are good candidates for clinical trials. Outside the context of clinical trials, conventional systemic therapy should be offered. Trabectedin has been broadly explored in several phase I-II trials. Although the objective response rates were modest, a higher progression arrest rate was observed, especially in liposarcoma (notably myxoid liposarcoma, 88 %) [bib_ref] Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study, Grosso [/bib_ref] , synovial sarcoma and leiomyosarcoma, but also in other tumour types. Tumour response had a particular pattern with early decrease in tumour density on CT or decrease in MRI contrast enhancement, followed by delayed tumour shrinkage. A randomized phase II trial in previously treated advanced liposarcoma or leiomyosarcoma comparing trabectedin infusion 1.5 mg/m 2 over 24 h every 21 days versus a weekly scheme over 3 h demonstrated the superiority of the 24-h infusion in terms of time to progression [bib_ref] Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma..., Demetri [/bib_ref]. Based in these studies, trabectedin was approved in Europe for patients with STS after progression to doxorubicin and ifosfamide or in patients ineligible for these treatments. The preliminary results of a recently reported phase III trial showed that trabectedin improves disease control in comparison with the classically standard second-line DTIC, in advanced pre-treated metastatic liposarcoma or leiomyosarcoma [bib_ref] A randomized phase III study of trabectedin or dacarbazine for the treatment..., Demetri [/bib_ref] (I, A). Premedication with dexametasone and administration through a central venous access device are recommended. Gemcitabine has been evaluated in several phase II trials showing limited activity (II, B). If used, a fixed dose rate infusion (10 mg/m 2 /min) is usually recommended. DTIC alone has also limited activity, with 18 % short living responses [bib_ref] High-dose DTIC in advanced soft-tissue sarcomas in the adult. A phase II..., Buesa [/bib_ref]. However, the superiority of the combination of gemcitabine (1800 mg/m 2 at 10 mg/m 2 /min) with DTIC (500 mg/m 2 ) every 14 days versus DTIC alone has been reported in a randomized phase II trial in terms of median progression-free survival (PFS) and overall survival (OS), with a favourable toxicity profile [bib_ref] Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in..., García-Del-Muro [/bib_ref]. The benefit of this combination appears to be more pronounced in leiomyosarcoma, although other subtypes may also benefit (II, B). Docetaxel in monotherapy is not active in STS, but in combination with gemcitabine has demonstrated interesting responses, especially in uterine leiomyosarcoma. A multicentric randomized phase II trial showed response rates of 16 versus 8 % and superior median PFS and median OS for the combination versus gemcitabine alone [bib_ref] Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone..., Maki [/bib_ref]. Patients with leiomyosarcoma and undifferentiated pleomorphic sarcoma appeared to be benefitted the most, but at the expense of greater toxicity. Contradictory results have been reported in another small phase II trial, particularly for non-uterine leiomyosarcomas(II, C). A randomized double-blind phase III study (the PAL-ETTE trial) [bib_ref] Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3..., Van Der Graaf [/bib_ref] comparing pazopanib (800 mg daily) versus placebo in 369 patients with non-adipocitic sarcomas progressing after first-line chemotherapy (including an anthracycline) showed a benefit in median PFS and disease stabilization favouring pazopanib (4.6 vs. 1.6 months, 67 vs. 38 %, respectively) with no significant difference in OS. All the included subtypes seemed to benefit to the same extent. Given the risk for serious hepatotoxicity, close monitoring of liver function tests is recommended, particularly in the first nine weeks of therapy (basal, week 3, 5, 7 and 9). Pazopanib constitutes an appropriate option after first line or thereafter progression in non-adipocitic sarcoma (I, A). Additionally, a dose-response relationship has been shown for ifosfamide. Therefore, patients who have previously received ifosfamide may be treated with high-dose ifosfamide (>10 g/m 2 ) [bib_ref] High-dose ifosfamide: circumvention of resistance to standard-dose ifosfamide in advanced soft tissue..., Cesne [/bib_ref]. Particular sensitivity has been reported for synovial sarcoma. Its main toxicities are hemorrhagic cystitis, renal and central nervous system toxicity. Concurrent administration of the uroprotectant mesna and appropriate hydration decreases the incidence of hemorrhagic cystitis. For the majority of STS, there is no evidence that a particular drug sequence is better than another and probably most patients with good performance status benefit from being exposed to the largest number of available drugs (IV, C). As previously stated, some tumour types are specially sensitive to certain drugs, and this fact could help to select the second-line therapy, for example: high-dose ifosfamide for synovial sarcoma, trabectedin for myxoid liposarcoma and leiomyosarcoma, gemcitabine with docetaxel or with DTIC in leiomyosarcoma. ## Therapeutic considerations for specific sts subtypes ## Retroperitoneal sarcomas Retroperitoneal sarcomas (RPS) are characterized by poor prognosis. More than half are high grade and adequate surgical margins are rarely obtained. The standard imaging procedure is a chest-abdominal CT scan. Fine-needle aspiration is not adequate for primary diagnosis. An extraperitoneal biopsy via core needle is the procedure of choice. Nevertheless, it is reasonable to avoid biopsy in the case of a resectable retroperitoneal mass with a clear-cut CT scan indicating adipocitic well-differentiated liposarcoma. En bloc resection of the tumour including adjacent organs is the only curative treatment for RPS, negative margins being the main prognostic factor (IV B) [bib_ref] Differences between en bloc resection and enucleation of retroperitoneal sarcomas, Lopez [/bib_ref]. Postoperative radiation is an option in highly selected patients with well-defined target regions (IV B) [bib_ref] Prognostic factors in retroperitoneal sarcoma: a multivariate analysis of a series of..., Stoeckle [/bib_ref]. Adjuvant and neoadjuvant chemotherapy should not be routinely employed in RPS due to lack of evidence of benefit (IV B). ## Uterine sarcomas Uterine sarcomas (US) are composed of different tumour entities: leiomyosarcomas, high-grade uterine sarcoma and sarcomas of endometrial stromal origin. Carcinosarcomas behave like epithelial carcinomas and are not covered by the following guidelines. Standard surgery of localized US consists of total abdominal hysterectomy plus double oophorectomy and full abdominal cavity exploration. It is not clear whether bilateral oophorectomy is always needed, particularly in low-grade US. Lymphadenectomy is not indicated. If an unsuspected US is diagnosed after surgery, a second-look intervention is not recommended if a total hysterectomy has been performed and macroscopic tumour does not remain. Adjuvant radiotherapy is controversial. Most available clinical trials are not optimally designed but tend to show a decrease in local relapse risk. No trial has proven an overall survival advantage [bib_ref] European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group, Reed [/bib_ref]. Thus, adjuvant radiotherapy it is not routinely considered, but it is justifiable in selected cases with a high relapse risk (II, C). A clinical trial comprising a small number of patients with uterine leiomyosarcoma showed a benefit of adjuvant gemcitabine plus docetaxel compared with historical controls [bib_ref] Adjuvant gemcitabine plus docetaxel for completely resected stages I-IV high grade uterine..., Hensley [/bib_ref]. There is not enough evidence to recommend adjuvant chemotherapy, but it could be individually planned in some patients (III B). Hormonal therapy with megestrol acetate, gonadotropin-releasing hormone (GnRH) analogues and aromatase inhibitors can delay progression for long periods of time in low-grade oestrogen receptor-positive endometrial stromal sarcoma, and it is preferred over chemotherapy as front-line palliative treatment (IV, C). Doxorubicin, ifosfamide, gemcitabine, taxanes, and trabectedin are active against US. We recommend a cautious approach favouring less toxic monotherapy options in the first place (IV, B). Positive results have been published for leiomyosarcoma patients treated with gemcitabine plus docetaxel as first-or second-line treatment [bib_ref] Fixed-dose rate gemcitabine plus docetaxel as first-line therapy for metastatic uterine leiomyosarcoma:..., Hensley [/bib_ref]. It is acceptable to select either doxorubicin or this regime as first-line palliative chemotherapy (III, B). ## Desmoid tumours Desmoid tumours (DT) represent a mesenchymal neoplasm of intermediate behaviour. They rarely metastasize, but show a marked tendency to local relapse with progressive increasing aggressivity. Surgery remains the mainstay of DT curative treatment. It is usually straightforward in the case of limb and chest-wall tumours, but can be much more challenging in abdominal disease. The aim of surgery is the macroscopic removal of the whole tumour while minimizing morbidity. Wide margins, even microscopically negative ones, do not justify on their own mutilating surgeries or functional sequels, as the prognosis of macroscopically resected (R1) patients do not depend on the microscopical status of the margins [bib_ref] Optimizing treatment of desmoids tumours, Lev [/bib_ref] (III, A). A watch-and-wait approach is also acceptable in the case of small, nongrowing, asymptomatic extraabdominal tumours that do not impose a significant risk for nearby critical organs or structures. Non-treatment decisions should not be taken in the absence of a diagnostic biopsy (IV, B). Radiotherapy is able to control even bulky disease for long periods of time [bib_ref] Radiation therapy in the management of desmoids tumours, Ballo [/bib_ref]. It is recommended in several scenarios like unresectable tumours, R2 surgery, patients refusing surgical treatment, serious comorbidity that makes surgery too risky or cases in which radical surgery would impose serious functional or cosmetic sequels (III, B). Systemic treatment is appropriate for unresectable tumours, Gardner-related cases with multiple recurring DT, progressions in areas previously irradiated and functionally or aesthetically unacceptable surgery. Evidence-based options include non-steroidal anti-inflammatory drugs like sulindac (IV, D), anti-oestrogens (tamoxifen and toremifene) (IV, D), chemotherapy (low-dose methotrexate plus vinblastine or vinorelbine and liposomal doxorubicin) (III, B) and imatinib [bib_ref] A SARC phase II multicenter trial of imatinib mesylate (IM) in patients..., Chugh [/bib_ref] (III, B). ## Angiosarcoma Angiosarcoma (AS) is a heterogeneous type of sarcoma due to its age of presentation and location. Sometimes it is multifocal and can be associated to anaemia and coagulopathy [bib_ref] A 14-year retrospective review of angiosarcoma: clinical characteristics, prognostic factors, and treatment..., Fury [/bib_ref] [bib_ref] Angiosarcomas, a heterogeneous group of sarcomas with specific behavior depending on primary..., Fayette [/bib_ref] [bib_ref] Localised angiosarcomas: the identification of prognostic factors and analysis of treatment impact...., Lindet [/bib_ref] ]. The treatment of choice of localized AS is complete excision with wide margins. Adjuvant radiotherapy is recommended if optimal surgery is not feasible due to multifocality or difficulty in defining the true margins [bib_ref] A 14-year retrospective review of angiosarcoma: clinical characteristics, prognostic factors, and treatment..., Fury [/bib_ref] [bib_ref] Angiosarcomas, a heterogeneous group of sarcomas with specific behavior depending on primary..., Fayette [/bib_ref] (IV, B). In advanced AS, systemic chemotherapy with either anthracyclines or taxanes are acceptable treatment options (II B). However, in the AS of the scalp, frequently seen in elderly patients, weekly paclitaxel is the drug of choice because it seems to have better response rate than anthracyclines [bib_ref] Comparison of doxorubicin and weekly paclitaxel efficacy in metastatic angiosarcomas, Italiano [/bib_ref] [bib_ref] Metastatic angiosarcomas: doxorubicin-based regimens, weekly paclitaxel and metastasectomy significantly improve the outcome, Penel [/bib_ref] [bib_ref] Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX Study, Penel [/bib_ref]. Anti-angiogenic drugs like bevacizumab and sorafenib have also been tested in metastatic AS with promising activity [bib_ref] Sorafenib for patients with advanced angiosarcoma: a phase II Trial from the..., Ray-Coquard [/bib_ref] [bib_ref] An open-label, multicenter, phase II study of bevacizumab for the treatment of..., Agulnik [/bib_ref] (III, B). ## Alveolar soft part sarcoma Alveolar soft part sarcoma (ASPS) often occurs in adolescents and young adults. Complete excision with wide margins is the treatment of choice. The administration of adjuvant radiotherapy follows the common guidelines for STS (IV, B). ASPS is not particularly sensitive to classic chemotherapeutic agents used in STS. However, ASPS has an upregulation of angiogenesis elements, and cediranib has proven to be active in advanced disease [bib_ref] Cediranib for metastatic alveolar soft part sarcoma, Kummar [/bib_ref]. Several partial responses to sunitinib and bevacizumab have also been reported [bib_ref] Sunitinib in advanced alveolar soft part sarcoma: evidence of a direct antitumour..., Stacchiotti [/bib_ref] [bib_ref] Alveolar soft part sarcoma: a single-center 26-patient case series and review of..., Ogura [/bib_ref] (IV, B). ## Dermatofibrosarcoma protuberans Dermatofibrosarcoma protuberans (DFSP) is a cutaneous mesenchymal tumour of intermediate behaviour. Although DFSP metastasize exceptionally, it has an important local infiltrative ability. In cases of localized DFSP complete resection with wide margins (2-4 cm) is the treatment of choice. Mohs surgery can be planned to avoid major cosmetic defects (III B). Adjuvant radiation therapy should be considered when margins are positive and re-resection is not feasible [bib_ref] Dermatofibrosarcoma protuberans (DFSP): predictors of recurrence and the use of systemic therapy, Fields [/bib_ref] [bib_ref] Dermatofibrosarcoma protuberans: long-term outcomes of 53 patients treated with conservative surgery and..., Castle [/bib_ref] [bib_ref] Dermatofibrosarcoma protuberans: recurrence is related to the adequacy of surgical margins, Heuvel [/bib_ref]. In unresectable, recurrent or metastatic DFSP, imatinib is recommended (III B) [bib_ref] Imatinib mesylate in advanced dermatofibrosarcoma protuberans: pooled analysis of two phase II..., Rutkowski [/bib_ref]. ## Clear cell sarcoma Clear cell sarcoma (CSS) tends to metastasize to lymph nodes, unlike other STS. In localized CCS, wide surgical resection is the mainstay of treatment. Elective lymphadenectomy or sentinel node biopsy could be also considered (IV C). Lymphadenectomy should be performed in cases of lymph node metastasis (IV B). The administration of adjuvant radiotherapy follows the common guidelines for STS (IV, B). In advanced CSS, response rate to chemotherapy is generally low [bib_ref] Clear cell sarcoma of tendons and aponeuroses: a study of 75 patients, Kawai [/bib_ref] [bib_ref] Clear cell sarcoma of tendons and aponeuroses in pediatric patients: a report..., Ferrari [/bib_ref] [bib_ref] A retrospective analysis of antitumour activity with trabectedin in translocationrelated sarcomas, Cesne [/bib_ref]. However, some isolated responses have been described with antiangiogenic agents such as sorafenib or sunitinib [bib_ref] Tumour response to sunitinib malate observed in clear-cell sarcoma, Stacchiotti [/bib_ref] [bib_ref] Objective response to sorafenib in advanced clear-cell sarcoma, Mir [/bib_ref] (V, D). ## Solitary fibrous tumour Solitary fibrous tumour (SFT) can be found in different locations, one of the most frequent is the pleura. Despite the majority of cases being benign, up to 40 % can be classified as malignant, which have a higher rate of local and distant recurrences [bib_ref] Solitary fibrous tumour: a clinicopathological study of 110 cases and proposed risk..., Demicco [/bib_ref] [bib_ref] Malignant solitary fibrous tumours of the pleura: retrospective review of a multicenter..., Lococo [/bib_ref]. The backbone of treatment of localized SFT is surgical resection with wide margins. Adjuvant radiation therapy can be administered (IV, B). In metastatic or locally advanced SFT, chemotherapy following the common guidelines for STS could be administered (III B). Moreover, antiangiogenic agents such as sunitinib or the combination of temozolomide plus bevacizumab constitute active options [bib_ref] Activity of temozolomide and bevacizumab in the treatment of locally advanced, recurrent,..., Park [/bib_ref] [bib_ref] Sunitinib malate and figitumumab in solitary fibrous tumour: patterns and molecular bases..., Stacchiotti [/bib_ref] [bib_ref] Sunitinib malate in solitary fibrous tumour (SFT), Stacchiotti [/bib_ref] (IV, B). ## Inflammatory myofibroblastic tumour Clinical manifestations of inflammatory myofibroblastic tumour (IMT) are secondary to local tumour. However, some patients can present systemic symptoms like fever and weight loss, as well as laboratory abnormalities like anaemia, thrombocytosis and polyclonal hypergammaglobulinemia [bib_ref] Inflammatory myofibroblastic tumours in childhood: a report from the Italian Cooperative Group..., Alaggio [/bib_ref]. IMT is associated with rearrangements of the ALK (anaplastic lymphoma kinase) locus on chromosome 2p23.13 [bib_ref] Crizotinib in ALK-rearranged inflammatory myofibroblastic tumour, Butrynski [/bib_ref]. In localized IMT the mainstay of treatment is wide resection. Generally, the surgery is curative and adjuvant chemotherapy is not recommended. In advanced IMT ALK-translocated, ALK-inhibitors, like crizotinib, produce sustained responses and are recommended [bib_ref] Crizotinib in ALK-rearranged inflammatory myofibroblastic tumour, Butrynski [/bib_ref] (IV, B). Chemotherapy with different regimens has been classically used with variable efficacy (methotrexate plus vinorelbine, vincristine plus etoposide, cisplatin/carboplatin or ifosfamide regimens) [bib_ref] Inflammatory myofibroblastic tumour successfully treated with chemotherapy and nonsteroidals: a case report, Yun-Lu [/bib_ref] [bib_ref] Carboplatin plus Paclitaxel in the Successful Treatment of Advanced Inflammatory Myofibroblastic Tumour, Kubo [/bib_ref] and could constitute a second-line option (IV B). [table] Table 1: Soft tissue sarcoma: compartmental and extracompartmental locations [/table]	None	https://link.springer.com/content/pdf/10.1007/s00280-015-2809-5.pdf	None
de3ba8502cbedff990a9db9b0702f5f94dacae67	pubmed	Tumour assessment and staging: United Kingdom National Multidisciplinary Guidelines	Tumour assessment and staging: United Kingdom National Multidisciplinary Guidelines In general, the first decision to be made in a patient with a confirmed head and neck cancer is whether or not to treat the patient before deciding what form of management strategy is appropriate. There is no more important an aspect of head and neck cancer care than the initial evaluation of the patient and the patient's tumour. The practice requires specific expertise and judgement. The current tumour-node-metastasis system relies on morphology of the tumour (anatomical site and extent of disease) but the final decision on treatment hinges on a full assessment of the patient including physiological age and general condition. The aim of this paper is primarily to describe why and how we appraise a patient and their tumour. It addresses the general principles applicable to the topic of evaluation, classification and staging. In addition, the limitations and pitfalls of this process are described.Recommendations- All patients with head and neck cancer (HNC) should undergo tumour classification and staging prior to treatment. (R) - Pre-therapeutic clinical staging of HNCs should be based on at least a C2 factor (evidence obtained by special diagnostic means, e.g. radiographic imaging (e.g. computed tomography, magnetic resonance imaging or ultrasound scan), endoscopy, biopsy and cytology). (R) - Imaging to evaluate the primary site should be performed prior to biopsy to avoid the effect of upstaging from the oedema caused by biopsy trauma. (G) - Panendoscopy is only recommended for symptomatic patients or patients with primary tumours known to have a significant risk of a second (synchronous) primary tumour. (G)Sites in the head and neck regionThe TNM classification applies only to carcinomas and melanomas in the following sites: lip and oral cavity, pharynx (oropharynx, nasopharynx and hypopharynx), larynx, maxillary sinus, nasal cavity and ethmoid sinus, mucosal malignant melanoma, major salivary glands and thyroid gland. Each site is described having rules for classification, anatomical sites and subsites where appropriate, the clinical TNM (cTNM) classification, the pathological TNM (pTNM) classification, G histopathological grading, stage grouping and a summary. The main aspects are described here, but specific details can be found in the most recent UICC and AJCC TNM booklets. 1,2 # Introduction There are many aspects affecting the outcome of patients with malignant head and neck tumours. These may relate to the tumour (e.g. the anatomical site and extent of the disease), the host (age, general condition and any concurrent disease) and management (treatment options, expertise available and patient preference). Staging of head and neck cancer (HNC) is a system designed to express the relative severity, or extent, of the disease. The objectives are illustrated in . The nature of staging has meant that the data to support the concept have been largely drawn from retrospective and observational studies. Much of the systems development has been through the opinion of expert panels using these data. Both the International Union against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) published rules on classification and staging which correspond in their 7th editions (2009) and have approval of all national tumour-node-metastasis (TNM) committees.General rules The TNM system for describing the anatomical extent of the disease is based on three components [fig_ref] TABLE I OBJECTIVES: OF STAGING 1 [/fig_ref] : T -Extent of the primary tumour N -Absence or presence and extent of regional lymph node metastases M -Absence or presence of distant metastases All cases should be confirmed microscopically. Two classifications should be documented for each site, namely: cTNM (clinical (pre-treatment) classification) and pTNM (post-surgical histopathological classification). The clinical stage is essential to select and evaluate therapy, while the pathological stage provides the most precise data to estimate prognosis and calculate end results. It should be remembered that if there is doubt concerning the correct T, N or M category to which a particular case should be allotted, then the lower (i.e. less advanced) category should be chosen. After assigning the cTNM and pTNM categories, the patient should then be classified in a Stage Group. Once established, this must remain unchanged in the medical records.See site-specific chapters for each detailed tumour classification. ## Histopathological grading The histological grading of squamous cell carcinoma represents estimation by the pathologist of the expected biologic behaviour of the neoplasm. Although it is subject to inter-and intra-observer errors, it has been suggested such information in conjunction with other characteristics of the primary tumour is useful in the rational approach to therapy. [bib_ref] The value of grading squamous cell carcinoma of the head and neck, Roland [/bib_ref] The grade can be applied to all head and neck sites except thyroid. ## Additional descriptors Designation is now applicable when sentinel lymph node biopsy is attempted using the suffix (sn) after N stage. Optional descriptors for perineural invasion (Pn), lymphatic invasion (L) and venous invasion (V) may be used. The absence or presence of residual tumour after treatment may be described by the symbol R. A recurrent tumour, when classified after a disease-free interval is identified by the prefix 'r'. The prefix 'a' indicates that classification is first determined at ## S54 autopsy. The suffix 'm' is used to indicate the presence of multiple primary tumours at a single site. In cases where multimodality treatment is used, the cTNM or pTNM is identified by a 'y' prefix which categorises the extent of tumour actually present at the time of that examination. The C-factor, or certainty factor, reflects the validity of classification according to the diagnostic methods employed (C1-C5). C1 would be evidence from standard diagnostic means whereas C5 is evidence from autopsy. Generally speaking, pre-therapeutic clinical staging of HNCs is equivalent to C1, C2 and C3, whilst pathological classification is equivalent to C4. 1,2 # Related classifications The World Health Organization (WHO) has developed a series aimed at classification of tumours. The WHO International Classification of Diseases for Oncology (ICD-O) is a coding system for neoplasms by topography and morphology and for indicating behaviour (e.g. malignant and benign).This coded nomenclature is identical in the morphology field for neoplasms to the Systemised Nomenclature of Medicine. 5 It is recommended that the WHO classification of tumours is used for classification and definition of tumour types and that the ICD-O code is used for storage and retrieval of data. ## Stage grouping After TNM, classification of tumours should be assigned a stage grouping between 0 or I and IV (Tables V). The grouping adopted is designed to ensure, as far as possible, that each group is more or less homogeneous in respect of survival and that the survival rates for each cancer stage are distinctive. Carcinoma in situ is categorised as stage 0; cases with distant metastasis as stage IV. The exceptions to this grouping are for carcinoma of the nasopharynx, carcinoma of the thyroid (Tables VI and VII) and mucosal melanoma. 1,2 # Methods of assessment The aim is to define in each patient all of the factors relevant to the natural history and outcome of the relevant disease, thereby enabling a patient with cancer to be grouped with other similar cases. The sex and age of the patient, the duration and severity of symptoms and signs and the presence and severity of concurrent disease should all be documented. Computed tomography (CT) and magnetic resonance imaging are now established as the mainstay investigations in the pre-operative work-up of patients with HNC, to delineate the extent and size of the primary tumour, to determine the presence (particularly when risk of occult nodes is >20 per cent), number and position of cervical lymph nodes, to search for an occult primary and to locate a synchronous primary or distant metastases (particularly the chest). Appropriate screening for synchronous tumours and distant metastases is particularly important in advanced tumours. Several studies have suggested that a CT scan should be obtained in preference to a plain chest X-ray as this may miss significant lung pathology. [bib_ref] Detection of synchronous lung tumors in patients presenting with squamous cell carcinoma..., Ghosh [/bib_ref] There is a [fig_ref] TABLE I OBJECTIVES: OF STAGING 1 [/fig_ref] Any N M0 Stage IVC Any T Any N M1 growing body of evidence that points to the value of 18F fluoro-deoxyglucose-positron emission tomography/ CT in the management of HNC patients and predicting patient-related outcomes. It is invaluable in the detection of the unknown primary and useful in the confirmation of residual or recurrent disease, but is not routinely used in initial staging assessment. [bib_ref] 18F FDG PET/CT and head and neck cancer: patient management and outcomes, Sheikhbahaei [/bib_ref] Endoscopy and biopsy should be performed by a senior surgeon and in all cases by the head and neck surgeon responsible for any future procedure. This should include for each tumour a description, diagrammatic representation and preferably also photographic documentation. Routine panendoscopy (oesophagoscopy and bronchoscopy) is contentious. Proponents point out that these procedures require very little time, and may be performed easily during planned, direct laryngoscopy. A large meta-analysis found a small advantage to panendoscopy in detection of second primary tumours during analysis of multiple prospective studies. [bib_ref] Meta analysis of second malignant tumours in head and neck cancer: the..., Haughey [/bib_ref] Opponents point out that the appropriate use of symptom directed investigations in addition to routine chest radiography have a similar detection rate compared with screening endoscopy and avoid unnecessary risk and expense in asymptomatic patients. [bib_ref] The role of panendoscopy in the management of mucosal head and neck..., Davidson [/bib_ref] McGarey et al. [bib_ref] Rigid esophagoscopy for head and neck cancer staging and the incidence of..., Mcgarey [/bib_ref] concluded that while rigid oesophagoscopy is safe, the utility is low for cancer staging and for detection of non-malignant oesophageal disease. Review of the literature and analysis of a large national cancer dataset indicate that the incidence of synchronous oesophageal malignant neoplasms in patients with head and neck squamous cell carcinoma is low and has been decreasing during the past three decades. [bib_ref] Rigid esophagoscopy for head and neck cancer staging and the incidence of..., Mcgarey [/bib_ref] Thus, screening oesophagoscopy should be limited to patients with head and neck squamous cell carcinoma who are at high risk for synchronous oesophageal malignant neoplasms. There is a natural desire to confer a stage on the tumour at presentation in the clinic and certainly after endoscopy. This should be avoided. It is better to rely on descriptive text to avoid changing the stage as more information becomes available. The clinical (pre-treatment) classification (cTNM) based on examination, imaging, endoscopy and biopsy should be clearly documented in the case-file only when all of the above information is collated. The UICC book should be available in every theatre and clinic to assist in applying the correct stage. ## Regional lymph nodes The status of the regional lymph nodes in HNC is of such prognostic importance that they must be assessed for each patient and tumour. Lymph nodes are described as ipsilateral, bilateral, contralateral or midline; they may be single or multiple and are measured by size, number and anatomical location [fig_ref] TABLE I OBJECTIVES: OF STAGING 1 [/fig_ref]. Midline nodes are considered ipsilateral nodes except in the thyroid. Direct extension of the primary tumour into lymph nodes is classified as lymph node metastasis.Imaging for node detection and delineation is recommended in the following settings: the neck is being scanned as part of the evaluation of the primary tumour; there is a high chance of occult disease (e.g. supraglottic primary); to assess the extent of nodal disease; to define any deep nodal fixation; or if clinical assessment is difficult because of a short, fat or previously irradiated neck. Lymph nodes are subdivided into specific anatomic sites and grouped into seven levels for ease of description. The pattern of lymphatic drainage varies for different anatomic sites. However, the location of the lymph node metastases has prognostic significance. Survival is significantly worse when metastases involve lymph nodes beyond the first echelon of lymphatic drainage. [bib_ref] The level of cervical lymph node metastases: their prognostic relevance and relationship..., Jones [/bib_ref] It is particularly poor for lymph nodes in the lower regions of the neck, i.e. levels IV and V (supraclavicular area). International Union Against Cancer and AJCC recommend that each N-staging category be recorded to show, in addition to the established parameters, whether the nodes involved are located in the upper (U) or lower (L) regions of the neck, depending on their location above or below the lower border of the thyroid cartilage.The definitions of the N categories for all head and neck sites are the same [fig_ref] TABLE I OBJECTIVES: OF STAGING 1 [/fig_ref] except thyroid [fig_ref] TABLE I OBJECTIVES: OF STAGING 1 [/fig_ref] and nasopharynx [fig_ref] TABLE X N: STAGING FOR NASOPHARYNX NX [/fig_ref]. The natural history and response to treatment of cervical nodal metastases from nasopharynx are different, in terms of their impact on prognosis, so they justify a different N classification. Regional lymph node metastases from well-differentiated thyroid cancer do not significantly TABLE VIII N STAGING FOR REGIONAL LYMPH NODES NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph node. 3 cm or less in greatest dimension N2 N2a Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension N3 Metastasis in a lymph node more than 6 cm in greatest dimension TABLE IX N STAGING FOR THYROID CARCINOMA NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis N1a Metastasis in level VI (pre-tracheal, pre-laryngeal, paralaryngeal) nodes N1b Metastasis in other unilateral, bilateral or contralateral cervical or retropharyngeal or superior mediastinal lymph node(s) N ROLAND, G PORTER, B FISH et al. ## S56 affect the ultimate prognosis and therefore also justify a unique system. ## Pathological classification (ptnm) The pT, pN and pM categories correspond to the T, N and M categories, respectively. The extent of the tumour in terms of the location and level of the lymph node should be documented. In addition, the number of nodes that contain tumour and the presence or absence of extracapsular spread of the tumour should be recorded. Histological examination of a selective neck dissection including central compartment specimen usually includes six or more lymph nodes; a radical or modified radical neck dissection specimen includes 10 or more lymph nodes.The current TNM system relies on morphology of the tumour (anatomical site and extent of disease) with little or no attention given to patient factors. However, the literature does suggest that symptom severity 12 and comorbidity [bib_ref] Importance of comorbidity in head and neck cancer, Picirillo [/bib_ref] have a significant impact on outcomes. It is therefore recommended that these data be recorded. Definitions of TNM categories may be altered or expanded for clinical or research purposes as long as the basic definitions are recorded and not changed. Despite the obvious value of staging, both in the management of individual patients and for the grouping of patients in trials and reports of treatment, it does have its limitations. The most insidious of these is that attempts to increase the accuracy of staging leads to greater complexity, and hence paradoxically to more errors and an increased likelihood of non-compliance by the person responsible for staging. Advances in methods of collecting and recording data will hopefully reduce these errors. Changes in the TNM classification should and will only occur, based on the appropriate collection, presentation and analysis of data, in the forum of the UICC and AJCC. [bib_ref] The value of grading squamous cell carcinoma of the head and neck, Roland [/bib_ref] The principles, practice and limitations of the current staging system are well documented in many major texts.Changes between editions tend to be conservative and commentaries regarding HNC reflect this. [bib_ref] TNM classification of malignant tumours 7th edn: what's new for head and..., Paleri [/bib_ref] It is seven years since the 7th edition of the UICC and AJCC staging manuals and the updated version is eagerly awaited. The early indications are that changes will be only subtle and few. ## Key points - Staging of head and neck cancer is a system designed to express the relative severity, or extent, of the disease. It is meant to facilitate an estimation of prognosis and provide useful information for treatment decisions. Classification by anatomical extent of head and neck cancer as determined clinically and histopathologically is the TNM System - Radiological investigations to evaluate the primary site should be performed prior to biopsy to avoid the effect of upstaging from the oedema caused by biopsy trauma - The sex and age of the patient, the duration and severity of symptoms and signs, and the presence and severity of inter-current disease should all be documented - Assessment by endoscopy and biopsy should be performed by a senior surgeon and in all cases by the Head & Neck surgeon responsible for any future procedure - The clinical (pre-treatment) classification (cTNM) based on examination, imaging, endoscopy and biopsy should be clearly documented in the case-file only when all the information is collated - Individual TNM classifications should be assembled into four groupsstage groups (stages I-IV), each with similar survival outcomes - The UICC book should be available in every theatre, MDT meeting and clinic to assist in applying the correct stage. Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Unilateral cervical, unilateral or bilateral retropharyngeal lymph node(s), 6 cm or less in greatest dimension, above supraclavicular fossa N2 Bilateral cervical lymph node(s), 6 cm or less in greatest dimension, above supraclavicular fossa N3 Metastasis in lymph node >6 cm and/or (in the supraclavicular fossa: (N3a) Greater than 6 cm in dimension (N3b) In the supraclavicular fossa Note: Midline nodes are considered ipsilateral nodes, and the supraclavicular triangle is defined by the lines joining the following three pointsthe superior margin of the clavicle at its sternal and acromial ends, and the point where the line of the neck meets the shoulder. [table] TABLE I OBJECTIVES: OF STAGING 1. To aid the clinician in the planning of treatment 2. To give some indication of prognosis 3. To assist in evaluation of the results of treatment 4. To facilitate the exchange of information between treatment centres 5. To contribute to the continuing investigation of human cancer [/table] [table] TABLE II AN: OVERVIEW OF THE TNM STAGING TERMINOLOGY [/table] [table] TABLE VII STAGE: GROUPING FOR THYROID CARCINOMA [/table] [table] TABLE X N: STAGING FOR NASOPHARYNX NX [/table]	None	https://www.cambridge.org/core/services/aop-cambridge-core/content/view/DFDC1123FAB3835573F9326EA97ADA12/S002221511600044Xa.pdf/div-class-title-tumour-assessment-and-staging-united-kingdom-national-multidisciplinary-guidelines-div.pdf	Abstract In general, the first decision to be made in a patient with a confirmed head and neck cancer is whether or not to treat the patient before deciding what form of management strategy is appropriate. There is no more important an aspect of head and neck cancer care than the initial evaluation of the patient and the patient's tumour. The practice requires specific expertise and judgement. The current tumour–node–metastasis system relies on morphology of the tumour (anatomical site and extent of disease) but the final decision on treatment hinges on a full assessment of the patient including physiological age and general condition. The aim of this paper is primarily to describe why and how we appraise a patient and their tumour. It addresses the general principles applicable to the topic of evaluation, classification and staging. In addition, the limitations and pitfalls of this process are described. Recommendations • All patients with head and neck cancer (HNC) should undergo tumour classification and staging prior to treatment. (R) • Pre-therapeutic clinical staging of HNCs should be based on at least a C2 factor (evidence obtained by special diagnostic means, e.g. radiographic imaging (e.g. computed tomography, magnetic resonance imaging or ultrasound scan), endoscopy, biopsy and cytology). (R) • Imaging to evaluate the primary site should be performed prior to biopsy to avoid the effect of upstaging from the oedema caused by biopsy trauma. (G) • Panendoscopy is only recommended for symptomatic patients or patients with primary tumours known to have a significant risk of a second (synchronous) primary tumour. (G)
10848c923130fec59f48153ee908583a00ddb5f6	pubmed	Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts	Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families. # Introduction Lynch syndrome (LS) ( previously referred to as hereditary non-polyposis colorectal cancer; HNPCC) is an autosomal dominant condition caused by a defect in one of the mismatch repair (MMR) genes. [bib_ref] Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and..., Lynch [/bib_ref] The syndrome is characterised by the development of colorectal cancer (CRC), endometrial cancer (EC) and various other cancers frequently diagnosed at an early age. LS is probably the most common hereditary CRC syndrome accounting for approximately 1-3% of all CRC. It has been estimated that in Europe approximately one million individuals are carriers of an MMR defect. [bib_ref] Recommendations to improve identification of hereditary and familial colorectal cancer in Europe, Vasen [/bib_ref] In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. [bib_ref] Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer), Vasen [/bib_ref] Since then substantial new information has become available necessitating an update of the guidelines. We used the same approach as for the development of the previous guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meeting. The group consisted of surgeons, clinical geneticists, molecular geneticists, pathologists, oncologists, epidemiologists and gastroenterologists. If a particular speciality was not represented specialists outside the group were consulted. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. [fig_ref] Table 1: Validity and grading of recommendations [/fig_ref] shows the criteria that were used for evaluation of studies, for the categorisation of evidence that they represented and for the strength of the recommendations that were made. ## Short update on ls LS was first described by In 1966, Henry Lynch reported two large families with hereditary CRC from the midwest. [bib_ref] Hereditary factors in cancer. Study of two large midwestern kindreds, Lynch [/bib_ref] Since then, many hundreds of families with the same pattern of cancer occurrence have been identified throughout the world. In the early 1990s the underlying gene defect was discovered, that is, a mutation in one of the MMR genes MLH1, MSH2, MSH6 or PMS2. Recently, two groups reported that a constitutional 3 0 end deletion of EPCAM, which is immediately upstream of the MSH2 gene, may cause LS through epigenetic silencing of MSH2. An MMR gene defect leads through loss of the corresponding normal alleles in the tumours of carriers to loss of MMR function and results in an accumulation of mutations in (coding and noncoding) microsatellites in such tumours (so-called microsatellites instability; MSI). Carriers of an MMR gene mutation have a very high risk of developing CRC (25-70%) and EC (30-70%) and an increased risk of developing other tumours. The main clinical features are an early age of onset and the occurrence of multiple tumours. Open Access Scan to access more free content Since 2007, many studies have been published on the risk of developing non-CRC, non-EC cancers in carriers of an MLH1 gene mutation, MSH2 gene mutation and MSH6 gene mutation. [bib_ref] Cancer risk in mutation carriers of DNA-mismatch-repair genes, Aarnio [/bib_ref] [bib_ref] MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation..., Vasen [/bib_ref] [bib_ref] Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset, Hampel [/bib_ref] [bib_ref] Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of..., Barrow [/bib_ref] [bib_ref] The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome, Watson [/bib_ref] [bib_ref] Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes..., Bonadona [/bib_ref] [bib_ref] Risks of Lynch syndrome cancers for MSH6 mutation carriers, Baglietto [/bib_ref] [bib_ref] Germ-line mutations in mismatch repair genes associated with prostate cancer, Grindedal [/bib_ref] [bib_ref] Risk and epidemiological time trends of gastric cancer in Lynch syndrome carriers..., Capelle [/bib_ref] [bib_ref] Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular..., Van Der Post [/bib_ref] [bib_ref] Risks of less common cancers in proven mutation carriers with Lynch syndrome, Engel [/bib_ref] [bib_ref] Risk of pancreatic cancer in families with Lynch syndrome, Kastrinos [/bib_ref] [bib_ref] The spectrum of urological malignancy in Lynch syndrome, Barrow [/bib_ref] Such studies are not yet available for carriers of a PMS2 gene mutation. A summary of the findings is shown in table 2. Those new studies also reported increased risks for pancreatic, bladder and breast cancer and possibly prostate cancer. Notably, carriers of MSH6 mutations appear to be particularly at risk of gastrointestinal cancer and EC, whereas carriers of an MSH2 gene mutation have the highest cancer risks across the spectrum, especially for the development of urinary tract cancer. The risks for MLH1 gene mutation carriers are between the cancer risks reported for MSH6 carriers and those for MSH2 carriers. [bib_ref] Cancer risk in mutation carriers of DNA-mismatch-repair genes, Aarnio [/bib_ref] [bib_ref] MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation..., Vasen [/bib_ref] [bib_ref] Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset, Hampel [/bib_ref] [bib_ref] Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of..., Barrow [/bib_ref] [bib_ref] The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome, Watson [/bib_ref] [bib_ref] Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes..., Bonadona [/bib_ref] [bib_ref] Risks of Lynch syndrome cancers for MSH6 mutation carriers, Baglietto [/bib_ref] [bib_ref] Germ-line mutations in mismatch repair genes associated with prostate cancer, Grindedal [/bib_ref] [bib_ref] Risk and epidemiological time trends of gastric cancer in Lynch syndrome carriers..., Capelle [/bib_ref] [bib_ref] Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular..., Van Der Post [/bib_ref] [bib_ref] Risks of less common cancers in proven mutation carriers with Lynch syndrome, Engel [/bib_ref] [bib_ref] Risk of pancreatic cancer in families with Lynch syndrome, Kastrinos [/bib_ref] [bib_ref] The spectrum of urological malignancy in Lynch syndrome, Barrow [/bib_ref] Moreover, a recent study reported on increased cancer risks for individuals with an EPCAM deletion. [bib_ref] Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a..., Kempers [/bib_ref] The investigators compared the cancer risks between 194 carriers of an EPCAM deletion and 473 carriers of a mutation in MLH1, MSH2, MSH6 or a combined EPCAM-MSH2 deletion. The risk of developing CRC for EPCAM deletion carriers was similar (75% by age 70 years) to the risks in carriers of an MLH1 or MSH2 mutation or a combined EPCAM-MSH2 deletion but was higher than the risk in MSH6 mutation carriers. By contrast, the risk of EC (12% by age 70 years) was significantly lower in female carriers of an EPCAM deletion compared to the risk in carriers of an MSH2 or MSH6 mutation or a combined EPCAM-MSH2 deletion. The EC risk in EPCAM deletion carriers was also lower than the risk in MLH1 carriers but this difference was not statistically significant. The wide variation in cancer risk within and between families is direct evidence that the risk is influenced by environmental and genetic factors. In the past 5 years many genome-wide association studies in CRC patients have identified a total of 20 variants that are associated with an increased risk of sporadic CRC. [bib_ref] Cumulative impact of common genetic variants and other risk factors on colorectal..., Dunlop [/bib_ref] A Dutch study evaluated whether six of these variants act as modifiers of the CRC risk in 675 gene mutation carriers. [bib_ref] Chromosome 8q23.3 and 11q23.1 variants modify colorectal cancer risk in Lynch syndrome, Wijnen [/bib_ref] Two variants (rs16892766 and rs3802842) were reported to increase the CRC risk in LS, the latter only in female carriers. An Australian group evaluated the effect of nine variants on the CRC risk in 684 MMR gene mutation carriers. [bib_ref] 3 and 11q23.1 as modifying loci influencing the risk for CRC in..., Talseth-Palmer [/bib_ref] They confirmed the association of the previously reported variants with CRC risk but only for MLH1 carriers. A French group did not find an association between these and other variants in 748 mutation carriers. [bib_ref] Evaluation of Lynch syndrome modifier genes in 748 MMR mutation carriers, Houlle [/bib_ref] In summary, more studies are needed to define the role of these variants in clinical practice. ## Question no 1 How can we improve the identification of LS? ## Relevant literature Identification of individuals with LS is extremely important because they can benefit from life-saving intensive-cancer surveillance. [bib_ref] Controlled 15-year trial on screening for colorectal cancer in families with hereditary..., Jarvinen [/bib_ref] However, it is the experience of most physicians specialising in familial cancer that LS is underdiagnosed. 28 There are many ways to improve the identification of this syndrome that have been described in a previous report from our group. [bib_ref] Recommendations to improve identification of hereditary and familial colorectal cancer in Europe, Vasen [/bib_ref] For example, efforts should be aimed at increasing the awareness of hereditary CRC in the general population and at promoting the taking of an adequate family history in all patients visiting a physician. However, probably the most effective way to identify LS is via patients who are diagnosed with CRC or EC. Many criteria have been proposed to identify LS among these patients mainly based on age at CRC diagnosis, the presence of multiple tumours and the number of affected family members. The revised Bethesda guidelines are thus probably the most commonly used criteria to select patients with CRC for further molecular analysis of their tumours (MSI/immunohistochemistry). [bib_ref] Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite..., Umar [/bib_ref] However, these criteria and guidelines have been criticised for being too complex and lacking in specificity and sensitivity. As a consequence, the criteria are poorly implemented in clinical practice. In view of these problems, systematic testing of all patients with CRC (or all individuals with CRC <70 years) has been recommended for loss of MMR function by means of MSI or immunohistochemistry independent of clinical criteria. [bib_ref] Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer), Hampel [/bib_ref] Since the 2007 guidelines, several studies have been published on the outcome of testing of all patients with CRC (or individuals with CRC <70 years) [fig_ref] Table 3: Outcome of prospective molecular screening of CRC or LS-associated cancer [/fig_ref]. [bib_ref] Feasibility of screening for Lynch syndrome among patients with colorectal cancer, Hampel [/bib_ref] [bib_ref] Identification in daily practice of patients with Lynch syndrome (hereditary nonpolyposis colorectal..., Julie [/bib_ref] [bib_ref] Yield of routine molecular analyses in colorectal cancer patients ≤70 years to..., Van Lier [/bib_ref] [bib_ref] Comparison between universal molecular screening for Lynch syndrome and revised Bethesda guidelines..., Perez-Carbonell [/bib_ref] [bib_ref] Screening for Lynch syndrome in colorectal cancer: are we doing enough?, Canard [/bib_ref] [bib_ref] Identification of Lynch syndrome among patients with colorectal cancer, Moreira [/bib_ref] The studies showed that this approach led to the identification of substantial numbers of LS mutation carriers (2.4-3.7% of all tested patients). Moreover, it was shown that many cases (12-28%) would have been missed if the revised Bethesda criteria had been used for selection. Two studies have shown that such an approach is cost effective. An alternative approach to the identification of LS is by testing unselected cases of EC for MSI and/or immunohistochemistry. Two studies revealed that such an approach led to the identification of LS in a proportion of patients (1.8-3.9%) comparable with CRC testing [fig_ref] Table 3: Outcome of prospective molecular screening of CRC or LS-associated cancer [/fig_ref]. Molecular screening of EC has also been found to be cost effective. [bib_ref] Lynch syndrome screening strategies among newly diagnosed endometrial cancer patients, Resnick [/bib_ref] A recent study of molecular screening of sebaceous adenomas and carcinomas led to the detection of LS in a subtantial proportion of cases (14%). [bib_ref] Mismatch repair protein deficiency is common in sebaceous neoplasms and suggests the..., Plocharczyk [/bib_ref] Due to the cascade effect, the identification of index cases by molecular screening leads on average to the detection of three additional relatives with LS, which demonstrates the utility of this approach and indicates its cost effectiveness. # Conclusion and recommendation Testing all CRC (or individuals with CRC<70 years) and all EC (or individuals with EC<70 years) by immunohistochemistry or MSI is useful for the identification of patients with LS (category of evidence IIb).The Mallorca group recommends investigation of all CRC (or individuals with CRC<70 years) by immunohistochemistry of the four MMR proteins or MSI (grade of recommendation C). These tests should be accompanied by methods that identify MLH1 promotor methylation. Investigation of all EC in individuals less than 70 years by immunohistochemistry or MSI can be considered to improve identification (grade of recommendation C). ## Question no 2 What is the optimal colorectal surveillance protocol for LS? ## Relevant literature Colorectal surveillance is the only surveillance protocol in LS proved to be effective. [bib_ref] Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer, Jarvinen [/bib_ref] Regular colonoscopy leads to a reduction of CRC-related mortality and also to a significant reduction of overall mortality in contrast with CRC screening in the general population. [bib_ref] Controlled 15-year trial on screening for colorectal cancer in families with hereditary..., Jarvinen [/bib_ref] However, there is an ongoing discussion about the optimal interval between colonoscopic examinations. Although a 3-year interval between colonoscopies has been proved to be effective, [bib_ref] Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer, Jarvinen [/bib_ref] there are no studies that have compared the effectiveness between different intervals. Since 2007, three prospective studies and one retrospective study analysing the effectiveness of colonoscopic surveillance have been published. [bib_ref] Development of colorectal tumors in colonoscopic surveillance in Lynch syndrome, Mecklin [/bib_ref] [bib_ref] One to 2-year surveillance intervals reduce risk of colorectal cancer in families..., Vasen [/bib_ref] [bib_ref] Efficacy of annual colonoscopic surveillance in individuals with hereditary nonpolyposis colorectal cancer, Engel [/bib_ref] [bib_ref] Impact of colonoscopic screening in male and female Lynch syndrome carriers with..., Stuckless [/bib_ref] The characteristics of the study populations, the intervals that were recommended and the outcomes are summarised in table 4. Unfortunately, it is difficult to compare the risks of developing an interval cancer (defined as a cancer that develops after a negative screening examination) between the studies due to the different methodologies used. The proportion of interval cancers with a local tumour (stages I and II) varied from 78% to 95%. Most tumours (57-62%) were located in the right colon, which emphasises the importance of careful investigation of this part of the colon. In the Dutch, German and Canadian series, most interval cancers were diagnosed in individuals older than 40 years. However, in the Finnish series a substantial proportion (20-30%) were diagnosed between the age of 30 and 40 years. In one study, the influence of the type of MMR gene defect on the risk of developing interval cancers was evaluated. That study demonstrated that the risk was lower for carriers of an MSH6 gene mutation, although the difference was not statistically significant. In the Finnish series, it was found that mortality due to CRC was associated with a lack of participation in the surveillance programme. This is concerning given that the lack of compliance with the recommended surveillance interval in the German and Canadian studies was 20% and 42%. To guarantee the continuity of surveillance and improve compliance with the surveillance recommendations patients should be registered at a regional or national hereditary cancer registry. Such registries can improve participation in surveillance by using reminder systems. [bib_ref] Decrease in mortality in Lynch syndrome families because of surveillance, De Jong [/bib_ref] Conclusion A 3-year interval between colonoscopies has been proved to be effective (category of evidence IIb). In view of the observation of (advanced) CRC detected between 2 and 3 years after surveillance colonoscopy, the recommended interval for mutation carriers is 1-2 years (grade of recommendation C). ## Question no 3 How effective is surveillance for endometrial and ovarian cancer? ## Relevant literature In LS, the risk of developing EC is very high and equals or even exceeds the risk of CRC in female gene carriers. [bib_ref] Risk of colorectal and endometrial cancer for carriers of mutations of the..., Quehenberger [/bib_ref] The overall prognosis of patients diagnosed with EC is relatively good, with a 10-year survival of approximately 80%. However, 20% of the patients will ultimately die from the disease. Moreover, a substantial proportion of patients need treatment with radiation and/or chemotherapy. The main goal of surveillance for EC is detection and treatment of premalignant lesions (ie, endometrial hyperplasia) or EC at an early stage and thereby improving the prognosis for the patients. The World Health Organization classifies endometrial hyperplasia as simple or complex determined by the degree of architectural abnormality, and as having or not having atypia. Nieminen et al 50 studied serial specimens of normal endometrium, simple hyperplasia and complex hyperplasia with and without atypia during 10 years of surveillance. MMR deficiency was observed in 7% of normal endometrium, 40% of simple hyperplasia, 100% of complex hyperplasia without atypia and 92% of complex hyperplasia with atypia, suggesting that in LS, contrary to the traditional view, complex hyperplasia with and without atypia was equally important as precursor lesions of EC. In 2011, Auranen and Joutsiniemi 51 performed a systematic review of all studies that addressed gynaecological cancer surveillance in women who belonged to LS families. The authors identified five studies in the literature that included a total of 647 women. [bib_ref] The outcome of endometrial carcinoma surveillance by ultrasound scan in women at..., Dove-Edwin [/bib_ref] [bib_ref] Gynecologic screening in hereditary nonpolyposis colorectal cancer, Rijcken [/bib_ref] [bib_ref] Surveillance for endometrial cancer in hereditary nonpolyposis colorectal cancer syndrome, Renkonen-Sinisalo [/bib_ref] [bib_ref] Performance of office hysteroscopy and endometrial biopsy for detecting endometrial disease in..., Lecuru [/bib_ref] [bib_ref] Improvement of endometrial biopsy over transvaginal ultrasound alone for endometrial surveillance in..., Gerritzen [/bib_ref] The screening methods applied in the studies varied from only transvaginal (or transabdominal) ultrasound (two studies) to a combination of transvaginal ultrasound and endometrial biopsy (two studies) and hysteroscopic endometrial biopsy (one study). The intervals between examinations varied between 1 year in three studies, 1-2 years in one study and 2-3 years in another study. In the studies that used only ultrasound as the screening tool, no EC were detected and only interval cancers occurred. However, in the studies with a protocol that also included endometrial biopsies, the detection of premalignant lesions and EC was improved. Renkonen-Sinisalo et al 54 compared the Federation of Gynecology and Obstetrics (FIGO) stages of the screendetected cancers with those of EC diagnosed after presentation of signs or symptoms. Although less advanced cancers were observed in the screen-detected group, the difference was not statistically significant. The main advantage of the surveillance programme seems to be the identification of precursor lesions. No benefit was shown for ovarian cancer surveillance. Auranen and Joutsiniemi 51 concluded that the available studies do not adequately allow for evidence-based clinical decisions. Since that review, another retrospective study was published on the impact of gynaecological screening in MSH2 carriers (n=54). [bib_ref] Impact of gynecological screening in lynch syndrome carriers with an MSH2 mutation, Stuckless [/bib_ref] Nine women were diagnosed with EC, five of which were within 1 year of the previous negative screening test (transvaginal ultrasound and/or endometrial biopsy) and two were at initial screening. Of the nine EC, seven were localised cancers (stage I), and one was at an advanced stage (stage III). There were no deaths due to EC. Six women had ovarian cancer, three of which were within 1 year of a previous normal screening. Two died from ovarian cancer. The authors concluded that gynaecological screening did not result in earlier detection of gynaecological cancer. In view of the uncertain effect of the surveillance programme, it is important to consider possible disadvantages of the programme. Elmasry et al 58 assessed the patient acceptability of the available screening modalities. Transvaginal ultrasound was associated with less discomfort than hysteroscopy or Pipelle biopsy. There was no significant difference between the pain scores for hysteroscopy and Pipelle biopsy. Huang et al 59 compared a new patient-centered approach by combining endometrial biopsies and colonoscopy under sedation. This approach was much more acceptable than an endometrial biopsy as a single procedure without sedation. Wood et al 60 evaluated the effect of gynaecological screening in LS families on psychological morbidity. The authors did not demonstrate any adverse psychological effect in the screened population, even in those with false positive screening results. # Conclusion The value of surveillance for EC is still unknown. Surveillance of the endometrium by gynaecogical examination, transvaginal ultrasound and aspiration biopsy starting from the age of 35-40 years may lead to the detection of premalignant disease and early cancers (category of evidence III) and should be offered to mutation carriers (grade of recommendation C). The pros and cons should be discussed [fig_ref] Table 5: Pros and cons of surveillance for gynaecological cancer [/fig_ref]. Given the lack of evidence of any benefit, gynaecological surveillance should preferably be performed as part of a clinical trial. ## Question no 4 What is the role of prophylactic hysterectomy with or without oophorectomy? ## Relevant literature Schmeler et al [bib_ref] Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch..., Schmeler [/bib_ref] have shown in a retrospective study that prophylactic hysterectomy and oophorectomy is very effective in LS: none of the patients who underwent prophylactic surgery (61 out of 315) developed endometrial or ovarian cancer, whereas 33% of patients who did not have surgery developed EC and 5.5% developed ovarian cancer. A recent study documented two cases of LS patients who developed primary peritoneal cancers after prophylactic surgery. [bib_ref] Primary peritoneal cancer after bilateral salpingo-oophorectomy in two patients with Lynch syndrome, Schmeler [/bib_ref] A cost-effectiveness analysis of prophylactic surgery versus gynaecological screening showed that risk-reducing surgery was associated with both the lowest costs and highest number of quality-adjusted life years. In view of the very high risk of EC, the substantial proportion of women who will die from the disease, the morbidity associated with treatment and the effectiveness of prophylactic surgery, there is agreement that the option of prophylactic hysterectomy should be discussed with mutation carriers who have completed their family. However, there are still some important questions that should be addressed. First, should prophylactic surgery include salpingooophorectomy? The risk of developing ovarian cancer in mutation carriers is approximately 9% with the highest risks in MLH1 and MSH2 mutation carriers and the lowest risk in MSH6 mutation carriers. Although the prognosis of unselected patients with ovarian cancer (and also of patients with ovarian cancer associated with BRCA1 and BRCA2 mutations) is very poor, recent studies suggested that the biology of ovarian cancer associated with LS may be different. Three studies showed that the majority of symptomatic ovarian cancers (77-81%) in LS are diagnosed at an early stage (FIGO stages I and II). [bib_ref] Survival of patients with ovarian cancer due to a mismatch repair defect, Crijnen [/bib_ref] [bib_ref] Survival in women with MMR mutations and ovarian cancer: a multicentre study..., Grindedal [/bib_ref] [bib_ref] Ovarian cancer linked to Lynch syndrome typically presents as early-onset, non-serous epithelial..., Ketabi [/bib_ref] In a multicentre study, Grindedal et al 66 collected a large number (n=144) of prospectively diagnosed cases of ovarian cancer and demonstrated a very good prognosis with a 10-year survival of 81%. Prophylactic surgery in postmenopausal women should include salpingo-oophorectomy. However, salpingo-oophorectomy in premenopausal women is associated with various adverse effects such as an immediate onset of menopause as a result of oestrogen deprivation potentially resulting in vasomotor symptoms and possible sexual dysfunction. Oestrogen deprivation may also lead to a higher risk of osteoporosis. A large study by Madalinska et al 68 in 846 carriers of a BRCA1 and BRCA2 mutations reported significantly more endocrine symptoms in the patients who underwent prophylactic oophorectomy compared to women who underwent surveillance of the ovaries. No significant differences were observed in the level of sexual activities between the two groups, but women in the prophylactic surgery group reported significantly more discomfort (vaginal dryness and dyspareunia), less pleasure and less satisfaction during sexual activities. Despite this, the study did not reveal any other differences in quality of life. Usually, hormone replacement therapy is prescribed in premenopausal women after salpingo-oophorectomy, which may partly reduce the vasomotor symptoms but has no effect on sexual discomfort. [bib_ref] The impact of hormone replacement therapy on menopausal symptoms in younger high-risk..., Madalinska [/bib_ref] In view of the recent study that suggests a relatively good prognosis of ovarian cancer in LS, it is questionable whether the possible small gain in life expectancy outweighs the adverse effects of prophylactic salpingo-oophorectomy at a young age. The second question is how these issues should be discussed with the patient and how the patient can be supported in their decision-making? The best approach is to inform the patient fully about all pros and cons of prophylactic surgery. As a basis for this discussion, the pros and cons are summarised in table 6. Depending on the type of information, a gynaecologist, geneticist, clinical psychologist or other specialists should be involved. Ideally, this information should also be available in written form. The third question is from which age surgery should be recommended. The risk of endometrial and ovarian cancer increases from the age of 40 years. The optimal timing of prophylactic surgery, therefore, would be around the age of 40 years. # Conclusion Hysterectomy and bilateral oophorectomy largely prevents the development of endometrial and ovarian cancer (category of evidence III) and is an option to be discussed with mutation carriers who have completed their families especially after the age of 40 years (grade of recommendation C). Also, if CRC surgery is scheduled, the option of prophylactic surgery at the same time should be considered. All pros and cons of prophylactic surgery should be discussed. ## Question no 5 What is the effectiveness of surveillance for other cancers? ## Gastric cancer In LS, the cumulative risk of developing gastric cancer by the age of 70 years is approximately 5%. Recent studies have shown that there is no evidence for the clustering of gastric cancer in specific LS families. In parts of the world with a high background incidence of gastric cancer in the population (Korea, Japan), the risk of developing gastric cancer in LS families is also higher, suggesting the role of environmental factors. Although not proved, the impression exists that the incidence of gastric cancer in LS in the western world seems to be decreasing in parallel to the declining incidence of gastric cancer in the general population. [bib_ref] Risk and epidemiological time trends of gastric cancer in Lynch syndrome carriers..., Capelle [/bib_ref] The prognosis in unselected patients with cases of gastric cancer is poor, with an average 5-year survival rate of 20-25%. According to the Lauren's classification, tumours are separated into 'diffuse', 'intestinal' and 'mixed' types. [bib_ref] Gastric carcinoma, Lauwers [/bib_ref] In 'high incidence' areas, patients with Helicobacter pylori-associated chronic gastritis may develop atrophy followed by intestinal metaplasia over time. This may culminate in neoplastic changes, especially adenocarcinoma of 'intestinal' type. Two studies showed that the majority of gastric cancer associated with LS is of the intestinal type (73-79%). The goal of surveillance for gastric cancer would be the detection of precursor lesions and gastric cancer at an early curable stage. It is well known that early detection of diffuse gastric cancer is extremely difficult, and for this reason prophylactic gastrectomy is recommended in carriers of a CDH1 mutation. However, as most cancers in LS are of the intestinal type, regular upper gastrointestinal endoscopy may lead to the early detection of precursor lesions and early cancer. Indeed, a Finnish study reported potential precursor lesions in a substantial proportion of 73 MMR gene mutation carriers: H pylori infection was observed in 26%, atrophy in 14% and intestinal metaplasia also in 14%. [bib_ref] No support for endoscopic surveillance for gastric cancer in hereditary non-polyposis colorectal..., Renkonen-Sinisalo [/bib_ref] There are no (other) studies in the literature that have evaluated the effectiveness of surveillance for gastric cancer. In view of the relatively low risk of gastric cancer and the lack of established benefit, the Mallorca group does not advise surveillance for gastric cancer. On the other hand, the Mallorca group recommends screening mutation carriers for the presence of an H pylori infection and subsequent eradication if detected. In countries with a high incidence of gastric cancer in LS, surveillance might be performed in a research setting. ## Cancer of the small bowel The risk of developing this cancer in carriers of an MLH1 or MSH2 mutation is approximately 5%. In carriers of a MSH6 mutation, small bowel cancer is relatively rare. There is no evidence for the clustering of small bowel cancer in specific families. [bib_ref] The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome, Watson [/bib_ref] The tumours in LS families are mainly located in the proximal small bowel (43%) and the jejunum (33%); 7% are located in the ileum. Patients with small bowel cancer have a poor prognosis. The 5-year survival rate is 30-35%. A French study recently compared the use of CT enteroclysis and video-capsule endoscopy in 35 mutation carriers. [bib_ref] Small-bowel capsule endoscopy diagnoses early and advanced neoplasms in asymptomatic patients with..., Saurin [/bib_ref] Video-capsule endoscopy detected three (10%) lesions of which two were missed by CT enteroclysis. The lesions included two adenomas and one jejunal cancer. Although the yield of this small study is noteworthy, more studies are needed to confirm the findings and to assess the cost effectiveness. Currently, the Mallorca group does not recommend surveillance for this cancer. As small bowel cancer is frequently located in the duodenum and ileum, we suggest inspection of the distal duodenum during upper gastrointestinal endoscopy (if performed) and also of the ileum during colonoscopy. ## Cancer of the urinary tract Many studies have reported an increased risk of urothelial cancers of the upper urinary tract in LS. Recent studies have also demonstrated an increased risk of bladder cancer. [bib_ref] Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular..., Van Der Post [/bib_ref] The estimated risk varies from 5% to 20%, with the highest risk in male carriers and those with an MSH2 mutation. The risk for non-urothelial tumours was not increased. The classic presenting sign of urothelial tumours is haematuria without pain. The prognosis of patients with urothelial tumours depends on the stage and grade of the tumours. The 5-year survival of non-invasive, low grade cancers is over 90%, while for those with high grade cancers, it is 60-70%. Periodic examination may lead to the detection of cancers at earlier stages. Options for urinary tract cancer screening include dipstick testing of the urine for microscopic haematuria, urine cytology, screening for tumour-specific molecular markers in the urine and abdominal ultrasound. Cystoscopy is the gold standard for bladder cancer detection. However, although flexible cystoscopy has a high sensitivity and positive predictive value, it is not considered appropriate for screening in the general population or highrisk groups due to its cost, procedural nature, and (small) risks. Urothelial carcinoma in the sporadic setting is known to be associated with tobacco, aryl amines and other chemical carcinogens. Urine cytology and cystoscopy have been used to screen workers who are at extremely high risk of developing bladder cancer through occupational exposure to known urothelial carcinogens. Although several non-randomised studies have documented a high incidence of bladder cancer in populations with heavy exposure to such carcinogens, they have not demonstrated that active screening alters the natural history of the disease in those who do develop bladder cancer. [bib_ref] Biomarker risk assessment and bladder cancer detection in a cohort exposed to..., Hemstreet [/bib_ref] [bib_ref] A protocol for bladder cancer screening and medical surveillance among high-risk groups:..., Marsh [/bib_ref] [bib_ref] The Drake Health Registry Study: findings from fifteen years of continuous bladder..., Marsh [/bib_ref] [bib_ref] Bladder cancer screening among primary aluminum production workers in Quebec, Theriault [/bib_ref] One Danish study has evaluated the effectiveness of surveillance of the urinary tract in LS. [bib_ref] Screening for urinary tract cancer with urine cytology in Lynch syndrome and..., Myrhoj [/bib_ref] The study reviewed records of 3411 relatives from LS families (n=263), or families that met the Amsterdam criteria I or II (n=426) or that had been suspected of LS (n=288). The authors collected results of urine cytology from the National Danish Pathology Database. A total of 977 patients had 1868 screening procedures involving a total of 3213 person years (median 2.8 years, range 0-11.5). In two patients (0.1%), the screening led to the identification of asymptomatic urinary tumours (two small non-invasive bladder cancers). During the study 14 patients (of the 997) developed a urinary cancer, including five interval cancers. The tumours consisted of seven bladder cancers without invasion, four bladder cancers with invasion, one renal pelvis tumour with invasion and one renal pelvis tumour without invasion and one renal cell carcinoma. The sensitivity of urine cytology was 29% in diagnosing asymptomatic tumours. The corresponding specificity was 96%. Eleven out of the 14 tumours were diagnosed in MSH2 families. The authors concluded that urine cytology is not an appropriate screening method of screening for urinary tract cancer in LS. The study does not allow any conclusion to be made about the benefit of surveillance in subgroups of families (eg, those with the MSH2 mutation). Although abdominal ultrasound has been recommended as a surveillance tool in LS, there are no reports on its effectiveness. In view of the lack of evidence for the benefit of surveillance for urinary tract cancer, the Mallorca group does not recommend surveillance for urinary tract cancer in LS outside the setting of a research project. ## Prostate cancer Prostate cancer is the most common cancer in men. The prognosis of these tumours is relatively good, with a 10-year survival of all men with prostate cancer of 72%. Previous studies did not show a (significantly) increased risk of prostate cancer in men with LS However, three recent studies did reveal an increased risk of developing this cancer in LS. A study by Engel et al 19 reported a significantly increased risk of prostate cancer in LS (17 cases in 1011 male mutation carriers; standardised incidence ratio (SIR) 2.5 . The highest risk was found in carriers of a MSH2 mutation (cumulative risk by the age of 70 years: MSH2: 18%; MLH1: 0%; MSH6: 4%). Another study reported a tenfold increased risk of prostate cancer in carriers of a MSH2 mutation (four cases in 130 male mutation carriers) but the cumulative risk by the age of 70 years was only 6%. [bib_ref] The spectrum of urological malignancy in Lynch syndrome, Barrow [/bib_ref] In the third study from Norway, out of 106 male carriers or obligate carriers of MMR mutations, nine had developed prostate cancer [bib_ref] Germ-line mutations in mismatch repair genes associated with prostate cancer, Grindedal [/bib_ref] (six in MSH2 carriers). Immunohistochemical analysis showed the absence of the corresponding MMR gene product in seven of eight available tumours. The number of men with a Gleason score between eight and 10 was significantly higher than expected. Kaplan-Meier analysis suggested that cumulative risk by 70 years in MMR mutation carriers may be 30% (SE 0.088) compared to 8.0% in the general population. Prostate-specific antigen screening of the general population is generally not recommended due to the serious side-effects of treatment and the indolent course of most screen-detected cancers. If the increased risk of prostate cancer and the development of aggressive tumours are confirmed in further studies of LS families, male gene carriers, especially of an MSH2 mutation might benefit from surveillance. Until more studies are available, the Mallorca group does not recommend surveillance for prostate cancer in LS families outside of appropriate research studies (see http://impact-study. co.uk). ## Pancreatic cancer Recent studies have revealed an increased risk of developing pancreatic cancer in LS. Kastrinos et al 20 reported a RR of 8 across 147 families with an MMR gene mutation, and calculated a cumulative risk of 3.7% by the age of 70 years. Win et al 75 studied 446 MMR mutation carriers and reported a SIR of 11 for pancreatic cancer. The prognosis of patients with pancreatic cancer is very poor, with an average life expectancy of 6 months after diagnosis. However, the benefit of surveillance for pancreatic cancer in high-risk groups is unknown and as the reported absolute risk is relatively low, the Mallorca group does not recommend surveillance for this cancer in LS families outside the setting of a research programme. ## Breast cancer Whether breast cancer is part of the tumour spectrum of LS is controversial. Loss of MMR function has been reported in a substantial proportion of breast cancers in LS. In a large study by Watson et al, 12 the risk of breast cancer was not increased (5.4% by age 70 years). In contrast, two recent studies reported increased risks of developing breast cancer. Barrow et al 11 reported an increased risk only in MLH1 carriers (18%). A large cohort study from the German and Dutch LS registry reported a significantly increased risk for developing breast cancer. [bib_ref] Risks of less common cancers in proven mutation carriers with Lynch syndrome, Engel [/bib_ref] The cumulative risk by the age of 70 years was 14% in all female carriers, with the highest risk in Further studies are needed to confirm these results and determine whether the increased risk is restricted to MLH1 mutation carriers. At present, female carriers of an MMR gene mutation should be advised to participate in population screening programmes for breast cancer (biannual mammography from the age of 45 or 50 years). # General conclusion A recent analysis on the causes of deaths in LS revealed that a large proportion (61%) of the cancer deaths were now associated with non-CRC non-EC. [bib_ref] Causes of death of mutation carriers in Finnish Lynch syndrome families, Pylvanainen [/bib_ref] Unfortunately, the benefit of surveillance for most extracolonic cancers is still unknown. Surveillance for these cancers should therefore only be performed in a research setting. The results of long-term surveillance should ideally be collected and evaluated at a regional or national or international LS registry. To ensure informed decision-making about surveillance by patients, all pros and cons of such programmes should be discussed with the patient. If surveillance is offered, patients should understand that there is uncertainty about the potential benefits sand harms. [fig_ref] Table 7: Surveillance protocol in LS [/fig_ref] shows the protocol recommended by the Mallorca group. ## Question no 6 What is the appropriate surgical treatment for CRC? ## Relevant literature In LS, the risk of developing a second CRC after partial colectomy for primary CRC has been reported to be approximately 16% at 10 years follow-up despite close surveillance. In view of this risk, more extensive treatment (total or subtotal colectomy) of the primary CRC might be considered. However, for decision-making it is important to address the following questions to determine the benefit of the patient: what is the risk of developing a second cancer under appropriate ( postoperative) surveillance; and what is the effect of more extensive surgery on the functional outcome and quality of life. Three recent studies reported the risk of developing an interval CRC under colonoscopic surveillance. [bib_ref] Development of colorectal tumors in colonoscopic surveillance in Lynch syndrome, Mecklin [/bib_ref] [bib_ref] One to 2-year surveillance intervals reduce risk of colorectal cancer in families..., Vasen [/bib_ref] [bib_ref] Efficacy of annual colonoscopic surveillance in individuals with hereditary nonpolyposis colorectal cancer, Engel [/bib_ref] In one study, a risk of 6% after 10 years of follow-up was reported. [bib_ref] One to 2-year surveillance intervals reduce risk of colorectal cancer in families..., Vasen [/bib_ref] In the other studies, the risk of developing CRC by the age of 60 years was between 22% and 35% depending on sex and surveillance interval. One study especially evaluated the functional outcome and quality of life after limited and extensive surgery in LS patients. [bib_ref] Quality of life after surgery for colon cancer in patients with Lynch..., Haanstra [/bib_ref] Although the functional outcome was significantly worse after extensive surgery, quality of life was similar in both groups. # Conclusion In view of the substantial risk of a second CRC after partial colectomy (category of evidence III) and similar quality of life after partial and subtotal colectomy (category of evidence III), the option of subtotal colectomy including its pros and cons [bib_ref] Cancer: Lynch syndrome-how should colorectal cancer be managed?, Vasen [/bib_ref] should be discussed with all LS patients with CRC, especially younger patients (grade of recommendation C). ## Question no 7 What is the influence of environmental and lifestyle factors on the development of adenoma or CRC in LS? ## Relevant literature There is ample evidence that the risk of developing cancer in LS is influenced by environmental factors. The tumour spectrum observed in the first LS syndrome family published in 1913 by included mainly gastric cancers and EC. Follow-up reports of this well-known family showed that in the current generations CRC was now the most common tumour. [bib_ref] Cancer family 'G' revisited: 1895-1970, Lynch [/bib_ref] The changes reflect the decrease of gastric cancer and increase of CRC in the general population in western countries. In addition, the spectrum of cancers in LS reported in Japan and South Korea also differs from the spectrum found in LS families in western countries, with more gastric cancers reported in families from eastern Asia. [bib_ref] Gene-environment interaction in hereditary nonpolyposis colorectal cancer with implications for diagnosis and..., Park [/bib_ref] An important question is which environmental and lifestyle factors influence the development of cancer in LS. In the past decade a large number of studies have been published that addressed this question. The studies are summarised in table 8. [bib_ref] Meat consumption and meat preparation in relation to colorectal adenomas among sporadic..., Voskuil [/bib_ref] [bib_ref] Environmental factors and colorectal tumor risk in individuals with hereditary nonpolyposis colorectal..., Diergaarde [/bib_ref] [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] 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] Smoking increases the risk for colorectal adenomas in patients with Lynch syndrome, Winkels [/bib_ref] [bib_ref] Dietary patterns and colorectal adenomas in Lynch syndrome: the GEOLynch Cohort Study, Botma [/bib_ref] Four studies showed that smoking was associated with a higher risk of developing colorectal neoplasias. In addition, two studies demonstrated that a higher body mass index (BMI) was associated with an increased risk of colorectal neoplasia. Alcohol (two out of three studies) was not associated and fruit and fibre intake was possibly related to decreased risks. A recent large randomised controlled trial showed that resistant starch (a component of dietary fibre) had no effect on the development of CRC in LS. [bib_ref] Long-term effect of resistant starch on cancer risk in carriers of hereditary..., Mathers [/bib_ref] Another study investigated the effect of various dietary patterns on the development of adenomas in LS. [bib_ref] Dietary patterns and colorectal adenomas in Lynch syndrome: the GEOLynch Cohort Study, Botma [/bib_ref] A 'snack' dietary pattern was associated with a higher risk of adenoma development. # Conclusion Smoking and a high BMI increase the risk of developing adenomas and CRC in LS (category of evidence IIb). Patients are advised to stay within the normal weight range and refrain from smoking (grade of recommendation B). ## Question no 8 What is the role of aspirin in the management of LS? ## Relevant literature The CAPP2 trial randomly assigned 1009 LS carriers to two tablets (600 mg) of enteric-coated aspirin daily for 2-4 years. The overall burden of adenomas and carcinomas at the end of the intervention phase was unchanged, 101 but re-analysis when the first recruits reached the planned long-term follow-up target of 10 years revealed a significant reduction in CRC and other cancers among those randomly assigned to aspirin versus A meta-analysis conducted by Rothwell et al 103 included a total of eight randomised trials on the prevention of vascular disease (seven placebo controlled) that examined daily aspirin use with an initial aspirin treatment period of at least 4 years). Using cancer registry data the impact on subsequent cancer incidence and mortality was investigated. Among the eight trials, with a total of 25 570 patients and 674 cancer-related deaths, aspirin treatment using doses between 75 and 1200 mg per day was associated with a 21% lower risk of death from any cancer during the in-trial follow-up period. Among those with data on cancer site, patients randomly assigned to aspirin had a reduced risk of CRC mortality that approached statistical significance (HR 0.41; 95% CI 0.17 to 1.00), an effect that became apparent 5 years after the initiation of aspirin treatment. The review suggested there was no greater benefit with doses higher than 75 mg per day, although adverse effects in the gut increased with higher doses. A dose inferiority trial, CaPP3, will start in 2013. Combining the available data, the recommendation is that all LS gene carriers should consider regular daily aspirin starting with their regular surveillance and that, when available, they should consider helping with studies to determine the optimal dose. The importance of testing for H pylori and subsequent eradication if detected has already been discussed in the section on surveillance for gastric cancer (see question 5). Before starting aspirin, eradication of H pylori may also be beneficial because it may decrease the risk of upper gastrointestinal tract injury, especially in those carriers with a history of peptic ulcer or complications. [bib_ref] Interaction of Helicobacter pylori infection and low-dose aspirin in the upper gastrointestinal..., Leung Ki [/bib_ref] Conclusion Regular aspirin significantly reduces the incidence of cancer in LS (category of evidence Ib). The optimal dose will be determined by further randomised studies. Given the lack of additional benefit revealed in the meta-analyses of follow-up data from former 'vascular' trials, a reasonable inference is that the option of taking low-dose aspirin should be discussed with gene carriers, including the risks, benefits and current limitations of available evidence (category of evidence IIb). ## Question no 9 What is the role of prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD) in LS? ## Relevant literature For some individuals, learning that they have LS may have implications for reproductive decision-making. In some cases, this knowledge impacts on the timing of decisions about having children-for example, because of their desire to have children before pursuing prophylactic salpingo-oophorectomy. In addition, some men and women planning on having children in the future may have concerns about possibly passing the genetic risk of LS-related cancers to their children. Individuals with LS should be adequately counselled about the risk of transmitting their hereditary predisposition to their future children and regarding their options for PND and PGD, including a complete discussion about the legal, practical and psychological aspects of these decisions and also the availability in various countries. [bib_ref] A clinical perspective on ethical arguments around prenatal diagnosis and preimplantation genetic..., Clancy [/bib_ref] PND is a technique that is performed in early pregnancy. If the family mutation is detected, abortion can be offered. PGD is a technique that always takes place in conjunction with assisted reproduction (in-vitro fertilisation; IVF). Following a succesful IVF procedure, one to two cells from the blastocyst can be tested for the family mutation. Only those embryos without the relevant mutation are selected for placement in the uterus. Dewanwala et al 106 recently reported that of patients found to carry a gene mutation associated with LS, 42% would consider using prenatal testing and one in five women would consider having children earlier in order to proceed with prophylactic surgery to reduce their risk of developing gynaecological cancers. In addition, the majority of individuals undergoing genetic testing for LS felt that it would be ethical to offer prenatal genetic testing, either PND or PGD, to those with pathogenic MMR gene mutations. Interestingly, while most of the subjects in their study believed prenatal testing would be ethical, only a minority would consider it themselves. These facts reinforce the idea that decisions regarding childbearing are very personal ones and may be influenced by an individual's personal and family history of cancer. # Conclusion and recommendation Cancer geneticists and genetic counsellors should be prepared to discuss the option of PND and assisted reproductive technologies during genetic counselling of individuals with LS who are of childbearing age (grade of recommendation C). ## Question no 10 What are the psychosocial implications of genetic testing and surveillance? ## Relevant literature Many studies have evaluated the psychological distress of genetic testing for LS. Most studies showed that immediately after disclosure of the test result, distress significantly increases, but decreases again after 6 months. [bib_ref] Motivations and psychosocial impact of genetic testing for HNPCC, Esplen [/bib_ref] [bib_ref] Genetic testing in families with hereditary nonpolyposis colon cancer, Lerman [/bib_ref] [bib_ref] Psychological consequences of predictive genetic testing for hereditary non-polyposis colorectal cancer (HNPCC):..., Aktan-Collan [/bib_ref] [bib_ref] Predictive genetic testing for hereditary breast and ovarian cancer: psychological distress and..., Claes [/bib_ref] [bib_ref] Psychologic distress after disclosure of genetic test results regarding hereditary nonpolyposis colorectal..., Murakami [/bib_ref] [bib_ref] Psychological impact of genetic testing for hereditary non-polyposis colorectal cancer, Meiser [/bib_ref] [bib_ref] Monitoring coping style moderates emotional reactions to genetic testing for hereditary nonpolyposis..., Shiloh [/bib_ref] Long-term studies have demonstrated that post-result increases in distress return to baseline by 1-3 years. [bib_ref] Evaluation of psychosocial effects of pre-symptomatic testing for breast/ovarian and colon cancer..., Arver [/bib_ref] [bib_ref] A systematic review of perceived risks, psychological and behavioral impacts of genetic..., Heshka [/bib_ref] [bib_ref] The impact of predictive genetic testing for hereditary nonpolyposis colorectal cancer: three..., Collins [/bib_ref] However, a substantial subgroup may experience adjustment problems. The psychological implications of surveillance for hereditary cancer has recently been reviewed by Gopie et al. [bib_ref] Surveillance for hereditary cancer: does the benefit outweigh the psychological burden? A..., Gopie [/bib_ref] In general, normal psychosocial functioning was reported in LS families, and a percentage comparable to the normal general population (10%) had clinically relevant distress levels. However, individuals with a higher cancer risk perception, decreased vitality, lower general mental health status and more anxiety are at risk of developing psychological problems. [bib_ref] Long term follow-up of HNPCC gene mutation carriers: compliance with screening and..., Wagner [/bib_ref] [bib_ref] Individuals with an increasedrisk of colorectal cancer: perceived benefits and psychological aspects..., Liljegren [/bib_ref] [bib_ref] Colorectal cancer in the family: psychosocial distress and social issues in the..., Bleiker [/bib_ref] In a Swedish study on 240 individuals at high risk of CRC (including MMR gene mutation carriers, HNPCC family members and individuals with familial CRC) evaluation of the quality of life using SF-36 (five of eight scales) showed generally normal levels but lower levels regarding mental health and vitality compared with the reference population. [bib_ref] Individuals with an increasedrisk of colorectal cancer: perceived benefits and psychological aspects..., Liljegren [/bib_ref] A study from the Danish HNPCC register demonstrated that living with the knowledge of LS has limited impact on self-concept. [bib_ref] Limited impact on self-concept in individuals with Lynch syndrome: results from a..., Petersen [/bib_ref] Three studies evaluated the experience of patients undergoing colonoscopies. The studies showed that a substantial proportion of these patients (30-60%) considered undergoing colonoscopies as unpleasant, painful and frightening. [bib_ref] Prospective study of combined colon and endometrial cancer screening in women with..., Huang [/bib_ref] After being counselled about genetic test results, index patients play an important role in the communication of information regarding LS, the gene defect in the family and the preventive measures. Aktan-Collan et al 123 investigated how parents with LS share knowledge of genetic risk with their offspring. The study reported that out of 248 mutation carriers with children, 87% reported disclosure and 13% non-disclosure. Reasons for nondisclosure were mainly the young age of offspring, socially distant relationships, or a feeling of difficulty in discussing the topic. The most difficult communication aspect was discussing cancer risk with offspring. One third of the parents suggested that health professionals should be involved in passing on this information and that a family appointment at the genetic clinic should be organised at the time of disclosure. The authors concluded that it is a great challenge to improve the communication processes, so that all offspring get information that is important for their healthcare and parents get the professional support they desire at the time of disclosure to their children. ## Recommendation Professionals should be aware of the potential psychosocial problems before and after genetic testing and during follow-up and surveillance visits. People with increased psychological distress should be offered referral to a clinical psychologist. All efforts should be made to make colonoscopies as comfortable as possible by paying full attention to adequate pain control and sedation. [table] Table 1: Validity and grading of recommendations [/table] [table] Table 2: Cumulative risk (%) of non-colonic and non-endometrial cancers according to type of mismatch repair gene mutation by age 70 years [/table] [table] Table 3: Outcome of prospective molecular screening of CRC or LS-associated cancer [/table] [table] Table 4: Outcome of colonoscopic surveillance in LS *Defined as CRC that develops after a negative screening colonoscopy. CRC, colorectal cancer; LS, Lynch syndrome. [/table] [table] Table 5: Pros and cons of surveillance for gynaecological cancer [/table] [table] Table 6: Pros and cons of prophylactic hysterectomy with and without salpingo-oophorectomy [/table] [table] Table 7: Surveillance protocol in LS [/table] [table] Table 8: Outome of studies on the effect of environmental factors on the risk of adenomas and CRC in LS those randomly assigned to placebo. The study remained double blind.102 Forty-eight participants developed 53 primary CRC (18 recruits with 19 CRC/427 randomly assigned to aspirin, 30 recruits with 34 CRC/434 assigned to aspirin placebo). Intention-to-treat analysis of the time to first CRC showed a HR of 0.63 (95% CI 0.35 to 1.13, p=0.12). Poisson regression taking account of the multiple primary events gave an incidence rate ratio (IRR) of 0.56 (95% CI 0.32 to 0.99, p=0.05). The primary endpoint of the trial was the number, size and stage of CRC after 2 years aspirin treatment. This 'per protocol' analysis yielded a HR of 0.41 (95% CI 0.19 to 0.86, p=0.02) and an IRR of 0.37 (95% CI 0.18 to 0.78, p=0. 008). Secondary analysis revealed fewer LS-related cancers in those on aspirin for at least 2 years (IRR 0.42, 95% CI 0.25 to 0.72, p=0.001). There was a negative association of LS cancer incidence with the numbers of aspirin taken ( p=0.002). In other words, the more aspirin someone had taken, the greater was the reduction in cancers developed in the gastrointestinal tract and elsewhere. [/table]	None	https://gut.bmj.com/content/gutjnl/62/6/812.full.pdf	Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families.
b0d1ad46f17469d95046f361d9a03a6f4943e974	pubmed	Summary of the Standards, Options and Recommendations for the use of positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose (FDP-PET scanning) in oncology (2002)	Summary of the Standards, Options and Recommendations for the use of positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose (FDP-PET scanning) in oncology (2002) OBJECTIVESThe objective was to review the available scientific data and to develop the Standards, Options, and Recommendations (SORs) for the role of and indications for FDG-PET scanning in oncology. The main steps in patient care that were studied were diagnosis of the primary disease, initial and secondary metastatic assessment, evaluation of treatment response, and detection of recurrent disease. The recommendations made relate to the primary cancer sites defined as priorities on the basis of the available scientific Correspondence: FNCLCC -Standards, Options, Recommendations, 101, rue de Tolbiac, When positron emission tomography (PET) scanning was introduced at the end of the 1970s, its technical characteristics and biological potential aroused immediate interest. The available tracers at time (isotopes of oxygen, nitrogen, and carbon) made it possible to study blood flow, regional oxygen consumption, the main metabolic pathways and ligand -receptor interactions in the brain, heart and other major organs, without physiological perturbations. Although the promise of the technique was fulfilled, its use has not developed as rapidly as expected. Positron emission tomography scanning was initially used to study the brain and the heart, but today it is used mainly in oncology. This is partly due to technological developments that allow whole-body examinations. There is also a growing number of publications suggesting that this technique is useful in the management of many cancers, from initial staging to posttherapeutic follow-up. The tracer generally used is 2-[ 18 F]fluoro-2-deoxy-D-glucose (FDG), which is a glucose analogue that competes with glucose at the level of transmembrane transporters. Although other tracers have been proposed ([ 11 C]methionine, [ 11 C]tyrosine and [ 11 C]thymidine), their use has not yet been validated, and the carbon-11 label is a limiting factor for extensive routine use. Nearly 70 years ago, Warburg demonstrated an increase in glycolytic activity in cancer cells, and this is the basis for use of FDG in oncology. Briefly, in most cancers, neoplastic transformation induces an increase in glucose transporters (particularly GLUT1) and in the activity of glycolytic enzymes (particularly hexokinase). These changes are responsible for an increase in glycolytic activity in cancer cells, under both aerobic and anaerobic conditions. The glycolytic activity is related to the viable tumour cell mass, as the increase in glucose transport reflects cell proliferation. Accumulation of glucose is not specific to malignant tumours but can also be increased in benign tumours and in inflammatory diseases, such as sarcoidosis and granulomatosis. In 2001, there were only four operational PET scanners in France, dedicated to clinical use. Since then, the Government has authorised the installation of about 40 sites, with a final objective of 60 PET scanners so as to provide adequate access throughout the country. The most important question about the use of PET scanning in oncology is: 'What is its usefulness in comparison with other imaging techniques?' The answer requires not only comparing the performance of PET scanning with that of other imaging techniques, but also evaluating the impact of use of PET on the management of patients with cancer. Although, many studies are under way, only a few publications specifically addressing the question are available. As with most medical imaging techniques, the clinical use of PET has developed before its efficacy and efficiency have been clearly demonstrated. The fields of application of PET scanning are evolving continuously with new research findings. However, the rapid pace of technological improvements to PET scanning results in an ever increasing list of applications, but this also prevents the accumulation of convincing data for evaluation. In this context, it was decided that clinical practice guidelines were needed to define the potential and recognised indications for FDG-PET scanning in oncology. data: cancers of lung and pleural, melanoma, gynaecological cancers, gastrointestinal cancers, head-and-neck cancers, urological cancers, lymphomas, soft-tissue and bone sarcomas, and cancers of the thyroid, and also carcinomas of unknown primary site. For some cancer sites, the working group considered that an evaluation was either not timely or that the available data were inadequate. These topics, in particular cerebral tumours and childhood cancers, will be addressed when these recommendations are updated. # Methods The details of the methodology have been published previously [bib_ref] SOR: project methodology, Fervers [/bib_ref]. For this particular SOR, a multidisciplinary group of experts was set up by the French National Federation of Cancer Centres (FNCLCC) and the French Society for Biophysics and Nuclear Medicine (Société Franc¸aise de Biophysique et Médecine Nuclear, SFBMN) to critically appraise the available evidence on the role of and indications for FDG-PET scanning in oncology. Literature searches were performed for each cancer site in Medline s , from January 1996 to November 2001, and in the Cochrane s Library, Issue 3, 1999. The Cancerlit s database and the proceedings from American Society of Clinical Oncology conferences were also searched. The search excluded articles in languages other than English and French, as well as in vitro and animal studies. Studies in which tracers other than FDG were used were not specifically sought, although studies comparing FDG with other tracers were included for certain cancer sites, when they provided data for the relevant outcomes. The review met with a recurrent difficulty: multiple publication in different journals of the same study, with an increasing number of patients, and sometimes with the authors in a different order. In this situation, only the last publication, including the largest number of patients, was retained for this report. The literature search was complemented with personal references supplied by the experts. In certain chapters, references published after November 2001 were added when the working group considered it necessary, especially when the new references had an impact on the definition of a standard or an option. The data analysis also included three reports of evaluations and recommendations for FDG-PET scanning [bib_ref] Positron emission tomography: establishing priorities for health technology assessment, Robert [/bib_ref] ; AETMIS, Agence d'évaluation des technologies et des modes d'intervention en santé, 2001) and the report of a German consensus conference [bib_ref] FDG-PET for clinical use, Reske [/bib_ref]. The working group selected and critically appraised pertinent references and then proposed the 'Standards', 'Options', and 'Recommendations' for the role of and indications for FDG-PET scanning in oncology, based on either the best available evidence or expert agreement. 'Standards' identify clinical situations for which there exist strong indications or contraindications for a particular FDG-PET application and 'Options' identify situations for which there are several alternatives, none of which have shown clear superiority over the others [fig_ref] Table 1: Definition of Standards, Options and Recommendations [/fig_ref]. In any SOR, there can be several 'Options' for a given clinical situation. 'Recommendations' enable the 'Options' to be weighted according to the available evidence. Several FDG-PET applications can be recommended for the same clinical situation, so that clinicians can make a choice according to specific clinical parameters, for example, local circumstances, skills, equipment, resources, and patient preferences. Adapting the SORs to a local situation is possible if the reason for the choice is sufficiently transparent and this is crucial for successful implementation. Inclusion of patients in clinical trials is an appropriate form of patient management in oncology and is recommended frequently within the SORs, particularly in situations where evidence is too weak to support a particular FDG-PET application. The type of evidence underlying any 'Standard', 'Option', or 'Recommendation' is indicated using a classification developed by the FNCLCC based on previously published models. The level of evidence depends not only on the type and quality of the studies reviewed, but also on the concordance of the results . When no clear scientific evidence exists, judgment is made according to professional experience and consensus of the working group ('expert agreement'). In this particular situation, that is, a diagnostic test, it is sometimes difficult to classify levels of evidence. In addition, PET scanning is an emerging technique, for which many indications are Procedures or treatments that are considered to be of benefit, inappropriate or harmful by unanimous decision based on the best available evidence Options Procedures or treatments that 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 explicit criteria (e.g. survival, toxicity) with an indication of the level of evidence Definition of level of evidence Level A There exist a high-standard meta-analysis or several high-standard randomised clinical trial 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 do not exist or there is only a series of cases ## Expert agreement The data do not exist for the method concerned, but the experts are unanimous in their judgement still being evaluated. The working group, therefore, decided to identify not only standards and options for protocols being evaluated but also indications that require confirmation. The standards are based on levels of evidence A or B and represent indications for which the working group considered that PET scanning is essential for the care of patients. The options are usually based on a high level of evidence (B2), whereas the indications that require confirmation are those for which published data are scarce or insufficient (levels of evidence C, D, and expert agreement). For certain indications, despite a low level of evidence, the clinical usefulness of PET scanning was considered by the working group to be high, thus the indication is classified as an option (expert agreement). The document containing the SORs was then reviewed by a group of independent experts (see the Appendix) and after taking into consideration their comments, the guidelines were validated by the working group. This English-language version is based on the summary version, which was itself based on the French full text version [bib_ref] Standards, Options and Recommandations for use of positrons emission tomography with [..., Bourguet [/bib_ref]. The French full text and summary versions are available on the FNCLCC web site (http://www.fnclcc.fr). A working group has been set up to monitor new scientific data on FDG-PET systematically. These clinical practice guidelines will be updated when new evidence becomes available or if there is a new consensus among the experts. In addition, patient-targeted information is being developed by the SOR SAVOIR PATIENT project, based on the specialist information (available late 2003). The SORs for use of FDG-PET scanning in oncology are summarised in [fig_ref] Table 3: Summary of Standards, Options, and Recommendations for FDP-PET scanning [/fig_ref] [table] Table 1: Definition of Standards, Options and Recommendations [/table] [table] Table 3: Summary of Standards, Options, and Recommendations for FDP-PET scanning [/table]	None	https://www.nature.com/articles/6601088.pdf	None
8326c32a33fb5a26a401a114bc632931914a4024	pubmed	Prevention of Venous Thromboembolism, 2nd Edition: Korean Society of Thrombosis and Hemostasis Evidence-Based Clinical Practice Guidelines	Prevention of Venous Thromboembolism, 2nd Edition: Korean Society of Thrombosis and Hemostasis Evidence-Based Clinical Practice Guidelines # Introduction Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a major cause of morbidity and mortality in hospitalized patients. PE is the third most common fatal vascular disorder following coronary artery disease and cerebrovascular accident [bib_ref] A population-based perspective of the hospital incidence and case-fatality rates of deep..., Anderson [/bib_ref] ; it is also the leading cause of preventable hospital death and a major cause of maternal mortality [bib_ref] Pregnancy-related mortality surveillance: United States, Chang [/bib_ref]. In addition to the clinical impact of VTE on morbidity and mortality, the economic burden of the disease is considerable [bib_ref] Economic burden of venous thromboembolism: a systematic review, Ruppert [/bib_ref]. Thus, VTE is a major public health concern in developed countries. For the treatment of VTE, thromboprophylaxis has been recommended based on the four following factors: the high incidence of VTE in hospitalized patients; the difficulty of early diagnosis due to vague symptomatology; the cost-effectiveness of medical prophylaxis; and the high mortality of PE without early diagnosis and prompt management. Furthermore, data from numerous clinical trials have demonstrated that appropriate prophylaxis to prevent VTE is safe and effective in both surgical and medical patients. Based on these results, several evidence-based guidelines have been proposed for VTE prevention [bib_ref] Asian venous thromboembolism guidelines: prevention of venous thromboembolism, Liew [/bib_ref] [bib_ref] NHMRC VTE Prevention Guideline Adaptation Committee. Prevention of venous thromboembolism in patients..., Wickham [/bib_ref]. Recently, the American College of Chest Physicians (ACCP) issued the evidence-based clinical practice guideline for antithrombotic therapy and prevention of thrombosis, which provides improved guidelines in an American setting (9th edition). The incidence of VTE is lower in the Korean population than in the Caucasian population; however, it appears to be rapidly increasing in response to the widespread adop-tion of the Western lifestyle. Additionally, the large proportion of the Korean population is comprised of the elderly, and advanced age has been recognized as a risk factor for VTE. After we proposed the first Korean Guideline for the Prevention of VTE in 2010 [bib_ref] Korean guidelines for the prevention of venous thromboembolism, Bang [/bib_ref] , awareness of the significance and risk of VTE has been increasing among both the public health community and physicians in Korea. However, the previous guidelines were not based on clinical evidence, but on a consensus of the opinions of the expert panel of the Korean Society of Thrombosis and Hemostasis with references of the second edition of the Japanese guidelines for the prevention of VTE, and the ACCP guidelines (8th edition). We recently revised the Korean guidelines for VTE prevention based on the Health Insurance Review and Assessment Service (HIRA) database [bib_ref] Incidence of venous thromboembolism (VTE) after major surgeries and proposal of evidence-based..., Bang [/bib_ref] and new ACCP guidelines. These guidelines were established to reflect Korean VTE epidemiology and serve as practical recommendations for physicians in Korea. They focus on patients undergoing major surgery and are intended to assist physicians in balancing the risks of death and morbidity from VTE against the complications and disadvantages of prophylaxis. Unfortunately, the extended content of these guidelines can be too much complex for physicians. This article represents a simplified, practical version of the revised guidelines that provide an overview of the key issues that are relevant to physicians. These guidelines stratify patients into 4 risk groups (very low, low, moderate, and high) according to the actual VTE risk and recommend an optimal VTE prophylaxis for each group. ## General recommendations ## Risk stratification The VTE risk of all hospitalized patients should be assessed using an accepted risk stratification method. Additionally, the method for risk stratification should be simple, efficient, and cost-effective. Classic risk factors for VTE include cancer, surgery, prolonged immobilization, fractures, puerperium, paralysis, use of oral contraceptives, antiphospholipid antibody syndrome, and other acquired or hereditary thrombophilic conditions. Most hospitalized patients have at least one risk factor for VTE, and decisions regarding the risk of VTE should include considerations of current and future thrombotic risks [bib_ref] The prevalence of risk factors for venous thromboembolism among hospital patients, Anderson [/bib_ref]. The ACCP Evidenced-Based Clinical Practice Guidelines (9th Edition) for the Prevention of VTE suggests a risk stratification model based on the symptomatic VTE rate [bib_ref] Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines:..., Guyatt [/bib_ref]. This model classifies patients into very low risk ( < 0.5%), low risk (0.5%-1.5%), moderate risk (1.5%-3.0%), and high risk ( > 3%) groups, depending on the symptomatic VTE rate. Because the ultimate target of VTE prevention is symptomatic VTE, this approach is both simple and practical. Thus, we used this risk-stratification method in the development of our revised guidelines. ## Non-pharmacologic thromboprophylaxis Ambulation increases venous blood flow and reduces venous stasis. Early ambulation is a simple measure that should be applied as standard practice to prevent VTE in all patients. Mechanical prophylaxis, including graduated compression stocking (GCS) and intermittent pneumatic compression (IPC), focuses on reducing venous stasis and blood stagnation by promoting venous blood flow through external compression. Mechanical methods have an additional advantage in that they are not associated with a risk of bleeding. Mechanical prophylaxis is recommended as an alternative to or in combination with pharmacological prophylaxis. The benefits of decreasing VTE risk were similar irrespective of the mechanical method used. ## Pharmacologic thromboprophylaxis Pharmacological prophylaxis is both reasonable and cost-effective and is therefore recommended as the initial form of prophylaxis in most patients without a high risk of bleeding. Effective pharmacological prophylaxis may include low-molecularweight heparin (LMWH; 20-100 U/kg (0.2-1 mg/kg) subcutaneously [SC] daily), low-dose unfractionated heparin (LDUH; 5,000 U every 8-12 hr SC), fondaparinux (2.5 mg SC daily), rivaroxaban (10 mg orally daily), dabigatran (150 mg orally each day), apixaban (2.5 mg every 12 hr orally), aspirin (100 mg orally each day), and warfarin (daily doses to maintain an international normalized ratio [INR] of 1.5-2.5) [fig_ref] Table 1: Methods of thromboprophylaxis [/fig_ref]. The duration of prophylaxis depends on the perceived benefits of anticoagulation versus the risks of bleeding and overall cost. Currently, dabigatran and apixaban are not approved by the Korean FDA for thromboprophylaxis. ## Stratification of vte risk in hospitalized patients Based on the risk stratification for individual patients, the risk of VTE can be stratified from very low to high . However, the prophylactic treatment selected is not solely procedure-specific, but depends on the individual's level of risk based on care- High-quality evidence: Evidence from a meta-analysis of randomized controlled trials or at least one or more randomized controlled trial(s) Moderate-quality evidence: Evidence from a randomized controlled study with a serious limitation or large-scale observational studies Low-or very low-quality evidence: Evidence from small-scale observational studies or non-experimental descriptive studies such as comparative studies, correlation studies, case-control studies, or expert opinions ful risk assessment. We defined patients at very low risk as those undergoing surgery for breast cancer, gastric cancer ( < 60 yr), or hepatobiliary cancer ( < 60 yr); cesarean section, hystectomy, or oophorectomy for benign disease; and transurethral resection of the prostate, nephrectomy, cystectomy, or prostatectomy for benign or malignant disease. For patients undergoing gastric cancer surgery ( ≥ 60 yr), hepatobiliary cancer surgery ( ≥ 60 yr), or hysterectomy (cervical cancer), we define these patients as low risk. Moderate-risk patients are defined as those undergoing surgery for colorectal, pancreatic, ovarian, or esophageal cancer; total hip arthroplasty (THA); total knee arthroplasty (TKA); or hip fracture surgery (HFS). If the moderate risk patients have an addition risk factor, including previous VTE or thrombophilia, we define these patients as high-risk patients. ## Thromboprophylaxis according to risk stratification We recommend the selection of an optimal prophylactic treatment based on VTE risk levels. Generally, mechanical prophylaxis is recommended for low or moderate risk patients, and pharmacological prophylaxis is recommended for moderate or high-risk patients. For patients with very low risk of VTE, we recommend early ambulation or exercise only; for patients with low risk of VTE, we recommend mechanical prophylaxis with GCS or IPC; for patients with moderate risk of VTE, we recommend mechanical or pharmacological prophylaxis; and for patients with high risk of VTE, we recommend pharmacological prophylaxis with or without a mechanical method. ## Grade of recommendation We adopted the quality of evidence and strength of recommendations from the 9th ACCP guidelines [bib_ref] Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines:..., Guyatt [/bib_ref]. The grade of recommendation indicates the strength of the guideline and the degree of consensus agreement. We define the Grade 1A as a strong recommendation with high-quality evidence; Grade 1B as a strong recommendation with moderate-quality evidence; Grade 1C as a strong recommendation with low-or very-low-quality evidence; Grade 2A as a weak recommendation with high-quality evidence; Grade 2B as a weak recommendation with mod- erate-quality evidence; and Grade 2C as a weak recommendation with low-or very-low-quality evidence [fig_ref] Table 3: Strength of recommendations and quality of evidence [/fig_ref]. ## General surgery The principles of risk stratification for general surgery are based on the type of surgery (cancer or non-cancer), the type of cancer (gastric, colorectal, hepatobiliary, or breast), age ( < 60 yr, and ≥ 60 yr), and the presence of previous VTE. According to these principles, patients were classified into four risk groups. We define the very-low-risk group as patients scheduled for non-cancer surgery or breast cancer surgery and patients ( < 60 yr) scheduled for gastric or hepatobiliary cancer surgery. For very-low-risk patients, we recommend early and frequent ambulation (Grade 2C). For patients ( ≥ 60 yr) undergoing gastric or hepatobiliary cancer surgery, we recommend mechanical prophylaxis with GCS or IPC (Grade 2C). We recommend mechanical prophylaxis with GCS or IPC for patients undergoing colorectal or pancreatic cancer surgery, but pharmacological prophylaxis with LMWH or LDUH may also be used for patients with a low risk of bleeding (Grade 2C). If patients undergoing any cancer surgery have an additional risk factor, including previous VTE or thrombophilia, we recommend pharmacological prophylaxis with LMWH or LDUH (Grade 1B) [fig_ref] Table 4: Levels of VTE risk and recommendations for general surgery [/fig_ref]. ## Orthopedic surgery Patients undergoing major orthopedic surgery, which includes total hip arthroplasty (THA), total knee arthroplasty (TKA), and hip fracture surgery (HFS), are at particularly high risk for VTE. Although routine prophylaxis is adopted these high-risk patients, the rate of clinically overt VTE in these patients remains at approximately 1.8% [bib_ref] American College of Chest Physicians. Prevention of VTE in orthopedic surgery patients:..., Falck-Ytter [/bib_ref]. Recently, a prospective study reported that the rate of symptomatic VTE is 1.5% in Asian patients who have a major orthopedic surgery without VTE prophylaxis [bib_ref] Epidemiology of venous thromboembolism in Asian patients undergoing major orthopedic surgery without..., Leizorovicz [/bib_ref]. The HIRA database also revealed that the rate of symptomatic VTE is 1.08% for TKA, 0.98% for THA, and 1.60% for HFS. Based on these results, we classified the patients scheduled for major orthopedic surgery into the moderate-risk group for VTE. We recommend pharmacological or mechanical prophylaxis for patients scheduled for major orthopedic surgery for at least 10-14 days (Grade 2A). We recommend pharmacological prophylaxis (LMWH, fondaparinux, dabigatran, apixaban, rivaroxaban, LDUH, warfarin, or aspirin) for patients undergoing TKA and THA, and mechanical prophylaxis for patients with a risk of bleeding. For patients undergoing HFS, we recommend pharmacological (LMWH, fondaparinux, LDUH, warfarin, or aspirin) or mechanical prophylaxis. For all patients undergoing major orthopedic surgery, we recommend mechanical prophylaxis (Grade 2B). If the patients have an additional risk factor, including advanced age, general anesthesia, previous VTE, or cancer, we recommend pharmacological prophylaxis (Grade 2B). Early ambulation should be encouraged for all patients after surgery (Grade 1A). Routine screening is not recommended in these patients (Grade 1A) [fig_ref] Table 5: Levels of VTE risk and recommendations for orthopedic surgery [/fig_ref]. ## Neurosurgery Neurosurgical patients are at an increased risk of both thrombosis and bleeding. The incidence of DVT and subsequent PE in neurosurgery patients has been reported to be as high as 25%, and the PE mortality rate has been reported to range from 9% to 50% [bib_ref] Enoxaparin plus compression stockings compared with compression stockings alone in the prevention..., Agnelli [/bib_ref] [bib_ref] Experience with external pneumatic calf compression in neurology and neurosurgery, Black [/bib_ref]. The important risk factors in neurosurgical surgery are the type of surgery (cranial, spinal, or vascular), duration of surgery, cancer, infection, immobilization, venous stasis, chronic lower extremity swelling, lower extremity trauma, advanced age, CHF, obesity, and sleep apnea. The HIRA database revealed that the rate of DVT is 0.14% and the rate of PE is 0.24% in patients who have undergone brain tumor surgery. We recommend mechanical prophylaxis for all neurosurgery patients (Grade 2C). If the patients have an additional risk factor, including advanced age, female, previous VTE, or brain cancer, we selectively recommend pharmacological prophylaxis (Grade 2C). Patients should be closely monitored for signs of bleeding during pharmacological prophylaxis (Grade 1A). ## Urologic surgery The important risk factors for the development of VTE in urological surgery patients are advanced age, obesity, cancer, and previous VTE. The HIRA database shows that the rate of VTE is 0.35% in kidney cancer patients who underwent nephrectomy, 0.17% in bladder cancer patients with cystectomy, 0.22% in prostate cancer patient with prostatectomy, and 0.06% in prostate hyperplasia patients who received transurethral resection of the prostate. Based on these results, we classified patients with these urologic surgeries into the very-low-risk group. We recommend early and frequent ambulation for transurethral resection of the prostate (Grade 2A). For cancer patients undergoing nephrectomy, cystectomy, and prostatectomy, early and frequent ambulation is recommended (Grade 2B). For patients with previous VTE or thrombophilia and elderly patients ( ≥ 60 yr) scheduled for major urologic surgery under general anesthesia, we recommend mechanical prophylaxis or pharmacological prophylaxis (LMWH or LDUH) or a combination of both pharmacological and mechanical prophylaxis (Grade 2B). ## Obstetric and gynecologic surgery The incidence of VTE is higher during pregnancy and may occur at any stage of pregnancy or in the weeks following delivery. The risk factors for VTE in pregnant women include previous VTE, a family history of VTE, presence of anti-phospholipid antibody, age ≥ 40 yr, prolonged bed rest, placenta previa, Cesarean section, and lower-extremity varicosities. The HIRA database shows that the incidence of pregnancy-associated VTE is 0.82 per 10,000 deliveries [bib_ref] Incidence of pregnancy-associated venous thromboembolism in Korea: from the Health Insurance Review..., Jang [/bib_ref]. We suggest that a thrombosis risk assessment be carried out in all women during pregnancy (Grade 1A). Early ambulation should be encouraged for all postpartum women (Grade 1A). For postpartum women without any risk factor for VTE, we do not recommend mechanical or pharmacological prophylaxis regardless of delivery mode (Grade 2A). Further, we do not recommend routine thrombophilia testing (Grade 1B). For pregnant women with hereditary thrombophilia, positive anti-phospholipid antibody, or previous VTE, antepartum plus postpartum prophylaxis is recommended (Grade 1B). Warfarin is contraindicated during pregnancy (category X) (Grade 1A) [bib_ref] The safety of antithrombotic therapy during pregnancy, Ageno [/bib_ref]. However, warfarin can replace LMWH after delivery for postpartum thromboprophylaxis (20) (Grade 1B). The risk factors for VTE associated with gynecologic surgery are giant uterine myoma, previous surgery for an ovarian tumor, ovarian cancer, uterine or cervical cancer, severe intrapelvic adhesions, ovarian hyperstimulation syndrome, hormonal therapy, and particularly protracted lymph node dissection requiring transfusion [bib_ref] Clinically significant venous thromboembolism after gynecologic surgery, Schorge [/bib_ref]. The HIRA database revealed that rates of VTE are 0.02% for hysterectomy associated with benign disease, 0.59% for hysterectomy associated with cervical cancer, 0.05% for oophorectomy associated with benign disease, and 1.21% for ovariectomy associated with ovarian cancer. We recommend early and frequent ambulation for very-low-risk patients (hysterectomy or oophorectomy with benign disease) (Grade 2B). For low-risk patients undergoing hysterectomy with cervical cancer, mechanical prophylaxis is recommended (Grade 2B). For moderate-risk patients undergoing oophorectomy with ovarian cancer, we recommend pharmacological prophylaxis with LMWH or LDUH (Grade 2B). If moderate-risk patients are at risk of bleeding during anticoagulation therapy, we recommend mechanical prophylaxis (Grade 2B). ## Major trauma and spinal cord injury VTE can cause significant morbidity in patients experiencing major trauma and occurs in up to 50% of patients without prophylaxis [bib_ref] A prospective study of venous thromboembolism after major trauma, Geerts [/bib_ref]. Previous studies have identified several risk factors for VTE including age, male gender, pelvic fractures, lower extremity fractures, traumatic brain injury, increased Injury Severity Score, chest injury, operative interventions, and acute spinal cord injury (SCI) [bib_ref] Thromboembolism after trauma: an analysis of 1602 episodes from the American College..., Knudson [/bib_ref] [bib_ref] Venous thromboembolism in patients with major trauma, Shackford [/bib_ref]. We recommend mechanical or pharmacological prophylaxis for major trauma patients (Grade 2C). If the patients have a high risk of bleeding (intracranial bleeding, lung injury, liver injury, spleen injury, and retroperitoneal bleeding associated with pelvic bone fracture), mechanical prophylaxis (GCS or IPC) should be implemented (Grade 2C). When the risk of bleeding has been eliminated, we recommend that pharmacologic prophylaxis with LDUH or LMWH be substituted for the mechanical prophylaxis (Grade 2C). Usually, pharmacological prophylaxis can be used within [bib_ref] Predictive and associative models to identify hospitalized medical patients at risk for..., Spyropoulos [/bib_ref] (Grade 2C). We recommend that pharmacological prophylaxis be continued for 3 months following trauma (Grade 2C). Patients with SCI have been shown to be at higher risk for DVT than many other trauma patients. Overall, the incidence of DVT without prophylaxis is estimated to be 40% based on a meta-analysis of DVT in patients with acute spinal cord injury [bib_ref] Etiology, incidence, and prevention of deep vein thrombosis in acute spinal cord..., Merli [/bib_ref]. Moreover, prevention of VTE is important because PE is a leading cause of death in SCI patients [bib_ref] Recent trends in mortality and causes of death among persons with spinal..., Devivo [/bib_ref]. We recommend pharmacological prophylaxis with LDUH, LMWH, or warfarin for SCI patients without a risk of bleeding (Grade 2C). If the patient is contraindicated for pharmacological prophylaxis, mechanical prophylaxis (GCS or IPC) should be implemented (Grade 2C). We recommend that prophylaxis be continued for 3 months (Grade 2C); however, the duration can be decreased after ambulation (Grade 2C). If patients are complicated with spinal or epidural hematoma, mechanical prophylaxis (GCS or IPC) should be implemented for several days (Grade 2C). When the risk of bleeding has decreased, we recommend that pharmacologic prophylaxis (LDUH or warfarin) be substituted for the mechanical prophylaxis or be combined with mechanical prophylaxis (Grade 2C). ## Neuraxial anesthesia Neuraxial anesthesia is a comprehensive term used for spinal, epidural, and caudal blocks. The risk for the development of spinal or epidural hematoma may be elevated by the concomitant use of anticoagulants and antiplatelet agents [bib_ref] Severe neurological complications after central neuraxial blockades in Sweden 1990-1999, Moen [/bib_ref]. The established risk factors for spinal or epidural hematoma after neuraxial blockade include an underlying hemostatic disorder, an anatomically deformed vertebral column, traumatic insertion of a needle or catheter, repeated insertion attempts, concomitant anticoagulation, continuous use of epidural catheters, and old age [bib_ref] Anticoagulants and spinalepidural anesthesia, Vandermeulen [/bib_ref] [bib_ref] Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic..., Geerts [/bib_ref]. We recommend against concomitant administration of medications affecting hemostasis, such as antiplatelet drugs or warfarin, during anticoagulation with LMWH or UFH (Grade 1B). The presence of blood during needle and catheter placement does not necessitate postponement of surgery. We suggest that initiation of LMWH therapy in this setting should be delayed for 24 hr postoperatively and that this consideration be discussed with the surgeon (Grade 2C). For patients receiving prophylactic doses of LMWH, we recommend a delay of at least 10-12 hr after the time of needle insertion (Grade 1C). For patients receiving therapeutic doses of LMWH, we recommend a delay of at least 24 hr before the time of needle insertion (Grade 1C). For patients receiving twice-daily dosing of LMWH, the first dose of LMWH should be administered no earlier than 24 hr postoperatively (Grade 1C). If the epidural catheter is left indwelling overnight, administration of LMWH should be delayed for 2 hr after catheter removal (Grade 1C). We recommend that the anticoagulant therapy be discontinued (ideally 4-5 days before the planned procedure) and the INR must be normalized before initiation of neuraxial block (Grade 1B). As prophylaxis with warfarin is initiated, we suggest that neuraxial catheters should be removed when the INR is less than 1.5 (Grade 2C). Cyclooxygenase-2 inhibitors have a minimal effect on platelet function and should be considered in patients who require anti-inflammatory therapy in the presence of anticoagulation (Grade 2C). We recommend an interval between the last dose of clopidogrel or aspirin and neuraxial blockade of at least 7 days (Grade 1C). ## Medical conditions Hospitalized patients with acute medical conditions are at a significant risk of VTE. Previous studies have shown that in the absence of prophylaxis, a significant proportion of acutely ill medical patients develop VTE, with DVT and PE incidence of 10-30% in general medical patients [bib_ref] Effective risk stratification of surgical and nonsurgical patients for venous thromboembolic disease, Caprini [/bib_ref] [bib_ref] Prevention of venous thromboembolism: International Consensus Statement: guidelines compiled in accordance with..., Nicolaides [/bib_ref] [bib_ref] A comparison of enoxaparin with placebo for the prevention of venous thromboembolism..., Samama [/bib_ref]. Despite extensive studies in medical patients, the morbidity and mortality of VTE remains significant. The risk of VTE was determined by assessing the probability of VTE in acutely ill medical patients according to predisposing risk factors (age > 70 yr, obesity, long-term immobility, tobacco use, varicosities, dehydration, estrogens, cancer, previous DVT, paraplegia, congenital or acquired thrombophilia, and inflammatory bowel disease) and acute medical illnesses currently under treatment (chronic obstructive pulmonary disease exacerbation, mechanical ventilator therapy, infection, congestive heart failure, and cerebrovascular attack) [bib_ref] Venous thromboembolism prophylaxis and risk assessment in medical patients, Arcelus [/bib_ref] [bib_ref] A risk assessment model for the identification of hospitalized medical patients at..., Barbar [/bib_ref] [bib_ref] Predictive and associative models to identify hospitalized medical patients at risk for..., Spyropoulos [/bib_ref]. We recommend routine assessment for VTE risk and bleeding risk in all acute medically ill patients (Grade 1A). The physician should decide the optimal VTE prophylaxis according to the number of VTE risk factors, level of VTE risk, and risk of bleeding (Grade 2C). For acutely ill medical patients who have one or more additional risk factors, including congestive heart failure, myocardial infarction, cerebrovascular attack, metastatic cancer, or previous VTE, we recommend pharmacological prophylaxis or mechanical prophylaxis (Grade 2C). The majority of patients admitted to the intensive care unit have multiple risk factors for VTE. These patients should be routinely assessed and offered pharmacological prophylaxis or mechanical prophylaxis (Grade 2A). For metastatic cancer patients who have previous VTE or thrombophilia, we recommend pharmacological prophylaxis (Grade 2A). Mechanical prophylaxis can be used when there is a contraindication to anticoagulation (Grade 1A) [fig_ref] Table 6: Levels of VTE risk in medical patients MI, CHF [/fig_ref]. ## Summary These guidelines emphasize strategies for the prevention of VTE in Korean patients experiencing surgery, pregnancy, trauma, cancer, and acute medical illness. Based on VTE risk factors (age, immobility, history of VTE, co-morbid illness, and type of surgery or trauma), patients can be stratified into very-low-, moderate-, and high-risk groups. For high-risk patients (any cancer surgery with previous VTE or thrombophilia, major orthopedic surgery with additional risk, and SCI), pharmacological prophylaxis is recommended. Mechanical prophylaxis should be used primarily in patients with a high risk of bleeding. For moderate-risk patients (colorectal or pancreatic cancer surgery, major orthopedic surgery without additional risk, and major trauma), prophylaxis with a mechanical method (GCS and/or IPC) or a pharmacological method can be used. For low-risk patients (gastric cancer surgery [ ≥ 60 yr], hepatobiliary cancer surgery [ ≥ 60 yr], and hysterectomy [cervical cancer]), mechanical prophylaxis is recommended. For very-low-risk patients, early and frequent ambulation is the only recommended prophylactic treatment. In conclusion, this article outlines the revised Korean guidelines issued for primary VTE prevention and provides a useful reference for clinicians. These guidelines must be updated based on results of well-controlled studies conducted in Korea. Our guidelines aim to define and clarify an optimal strategy for VTE prevention for patients with VTE risk; however, the ultimate decision should be individualized and determined by the physician. # Disclosure [table] Table 1: Methods of thromboprophylaxis [/table] [table] Table 3: Strength of recommendations and quality of evidence [/table] [table] Table 4: Levels of VTE risk and recommendations for general surgery [/table] [table] Table 5: Levels of VTE risk and recommendations for orthopedic surgery [/table] [table] Table 6: Levels of VTE risk in medical patients MI, CHF (NYHA grade III or IV) Metastatic cancer with immobilization Admitted to intensive care unit High Severe medical illness with previous VTE or thrombophilia Cerebral stroke complicated with paralysis VTE, venous thromboembolism; COPD, chronic obstructive pulmonary disease; MI, myocardial infarction; CHF, congestive Heart failure; NYHA, New York Heart Association. http://dx.doi.org/10.3346/jkms.2014.29.2.164 [/table]	None	None	In 2010, we proposed the first Korean Guidelines for the Prevention of Venous Thromboembolism (VTE). It was applicable to Korean patients, by modifying the contents of the second edition of the Japanese guidelines for the prevention of VTE and the 8th edition of the American College of Chest Physicians (ACCP) evidence-based clinical practice guidelines. From 2007 to 2011, we conducted a nationwide study regarding the incidence of VTE after major surgery using the Health Insurance Review and Assessment Service (HIRA) database. In addition, we have considered the 9th edition of the ACCP Evidenced-Based Clinical Practice Guidelines, published in 2012. It emphasized the importance of clinically relevant events as opposed to asymptomatic outcomes with preferences for both thrombotic and bleeding outcomes. Thus, in the development of the new Korean guidelines, three major points were addressed: 1) the new guidelines stratify patients into 4 risk groups (very low, low, moderate, and high) according to the actual incidence of symptomatic VTE from the HIRA databases; 2) the recommended optimal VTE prophylaxis for each group was modified according to condition-specific thrombotic and bleeding risks; 3) guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and/or physician advice. Graphical Abstract
6ec9055bb5bf809e728046c4c36aba89e7b61ce6	pubmed	Summary of the Standards, Options and Recommendations for the management of patients with nonmetastatic prostate cancer (2001)	Summary of the Standards, Options and Recommendations for the management of patients with nonmetastatic prostate cancer (2001) In 1995 the crude incidence of prostate cancer in France was estimated to be 260 -300 out of 100 000 for men aged between 60 and 70 years and over 500 out of 100 000 for men over 70 years of age. The majority of men (73%) are diagnosed when they are over 70 years old. The standardised incidence increased from 51.8 to 87.1 between 1985 and 1995. It has been estimated that in 1995, 26 474 new cases were diagnosed in France. The use of diagnostic tests has contributed to an increase in the number of patients detected with local or locoregional disease. The crude mortality rate for prostate cancer in France was 32.8 out of 100 000 in 1995, and remains stable. ## Objectives The objectives of these recommendations are to define good clinical practice guidelines for the diagnosis and treatment of patients with nonmetastatic prostate cancer. The management of patients with stage T4 cancer is not specifically covered in this document, but some of the studies appraised also included patients with this stage of cancer. # Methods The details of the methodology have been published previously [bib_ref] SOR: project methodology, Fervers [/bib_ref]. For this particular SOR, a multidisciplinary group of experts was set up by the French National Federation of Cancer Centres (FNCLCC) and the French Urology Association (Association Franc¸aise d'Urologie: AFU) to appraise critically the available evidence on the diagnosis and treatment of patients with prostate cancer. Medline s was searched from 1966 to 2000. This bibliography was completed by the references of the members of the working group, and a search for clinical practice guidelines published on the Internet. The working group selected and critically appraised pertinent references and then proposed the 'Standards', for the diagnosis and treatment of patients with nonmetastatic prostate cancer, based on either the best available evidence or expert agreement. 'Standards' identify clinical situations for which there exist strong indications or contra-indications for a particular intervention and 'Options' identify situations for which there are several alternatives, none of which have shown clear superiority over the others [fig_ref] Table 1: Definition of 'Standards, Options and Recommendations' [/fig_ref]. In any SOR, there can be several 'Options' for a given clinical situation. 'Recommendations' enable the 'Options' to be weighted according to the available evidence. Several interventions can be recommended for the same clinical situation, so that clinicians can make a choice according to specific clinical parameters, for example, local circumstances, skills, equipment, resources and patient preferences. Adapting the SORs to a local situation is possible if the reason for the choice is sufficiently transparent and this is crucial for successful implementation. Inclusion of patients in clinical trials is an appropriate form of patient management in oncology and is recommended frequently within the SORs, particularly in situations where evidence is too weak to support an intervention. The type of evidence underlying any 'Standard', 'Option' or 'Recommendation' is indicated using a classification developed by the FNCLCC based on previously published models. The level of evidence depends not only on the type and quality of the studies reviewed, but also on the concordance of the results . When no clear scientific evidence exists, judgement is made according to the professional experience and consensus of the expert group ('expert agreement'). The document containing the Standards, Options and Recommendations was then reviewed by a group of independent experts (see Appendix) and after taking into consideration their comments, the guidelines were validated by the working group. This is a translation of the summarised version based on the full text (in French) which has been published as a monograph [bib_ref] A Houlgatte (HIA du Val de Grâce, Paris), F Iborra (Montpellier), Villers [/bib_ref] and which is also available on the FNCLCC web site (http://www.fnclcc.fr). These clinical practice guidelines will be updated when new evidence becomes available or if there is a new consensus among the experts. ## Risk factors Family history (inherited or familial forms) and ethnogeographical origins (particularly African) enable high-risk groups to be defined as a priority for targeted screening (annual digital rectal examination and serum PSA determination in men over 40 years old). ## Classification of prostate adenocarcinoma The 1997 TNM classification, modified by the criteria of the American Joint Cancer Committee for stage T1a and T1b cancers, should be used (standard). A cancer should be classed as stage T1a when it accounts for at least 5% of the resected tissue (by transurethral or simple prostatectomy) with a Gleason score under 7 (i.e. no grade 4 or 5 disease) (standard). Prior to surgery, patients should be stratified by their initial PSA concentration, the ratio of number of positive biopsies to the total number of biopsies and the percentage of grade 4/5 disease, in order to evaluate the response to treatment (option). Histopathological findings from the radical prostatectomy specimen should be documented (option), as they are independently correlated with prognosis (i.e. the risk of PSA recurrence after 5 years). The three relevant criteria are the total tumour volume, the extent of any poorly differentiated tumour (Gleason grades 4 and 5) and tumour localisation outside or within the transition zone (option). ## Pathology histological diagnosis on biopsy specimens The diagnosis of prostatic adenocarcinoma is generally made using routine haematoxylin and eosin staining and is based on structural and cytological findings (standard). If an isolated area of highgrade prostatic intraepithelial neoplasia (PIN) or atypical or borderline lesions are detected, serial sections of all resected tissue should be made to locate any foci of microscopic carcinoma (standard). Anti-PSA and anti-PAP antibodies can be used to detect metastatic sites in those patients with poorly differentiated tumours of uncertain prostatic or urethral origin (standard). Immunohistochemistry with anti-cytokeratin 903 antibodies is a complementary diagnostic tool. The results should be interpreted in conjunction with the histological findings obtained using standard techniques (option). ## Gleason score The Gleason grading system is the standard staging system and the following rules should be applied: the Gleason grade(s) apply(ies) to the dominant growth patterns; the Gleason score corresponds to the sum of the two dominant grades; when three grades are present, the highest grade and the dominant grade should be used; the modified Gleason score should indicate the proportion of grade 4 and 5 disease present (option). Tumour grade should not be assessed in those patients who have been treated with radiotherapy or hormonal therapy. The use of the modified Gleason score, that is, proportion of grade 4 and 5 disease, is recommended. ## Histological types and histoprognostic factors The majority of malignant prostatic tumours are adenocarcinomas originating from the glands in the peripheral and transition zones. The histoprognostic factors that should be determined are: histological type; the modified Gleason score and the Gleason score; the pathological classification (TNM 97); extraprostatic extension; invasion of the seminal vesicles; the status of the margins and the nodal status (standards). Two other factors can be taken into consideration: perineural invasion and tumour volume (options). ## Pathology report Prostatic biopsies The pathology report for prostate biopsies should specify: the length of the biopsy core in millimetres; its quality (mentioning any breaks); the length of tumour involvement in millimetres or as a percentage of the biopsy length; the Gleason score and the presence of any capsular, pericapsular or extraprostatic extension (standard). Only high-grade PIN lesions should be noted. If these are isolated, all biopsy tissue should be examined for the presence of infiltrating microfoci. The report can contain a diagrammatic representation (or table) of the results and the modified Gleason score (proportion of grades Recommendations Additional information to enable the available options to be ranked using explicit 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 that give consistent results ## Level b There exist good quality evidence from randomised trials (BI) 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 do not exist or there is only a series of cases ## Expert agreement The data do not exist for the method concerned, but the experts are unanimous in their judgement SORs for management of non-metastatic prostate cancer patients A Villers et al 4 and 5) (options). In the conclusion, the number and localisation of affected areas should be summarised in an agreed format. In the absence of any definite malignant change, dystrophic lesions described in the report should not be mentioned in the conclusion, unless there is extensive destruction due to prostatitis (recommendation). Transurethral resection specimens All the resected cores, up to eight blocks, should be included (standard). When there are large amounts of tissue, an extra block should be included for each 5 g of resected tissue (standard). In certain situations, depending on the clinical context (e.g., a young patient or an elevated PSA concentration), it may be necessary to analyse all resected tissues immediately. There is no consensus as to the number of histological blocks that should be made from tissue from a simple suprapubic prostatectomy. A minimum of one block for every 5 g of tissue should be fixed, depending on the macroscopic appearance of the tissue (recommendation). The report should specify: the histological type of the cancer; the percentage of Gleason grades 4 or 5 and the Gleason score; the proportion of involved cores as a percentage of the total number of cores; and any extraprostatic extension (standard). The report should include (option): presence of perineural invasion; vascular invasion; PIN foci; post-therapeutic changes; atypical adenomatous hyperplasia and benign hypertrophy. Radical prostatectomy specimen The prostate should be examined using the Stanford serial section technique. The report should specify: histological type; Gleason score; pathological stage (pTNM, 1997); presence of extraprostatic and seminal vesicle invasion and the status of margins (standard). The report can include: the proportion of grades 4 and 5 (modified Gleason score); tumour volume (estimated in terms of the volume of the gland); tumour localisation (peripheral or transitional zonebenign hypertrophy); any associated lesions; perineural invasion; microvascular invasion and post-therapeutic changes (option). The inclusion of all prostatic sections guarantees the best assessment of the excision margins (recommendation). Pelvic lymphadenectomy specimen A frozen section can be examined prior to the definitive histopathological evaluation (option). The latter, performed following fixation, should include all nodes removed. They should be sectioned at several levels to increase the likelihood of detecting any micrometastases (standard). ## Methods of detection (figures 1 and 2) ## Rectal examination Any anomaly detected during digital rectal examination suggestive of prostate cancer in the absence of infection should be investigated further with a transrectal ultrasound-guided biopsy even if the PSA concentration is normal (standard). ## Psa determination Total serum PSA determination (upper limit of the reference range: 4 mg l À1 ) remains the reference test for screening and the primary indication for biopsy (standard). The value of free PSA determination in cancer screening remains to be determined. There is no consensus as to how often PSA concentrations should be determined. Repeated PSA determinations should be performed by the same laboratory using the same technique (standard). A lower upper limit of the reference range for total serum PSA concentration (between 2 and 4 mg l À1 ) can be used in men under 65 years old or those at risk (option). The adjustment of the upper limits of the reference range for PSA concentration, using age and prostatic volume (PSA density), has not been validated against the decision to perform biopsies (recommendation). ## Imaging There is no indication for imaging in the primary diagnostic workup (standard). Magnetic resonance imagery (MRI) and colour Doppler ultrasound are under evaluation for the detection of cancer following a negative result from initial biopsies (recommendation). ## Prostatic biopsy A diagnosis of prostate cancer is made following the histopathological examination of prostatic biopsy samples (standard). Transurethral resection is not recommended as a first-line biopsy if prostate cancer is suspected (standard). In potentially curative situations, at least six systematic transrectal ultrasound-guided biopsies, sampling particularly the posterior zone, should be taken. The aim and the practical aspects of this investigation should be explained to the patient (standard). Rectal preparation by enema and prophylactic antibiotics effective against Gram negative bacteria should be performed to prevent infectious complications (standard). The biopsies can be performed either in a day-hospital or outpatient setting, usually with local anaesthesia only (option). In a minority of patients, locoregional or general anaesthesia may be necessary. Additional biopsies may be performed on any zones found to be abnormal on clinical or ultrasound examination (option). When curative treatment is not planned, fewer biopsies can be performed (option). A more extensive procedure with 10 biopsies can be undertaken if the first series of biopsies gives negative results. The patient should be informed about the risks of this investigation. They must have the contact details of the emergency department they should contact, if any complications should occur. Indications and strategies for further biopsies after the diagnosis of PIN or suspicious lesions [fig_ref] Figure 2: Diagnostic investigation for patients with abnormal serum PSA concentration [/fig_ref] Only high-grade PINs should be noted on the histopathological report of the biopsy (standard, level of evidence: B2). The diagnosis of a high-grade PIN should not lead to a treatment plan (standard, expert agreement). A further series of biopsies should be performed within 3 months in situations where PIN or suspicious lesions have been diagnosed (standard, expert agreement). When curative treatment is not planned (life expectancy of less than 10 years, patient's choice, etc.), further biopsies are not recommended (recommendation). Further prostate biopsies after initial negative biopsy [fig_ref] Figure 2: Diagnostic investigation for patients with abnormal serum PSA concentration [/fig_ref] When curative treatment is not planned, an additional work-up is not indicated (standard). When curative treatment is planned there are two possible options: (1) no further biopsy; (2) wait for 3 months and then re-evaluate with serum PSA determination and ultrasound-guided biopsy. Depending on the degree of suspicion, the additional work-up for re-evaluation can include: PSA velocity and the percentage of free PSA; a further series of biopsies including the transition zone (the number of biopsies can be increased by including laterally directed biopsies in the peripheral zone) or a transurethral resection (option). If the test result is suspicious (PSA concentration, digital rectal examination), a second series of biopsies is recommended (recommendation). Management of patients following a diagnosis of stage T1a or T1b cancer [fig_ref] Figure 3: Management of patients with stage T1a and T1b tumours [/fig_ref] There are two therapeutic options possible for patients with a life expectancy of more than 10 years: primary curative treatment or evaluation of the remaining prostate to confirm the presence of residual tumour. The remaining prostate should be biopsied if the postoperative digital rectal examination is abnormal, and/or the 3-month postoperative PSA concentration is higher than 4 mg l À1 or has been reduced by less than 50%. If the results of the biopsies of the remaining prostate are negative, clinical surveillance and determination of serum PSA concentrations should be performed every 6 months (option). If the biopsies of the remaining prostate are positive, curative treatment should be undertaken. Curative treatment is not recommended for patients with a life expectancy of less than 10 years (recommendation, expert agreement). ## Staging (figure 4) staging by clinical examination and imaging Digital rectal examination and a transrectal ultrasound should be performed prior to, and used as a guide for, biopsies of the periprostatic tissue and seminal vesicles (standard). A renal ultrasound and CT scan should be performed for patients with stage T3 cancer (standard). Pelvic or endorectal coil MRI can be performed if radical prostatectomy or radiotherapy is indicated, if extraprostatic extension is suspected and if the results could modify the treatment plan (option). ## Evaluation of periprostatic metastatic spread Periprostatic metastatic spread can be evaluated by biopsy of the seminal vesicles or the periprostatic tissue (option). These biopsies should be taken at the same time as the first series of prostatic biopsies if the results of the digital rectal examination, imaging or the PSA concentration are suggestive of periprostatic involvement (recommendation). Biopsies of the seminal vesicles should be taken, as a second-line investigation, if the results of the biopsies of the bases of the two prostatic lobes are positive (recommendation). ## Imaging for node involvement Abdominal and pelvic CT scan should be performed in patients with: T2a stage disease or higher, a PSA concentration greater than 15 mg l À1 and a Gleason score of at least 7 (standard). MRI for the same indications is optional. ## Lymphadenectomy for staging Lymphadenectomy should be limited to the ilio-obturator regions (standard) and should be performed in those patients undergoing radical prostatectomy, (standard). It may not be necessary to perform a lymphadenectomy at the same time as radical prostatectomy if the patient has good prognostic factors: that is, stage T1 tumour; a Gleason score of under 6 and a pretherapeutic PSA concentration of less than 10 mg l À1 (option). An isolated lymphadenectomy should not be undertaken prior to radiotherapy. It can be performed if the risk of node invasion is high (option). ## Assessment of bone metastases by bone scan Irrespective of the planned treatment, a bone scan is indicated during the initial work-up in the presence of one of the following: bone pain; a locally advanced prostatic lesion (at least T3Nx or T1-4N1-3 or higher); the presence of Gleason grade 4 or 5 and a PSA concentration of at least 10 mg l À1 (standard). The interpretation of the bone scan should be made in light of the patient's PSA concentration and clinical history (recommendation). In situations other than those defined in this standard, the decision to undertake a bone scan is left to the discretion of the physician, with the knowledge that the average risk of bone metastases in this situation in Europe is 3.3% (option, expert agreement). Additional studies are needed to assess the prevalence of bone metastases in situations other than those defined in the standard (recommendation). ## Factors to consider when making a treatment plan (figures 5-7) Criteria for assessing response to curative treatment Screening using PSA concentration can detect stage T1c disease and enables the detection of prostate cancer 4 -5 years earlier than the stage T2 tumours reported in early series. The median actuarial delay between the appearance of metastases and death is 5 years. Specific follow-up for a minimum of 15 years is necessary to evaluate the efficacy of treatment of localised prostate cancer (standard). A 10-year metastasis-free survival is an acceptable criteria for evaluating treatment response for localised prostate cancer (standard). The criterion for complete remission after radical prostatectomy is an undetectable PSA concentration (under 0.1 mg l À1 ) for at least 7 years after radical prostatectomy (standard). The criteria for complete remission after externalbeam radiotherapy or brachytherapy have not yet been defined (standard). The criterion for progression after radical prostatectomy, external-beam radiotherapy or brachytherapy is an increase in PSA concentration measured on three successive occasions at monthly intervals (standard). The median delay between an increased PSA concentration and the appearance of metastases is 8 years (standard). ## Prognostic factors related to the prostate tumour Clinical tumour stage, Gleason score and the pretreatment PSA concentration are prognostic factors for locoregional metastatic spread and therefore, for treatment response (standard). Other prognostic factors that can be used are: the Gleason grades present; the number of affected biopsies; the extent of the tumour tissue in the core biopsy and perineural invasion (option). Partin tables can be used, before treatment, to evaluate the risk of extraprostatic metastatic spread and pelvic node invasion (option). # Patient-related prognostic factors Curative treatment should be offered to men with localised prostate cancer if their life expectancy is at least 10 years. Life ## Treatment: watch and wait policy (figure 8) For patients with stage T1c or T2 prostate cancer with a life expectancy of less than 10 years, a watch and wait policy can be considered (option, level of evidence: C). In patients with a life expectancy of less than 10 years, a watch and wait policy is even more appropriate for lower stage disease and grade (recommendation). ## Treatment: radical prostatectomy Prostatectomy is an effective treatment for stage T1a, T1b, T1c or T2 prostate cancer (standard, level of evidence: B2). Prostatectomy can be considered for stage T3 and pN1 cancers (option). Prostatectomy should be undertaken in stage T3 and pN1 cancers only in the setting of a randomised clinical trial assessing the efficacy of prostatectomy alone or in combination with other treatment (radiotherapy or hormone therapy) (recommendation). Radical prostatectomy is not recommended for stage pN1 highgrade tumours (Gleason score 47) (recommendation). ## Treatment: external-beam radiotherapy External-beam radiotherapy alone is an effective treatment for stage T1, T2 or T3, N0, M0 prostate cancer (standard, level of evidence: B2). The minimum recommended dose is 70 Gy, irrespective of the prognostic factors present (recommendation, level of evidence: B2). Patients should be included in randomised clinical trials assessing dose escalation. Quality control for external-beam radiotherapy Dosimetry, with CT planning, is recommended for defining the target tumour volume (recommendation, level of evidence: B2). ## Toxicity of external-beam radiotherapy Two types of external-beam radiotherapies are possible: conformal or conventional (option, level of evidence: C). Conformal radiotherapy reduces late toxicity compared with conventional radiotherapy and should be used when giving high doses (recommendation, level of evidence: C). Factors reported to affect the risk of complications following external-beam radiotherapy are transurethral prostatic resections prior to radiotherapy and the dose of external-beam radiotherapy used. ## Dose escalation Patients with a good prognosis (T1 -T2a, PSAo10 mg l À1 and Gleason score between 2 and 6) have not been shown to benefit from dose escalation above 70 -74 Gy. Patients with an intermediate prognosis receiving radiotherapy alone seem to benefit most from a dose escalation above 74 Gy. ## Treatment: brachytherapy Retropubic brachytherapy for prostate cancer should no longer be used (standard, level of evidence: C). ## Brachytherapy with temporary implants Technical data The isotope that should be used for brachytherapy is Iridium 192 (standard). Two types of brachytherapy can be used: low-dose rate or high-dose rate (option). Indications Dosimetric planning should be used. The combination of brachytherapy with temporary implants and external-beam radiotherapy is a therapeutic option for locally advanced prostatic cancer (option, level of evidence: D). Brachytherapy with temporary implants should not be used for stage T1 or T2a tumours outside the setting of a randomised clinical trial (recommendation). ## Brachytherapy with permanent implants Technical data Dosimetric planning should be used either prior to implantation or during the procedure (standard). The recommendation from Task Group 43 (TG-43) is that brachytherapy dosimetric parameters should be used for calculating the dose (standard, expert agreement). Postimplantation dosimetry should be performed 4 weeks and 2 -3 weeks after the implantation for iodine 125 and palladium 103, respectively (standard). The patient should be given information about radio-protective measures for children and pregnant women, the need to use condoms and to filter all urine and the need to inform physicians in the event of a pelvic intervention (standard, expert agreement). Training in brachytherapy techniques is essential and should be evaluated (standard, level of evidence: B2). It is not known whether freehand implantation or US/CT-guided template systems give better results (option, level of evidence: D). Similarly, there is no evidence that iodine 125 should be used in preference to palladium 103 (option, level of evidence: C). Transrectal ultrasound data should be used for predictive dosimetry and implantation (recommendation, expert agreement). The modified peripheral implantation technique is recommended to minimise the risk of urethral overdose (more than 200% of the prescribed dose) (recommendation, expert agreement). The minimum peripheral doses recommended are 144 Gy for iodine 125 in monotherapy and 100 -110 Gy in combination with radiotherapy (40 -50 Gy) and 115 and 80 -90 Gy for palladium 103 (recommendation, expert agreement). The report should specify: the volume implanted; the number of seeds implanted; the number of needles used; the total activity and the prescribed dose. Dosimetry should be performed following implantation using CT scanning, with the calculation of dose-volume histograms (DVHs). The recommended delay for postimplantation dosimetry is 4 weeks for iodine 125 (and 2 -3 weeks for palladium 103). The data to be reported are: D100, D90 and D80: isodose covering 100 (minimal peripheral dose), 90 and 80%, respectively, of the prostatic volume. A good-quality implant will have at least a D90 of the dose prescribed; V200, V150, V100, V90 and V80: the percentage of the prostatic volume receiving 200, 150, 100, 90 and 80%, respectively, of the dose prescribed; the total volume of the prostate obtained for the postimplantation dosimetry; the delay between the brachytherapy and the postimplantation dosimetry; the doses received by the ureter and the anterior wall of the rectum. Indications Prostatic brachytherapy alone using permanent implants is potentially curative in patients with the following characteristics: clinical stage T1 or T2a disease (TNM 1992), a Gleason score of 6 or lower and a PSA concentration of less than 10 mg l À1 (option). Continued evaluation of this treatment is recommended (morbidity, tumour control) in the setting of a randomised clinical trial (recommendation). Brachytherapy toxicity Brachytherapy is contraindicated in patients who have undergone a previous large transurethral resection (standard) and in patients with a previous limited transurethral resection . A prostatic volume of more than 50 -60 cm 3 and/or the presence of hypertrophy in the median lobe are relative contra-indications for brachytherapy (recommendations). The modified peripheral implantation technique is recommended. The use of questionnaires to evaluate urinary function prior to implantation is recommended (level of evidence: C). The length of ureter receiving more than 200% of the prescribed dose should be reported. The maximum length of the rectum receiving 100 and 120% of the prescribed dose should be limited to 10 and 5 mm, respectively (expert agreement). ## Prostatic biopsy to measure treatment response to brachytherapy Biopsies should not be performed until 18 -24 months after brachytherapy (recommendation). ## Treatment: hormonal therapy alone Hormone therapy alone for stage T1, T2, Nx or M0 cancer is not indicated in the absence of progressive disease (standard). Hormone therapy, either alone or in combination, can be considered in patients with nonmetastatic disease if curative treatment is not planned (option). This treatment modality is under evaluation. ## Treatment: chemotherapy The use of chemotherapy in nonmetastatic prostate cancer is not recommended (option). ## Combined treatments brachytherapy and hormonal therapy The combination of brachytherapy and hormonal therapy may be beneficial, compared with brachytherapy alone, in patients with an intermediate prognosis (Gleason score of more than 7 and/or PSA concentration higher than 10 mg l À1 ) (option, level of evidence: C). Combined brachytherapy and hormonal therapy should only be proposed in the setting of a randomised clinical trial (recommendation). ## Brachytherapy and external-beam radiotherapy The combination of external-beam radiotherapy and brachytherapy with permanent implantation can be considered in patients with an intermediate prognosis (option). The benefits of this combination should be evaluated against external-beam radiotherapy alone, or in combination with hormonal therapy in the setting of a randomised clinical trial (recommendation). ## Brachytherapy, external-beam radiotherapy and hormonal therapy The combination of brachytherapy, external-beam radiotherapy and hormonal therapy for patients with a poor prognosis should only be considered in the setting of a randomised clinical trial (recommendation). ## Neoadjuvant hormonal therapy before prostatectomy There is no benefit from neoadjuvant hormonal therapy for local stage cancers (T1 -T2) (standard, level of evidence: B1). Neoadjuvant hormonal therapy before radical prostatectomy is not indicated (option). Neoadjuvant hormonal therapy should not be considered for stage T3 cancers, outside the setting of a randomised clinical trial (recommendation, level of evidence: B1). ## Prostatectomy and adjuvant hormonal therapy Adjuvant hormonal therapy can be prescribed after radical prostatectomy for patients with node involvement (option, level of evidence: C). Patients with stage pT3 cancer and positive margins should be included in randomised clinical trials to determine the efficacy of adjuvant hormonal therapy (recommendation). ## Prostatectomy and adjuvant radiotherapy In patients with node involvement (pN1), adjuvant radiotherapy after radical prostatectomy has not been shown to improve outcome (option, expert agreement). Adjuvant radiotherapy may be considered in patients with widespread stage pT3a cancer, or with stage pT4 disease without node or seminal vesicle invasion or with positive surgical margins, particularly if the postoperative PSA concentration cannot be determined (option, level of evidence: C). One potential advantage of adjuvant radiotherapy is that the dose is lower than that used when treatment is deferred until a rise in PSA is detected. Patients should be included in randomised clinical trials to determine the efficacy of adjuvant radiotherapy. ## Hormonal therapy and radiotherapy The combination of radiotherapy and long-term hormone therapy can be considered in patients with locally advanced prostatic cancer, stages T2b, T3, and/or Gleason score of at least 8 (option). Short-term hormone therapy can be prescribed for patients with a good prognosis (option). Since the optimal combination of hormone and radiotherapy has not been established, combination treatment should be used only in the setting of a randomised clinical trial (recommendation). ## Treatments under evaluation Neutron therapy and transrectal treatment with targeted highintensity ultrasound are under evaluation. The efficacy of these treatments should be assessed against the newest radiotherapy techniques (recommendation). ## Post-treatment follow-up (figure 9 Follow-up after prostatectomy Total serum PSA should be measured between 1 and 3 months after radical prostatectomy (standard). Total serum PSA levels should be measured every 3 months during the first year (or less frequently if the concentration is below the limit of detection) and every 6 months for the following 7 years if the concentration is below the limit of detection (standard, level of evidence: B2). Digital rectal examination is optional in patients with a total serum PSA level below the limit of detection (option, expert agreement). ## Follow-up after radiotherapy After radiotherapy, follow-up should include PSA determination and digital rectal examination for an indefinite period (standard, expert agreement). PSA determination and digital rectal examination should be undertaken every 6 months (recommendation, Post-treatment follow-up. [fig] Figure 1: Tumour stage according to method of detection. [/fig] [fig] Figure 2: Diagnostic investigation for patients with abnormal serum PSA concentration (T1c) and/or suspicious digital rectal examination or imaging studies (T2, T3,). [/fig] [fig] Figure 3: Management of patients with stage T1a and T1b tumours. [/fig] [fig] Figure 4: Staging for a histologically proven invasive cancer. [/fig] [fig] Figure 5: Therapeutic management of patients with stage T1 or T2 tumours. [/fig] [fig] Figure 6: Therapeutic management of patients with stage T3 tumours. [/fig] [fig] Figure 7: Therapeutic management of patients with stage N1 tumour (imaging studies). [/fig] [fig] Figure 8: Watch [/fig] [table] Table 1: Definition of 'Standards, Options and Recommendations' [/table]	None	https://www.nature.com/articles/6601084.pdf	None
e6a1c51415fdbf28600cf2077aa272f528ea26a4	pubmed	Society for Cardiovascular Magnetic Resonance guidelines for reporting cardiovascular magnetic resonance examinations	Society for Cardiovascular Magnetic Resonance guidelines for reporting cardiovascular magnetic resonance examinations These reporting guidelines are recommended by the Society for Cardiovascular Magnetic Resonance (SCMR) to provide a framework for healthcare delivery systems to disseminate cardiac and vascular imaging findings related to the performance of cardiovascular magnetic resonance (CMR) examinations. # Background These reporting guidelines are recommended by the Society for Cardiovascular Magnetic Resonance (SCMR) to provide a framework for reporting results of cardiovascular magnetic resonance (CMR) examinations. This document builds on previously published guidelines from professional societies (ACC/AHA/ACR and others) , and is customized here for CMR practice in particular. The guidelines have been developed within the context of the US health-care system, and application in other health-care systems may vary. It is also recognized that the ultimate judgment regarding the propriety of any specific procedure or reporting methodology must be made by the physician or individuals participating within the healthcare delivery system that performs the CMR procedure. An alternative approach that differs from these guidelines, standing alone, does not necessarily imply that the different approach falls below the standard of care. To the contrary, a conscientious practitioner may reasonably adopt reporting elements different from those set forth in these recommendations when, in the reasonable judgment of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources, or a new advancement in knowledge or technology that may occur subsequent to the publication of this document. Prior to scanning, the SCMR recommends that patients be referred for CMR scans in accordance with Appropriateness Criteria developed by the SCMR, ACC, ACR, and AHA [bib_ref] appropriateness criteria for cardiac computed tomography and cardiac magnetic resonance imaging: a..., Accf/Acr/Scct/Scmr/Asnc/Nasci/Scai/Sir [/bib_ref]. The SCMR recommends that scans should be performed in accordance with SCMR developed Guidelines for scan acquisition [bib_ref] Standardized cardiovascular magnetic resonance imaging (CMR) protocols, society for cardiovascular magnetic resonance:..., Kramer [/bib_ref]. The SCMR recommends reporting key elements in all documents including information pertaining to a) site and equipment information, b) patient demographics, c) indications for study, d) study performance, e) cardiovascular imaging features of the examination, and f) concluding statements that synthesize the study results into a comprehensive diagnosis that can be used for planning therapy or determining prognosis. The SCMR wishes to emphasize that effective communication is an essential component of any diagnostic imaging procedures for patients with possible cardiovascular disease. Quality patient care is best achieved when study results are conveyed in a timely fashion to those ultimately responsible for treatment decisions. Accordingly, the SCMR recommends that a delivered, finalized report be available, where possible, within 1 business day of performance of the scan, but appropriate to the urgency of the examination. The following document serves as a guide to identify a) recommended and optional components of the report, b) the principles used to generate a final report, and c) suggested communications that may occur other than the final report. A final written interpretation or report shall be generated and archived following any CMR examination, procedure, or officially requested consultation to review images regardless of the setting where the CMR scan was performed (hospital, imaging center, physician office, mobile unit, etc.). Within the document, all recommended and optional components are in bold, and summarized in Additional files 1 and 2. ## Components of the report [formula] a) Height (recommended) b) Weight (recommended) [/formula] c) For studies using contrast, the SCMR suggests the value and date of acquisition of the most recent serum creatinine level and estimated glomerular filtration rate (GFR) should be provided. 6) Non-imaging findings associated with the examination (5 recommended elements) a) In those studies requiring 12-lead electrocardiogram, its interpretation should be provided. This includes the presence of Q-waves, ST segment or T-wave abnormalities, or other rhythm disturbances. b) For studies evaluating hemodynamically important conditions (i.e., valvular heart disease, intracardiac shunting, cardiac output, etc.), heart rates and rhythm, and systolic and diastolic blood pressure should be provided during the CMR acquisition. For tests incorporating stress testing, the heart rates and rhythm, oxygen saturation, systolic and diastolic blood pressures, and the predictive heart rate response for age should all be recorded during the following points in time: - Before study - At each level of stress - In recovery c) For studies utilizing cardiac active agents (i.e., stress testing), the agent, quantity, duration, and route of administration of the agents and associated medications should be provided. d) For studies utilizing contrast agents, the type (i.e. paramagnetic), name, route, site, and speed of administration should be provided. e) For studies utilizing sedation, general anesthesia, or supported ventilatory or cardiac (hemodynamic or electrical) assistance, the amount, type, route and measures of administration of these agents or support should be documented. Also, patients' cardiovascular and pulmonary responses (heart rate, blood pressure, respiratory rate, and oxygen saturation) should be recorded accordingly to local regulations. The reason for administration required of the agent should be provided. i. Intramural hematoma (IH): in cases of IH and penetrating aortic ulcer, the CMR practitioner should describe carefully the morphologic findings in much the same way as an aortic dissection paying careful attention to select wording to convey a diagnosis of limited ulceration or dissection. ii. Post-operative appearance: this should be described in accordance with (a-e) above noting additional graft insertion points and dimensions. f. Inflammatory diseases of the aorta (recommended): aortic wall thickness, multispectral appearance on different pulse sequences, contrast enhancement pattern, branch vessel involvement, presence of periaortic, pleural, or pericardial fluid g. Congenital disease involving the aorta and ventriculoarterial connections: see recommended congenital report below. h. Aortic flow (optional): On CMR scans of the aorta in which PC-MR measures are obtained, the direction and magnitude of flow should be provided. 2. Peripheral arterial disease (2 recommended, 1 optional): a) Vessel location and orientation. Descriptions of each territory are required when the study is ordered to examine the respective site (recommended). When severe stenoses or vessel occlusions are identified, common collateral pathways should be described. SCMR recommends that the CMR practitioner avoid descriptive terms such as "mild" or "moderate" stenosis, but rather adopt a semi-quantitative method that scores the severity of luminal occlusion. Accordingly, stenosis severity should be reported in 25% increments (i.e., <25%, 26% -50%, 51% -75%, and >75%) or, in cases with high spatial resolution, finer increments of 10% may be employed. Descriptive terms may convey the wrong impression to the clinical importance of occlusive disease (e.g. a series of "moderate" stenoses in the diabetic patient with poor wound healing of the lower extremity may be clinically significant) c) Optional functional measures of the vascular system may also be reported, including: i.) flow measurements in the forms of milliliters or liters per minute, and ii.) measures of vascular stiffness: aortic distensibility, or pulse wave velocity. When functional measures are provided it is recommended that the vascular territories be specified and values provided at the specific location of acquisition. ## B) cardiac size and function 1) The reporting of right ventricular (RV) and left and right atrial chamber sizes and volumes are optional. Reporting of left ventricular (LV) volumes is recommended when multi-slice cine short axes data are acquired from the mitral annulus to the cardiac apex. When reported, SCMR suggests that right-sided chambers measurements and the angulation from which the diameters or dimensions are acquired should be reported. For the leftsided cardiac chambers, the 3-chamber long axis view should be used for identifying LV dimensions. The SCMR encourages quantitative measures reported on their forms; however, determination of normal, enlarged, small, or not reported may be substituted. 2) Although not required, the SCMR encourages the reporting of LV end diastolic wall thicknesses acquired in the 3-chamber view of the left ventricle at the mitral leaflet tips; it is suggested that the end diastolic thickness be acquired at the septum and inferior lateral or posterior wall. 3) When assessing the right ventricle, the free wall end diastolic thickness (in the middle atrium portion of the wall) may be reported. ## 4) For those studies targeting the heart, the SCMR recommends the reporting of LV ejection fraction, and regional wall motion abnormalities. The method of acquisition should be reported, including: [formula] ▪ Visual estimation ▪ Area-length formula ▪ Multi-slice disk summation technique [/formula] Values should be reported as absolute values and indexed for body surface area. - Measurements derived from these values (i.e., cardiac output) should be expressed as absolute as well as indexed values and the reference heart rates used for these calculations should be provided in the report. - Regional wall motion should be described as qualitatively or quantitatively assessed in the 17-segment model adopted by the ACC/AHA guidelines 2 for noninvasive testing [fig_ref] Figure 1 17: -segment model of the LV myocardium developed by the ACC/AHA for reporting... [/fig_ref]. Qualitative assessments should follow the following nomenclature in which each segment is identified as: [formula] ▪ hyperkinetic ▪ normokinetic ▪ hypokinetic ▪ akinetic ▪ dyskinetic ▪ tardykinetic ▪ paradoxical ▪ not assessed [/formula] - If the respective site seeks to report quantitative measures, such as thickening or strain, these should be performed and reported according to previously published techniques. ## C) cardiovascular stress testing As described in the non-imaging findings component of the reported list above, parameters such as vital signs, medications, and contrast agent administration should be reported. The SCMR recommends the reporting of LV myocardial information in the format of a 17-segment model through the use of a chart, table, or bipolar maps (so called "Bullseye" plot) [bib_ref] Standardized Myocardial Segmentation and Nomenclature for Tomographic Imaging of the Heart: A..., Cerqueira [/bib_ref]. ## Wall motion stress: Wall function should be designated as qualitative (wall motion) or quantitative (referenced measure such as % wall thickening, or strain) during testing. In addition, wall motion score index (the sum of the wall motion scores divided by the number of segments scored) should be reported at each level of stress. Inducible ischemia or contractile reserve should be identified in each study according to previously published referenced methods. Identification should be made of when global LV function does not improve or worsens during stress. ## Gadolinium, 1 st pass myocardial perfusion: Existing literature regarding the prognostic significance of qualitative perfusion defects is unavailable at this time; nevertheless, SCMR suggests that perfusion in each of the 17 segments [fig_ref] Figure 1 17: -segment model of the LV myocardium developed by the ACC/AHA for reporting... [/fig_ref] be defined according to the transmurality, and persistence of the defect. The committee recommends that stress induced (vasodilator or inotropic) perfusion defects be compared with co-registered rest perfusion or late enhancement segments in order to identify ischemic, infarcted, or non-ischemic areas. The SCMR also recognizes that observed defects may be characterized as artifacts. These should be described. ## Late gadolinium enhancement (lge): 17-segment model of the LV myocardium developed by the ACC/AHA for reporting abnormalities of wall motion, per-fusion or injury The amount of intense signal >2 SD above the average of normal myocardium should be reported for the area within each segment. Overall, LGE should be described as subepicardial, intramural, subendocardial, or transmural. Patchy or linear streaks of LGE should be identified. The transmural extent of the LGE should be defined as 0, ≤ 25%, 26% to ≤ 50%, 51% to ≤ 75%, and 76% to 100%. In addition, the total amount of infarcted tissue (volume or grams) relative to the total myocardial volume or mass (g) may be reported. It is not recommended, but measures of LV end-diastolic wall thickness for the 17 myocardial segments may also be reported. When clinically appropriate, those providing an interpretation should indicate whether the pattern of LGE is consistent with ischemic heart disease, myocarditis, etc. ## Microvascular obstruction (mvo) : If MVO is observed during LGE, its location and presence within the 17 myocardial segments should be provided. ## Integrative stress imaging: It is recognized by the SCMR that the procedures mentioned above can be performed in a single setting and thus must be integrated to arrive at a diagnosis. The committee recommends reporting data for all 17 myocardial segments in all modalities . Based on previously published techniques, segments should be identified as ischemic, infarcted, mixed ischemia/infarction, or normal. It is recommended that all information for baseline function be reported in patients referred for stress testing or evaluation of acute or chronic ischemic syndromes. For these clinical conditions, the following items are recommended for reporting by the SCMR. - LV volumes (EDV, ESV, SV, EF) with and without indexing to body surface area. - Presence and extent of (T2) signal intensity ## - presence and extent of irreversible injury (lge) - presence of pericardial effusion - In the case of iron overload: T2* in ms may be reported - Optional: early enhancement ratio † or the % injury related to LV mass †: see Lake Louise Criteria, Consensus Group on CMR in Myocarditis ## E. coronary arterial segments It is recommended that when examining the course of anomalous coronary arteries, the origin and course of the coronary artery segments be reported, as well as the length of the segments visualized. If anomalous artery is intramural, it should be noted. If a study is performed for the purpose of identifying coronary artery or bypass graft anatomy, the patency of these conduits should be indicated. ## F. valvular heart disease The following lists of items should be reported for the cardiac valves. Qualitative parameters: - morphology of each component of the valve complex (e.g. leaflets, annulus, chordae) ## - presence of any insufficiency or reduced valvular excursion When quantitative flow measurements are acquired: - the velocity encoding Venc setting; - the peak velocity, a single value when recorded across semilunar valves or a vessel in cross-section, or both early (E) and late (A) peak velocities for atrioventricular valves; - the forward stroke volume and peak and mean transvalvular gradients; - the regurgitant volume and fraction; - the heart rate during acquisition; - the method and determination of valve area (by planimetry or the continuity equation); - the measurement of ventricular dimensions and volumes as described in III-B. ## G. arrhythmogenic rv cardiomyopathy (arvc) 1) It is recommended that each report identify major and minor criteria associated with ARVC. This should include a statement regarding: a) Global right ventricular performance (RVEF); b) RV dilation; c) Location of Regional RV wall motion abnormalities (infundibulum, body or apex of right ventricle). When acquired: a) Fatty infiltration of the right ventricle, and b) Occurrence of fibrosis by LGE should be provided. h. Cardiac and paracardiac masses (including pericardium) The standard report should consist of the following components: Quantitative elements that should be included in CMRbased PV reporting are: ## Myocardial mass description: ## Absent 1. Maximum ostial diameter of each pulmonary vein; 2. Cardiac phase (e.g. end-atrial diastole) and respiratory phase (e.g. end-expiration) during acquisition of images used for ostial measurements; 3. Minimum ostial diameter of each stenotic pulmonary vein; and 4. Imaging technique used for measurements The number and position of pulmonary veins is accounted for noting common trunks, accessory veins, and evidence for stenosis or thrombosis cross sectional area of the pulmonary vein may be provided. A 3D workstation may be used to calculate major and minor axes, and cross sectional area of each pulmonary vein ostium, and compare pre-and post-ablation images side by side. 8) The SCMR recognizes that more extensive historical information may be desired by certain institutions that perform CMR. At the time of this publication, SCMR considers this information optional for inclusion in the final report. Accordingly, in the case in which further data are desired, the following outline for data collection is pro- It is recognized that there may be findings unrelated to the cardiovascular system identified during CMR imaging procedures. Such findings should be reported in accordance with local standards. However, SCMR recognizes that the contrast, resolution and field of view of a CMR study are optimized for the cardiovascular system rather than to assess for abnormalities outside of the cardiovascular system. # Summary and conclusions SCMR recommends that each report conclude with appropriate statements that relate the study indications to the imaging acquisition and findings associated with performance of the study. SCMR recommends that these statements provide referring physicians with conclusions that allow the prescription of therapy based on the study findings. SCMR recommends that the conclusion of the report provide the written or electronic signature of the individual accomplishing the report along with the time and date of the signature. SCMR considers it optional to provide the National Provider Identifier for the physician signing the report. ## Principles of disseminating the final report 1) The final signed report is considered to be the definitive means of communicating to the referring physician or other relevant health care provider. Other methods of rapid communication are encouraged in certain situations, such as critical findings, unexpected abnormal findings, or findings that may immediately alter the patient's course of treatment. 2) The report should be reviewed to minimize interpretive, descriptive, or transcription errors prior transmitting the final results. 3) The final report should be completed in accordance with governmental or health care facility medical records regulations. 4) The signed written report should be immediately transmitted to the referring physician or health care provider who is treating the patient once it has been finalized and in accordance with appropriate governmental requirements. 5) When feasible, a copy of relevant key images should accompany the final report. 6) A copy of the final report should be archived at the imaging facility as part of the patient's medical record and be retrievable for future reference. Retention and distribution of these records should be in accordance with governmental regulations and facility policies. Communications other than the final report SCMR strongly encourages the rapid dissemination of a finalized report. It is recognized however, that preliminary reports may be necessary in certain situations. Preliminary reports should be identified as such; however, it is recognized by SCMR that their accuracy may be compromised. If a change is made by a disseminated preliminary discrepant from the final interpretation, then written documentation and communication to all treating or referring physicians is indicated. It is recommended that any methods of such communications be included in the final report such that documentation is complete. ## Self-referred and third party referred patients The SCMR recognizes that some individuals may seek imaging studies as part of a self-referral or referred by a third party, such as an insurer or an employer. Self-referred patients Imagers should recognize that performing imaging studies on self-referred patients establishes a doctor patient relationship that includes responsibility for communicating the results of imaging studies directly to the patient and arranging for appropriate followup. ## Third party referred patients Patients may be referred for imaging studies by insurance companies, employers, research studies, other benefit programs, or in some instances, attorneys. In such cases, the reports of these studies are frequently communicated through their requesting entity to a clinician or directly to the third party designated clinician. The results of these examinations are then communicated to the patient directly. Regardless of the source of the referral, the diagnostic imager has an ethical responsibility to insure communication of unexpected or serious findings to the patients. It is suggested that each imaging organization that desires to scan and generate reports on self referred patients develop communication policies within their centers to address evolving issues in this arena. [fig] Figure 1 17: -segment model of the LV myocardium developed by the ACC/AHA for reporting abnormalities of wall motion, perfusion or injury. [/fig] [table] j: Previous noninvasive cardiovascular imaging tests • Echocardiography • Nuclear myocardial scintigraphy • Cardiovascular computed tomography • Cardiovascular magnetic resonance • Cardiac catheterization • None j) Surgical risk • Low risk surgery • Intermediate risk surgery • High risk surgery k) For studies incorporating CV stress, prior to the procedure, the following information should be verified: • Prior MI • Prior coronary revascularization (PCI and/or CABG) • Pretest Probability of CAD (none, low, medium, high) • Is the ECG interpretable for ischema? Yes/No • Framingham Risk Score • Estimate of CAD risk (<10%, 10-20%, >20% over 10 years 9. Noncardiovascular Findings [/table]	None	https://jcmr-online.biomedcentral.com/counter/pdf/10.1186/1532-429X-11-5	None
14e7d8f61fa84ae603ff040ad94c0b8c627a2064	pubmed	Nose and paranasal sinus tumours: United Kingdom National Multidisciplinary Guidelines	Nose and paranasal sinus tumours: United Kingdom National Multidisciplinary Guidelines This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. With only limited high-level evidence for management of nasal and paranasal sinus cancers owing to low incidence and diverse histology, this paper provides recommendations on the work up and management based on the existing evidence base.Recommendations- Sinonasal tumours are best treated de novo and unusual polyps should be imaged and biopsied prior to definitive surgery. (G) - Treatment of sinonasal malignancy should be carefully planned and discussed at a specialist skull base multidisciplinary team meeting with all relevant expertise. (G) - Complete surgical resection is the mainstay of treatment for inverted papilloma and juvenile angiofibroma. (R) - Essential equipment is necessary and must be available prior to commencing endonasal resection of skull base malignancy. (G) - Endoscopic skull base surgery may be facilitated by two surgeons working simultaneously, utilising both sides of the nose. (G) - To ensure the optimum oncological results, the primary tumour must be completely removed and margins checked by frozen section if necessary. (G) - The most common management approach is surgery followed by post-operative radiotherapy, ideally within six weeks. (R) - Radiation is given first if a response to radiation may lead to organ preservation. (G) - Radiotherapy should be delivered within an accredited department using megavoltage photons from a linear accelerator (typical energies 4-6 MV) as an unbroken course. (R)Clinical presentation Initial symptoms such as nasal blockage, blood-stained discharge and loss of smell are often overlooked though their unilateral nature should raise suspicion. Delayed presentation is common. Subsequent extension into the orbit, nasolacrimal system, anterior cranial cavity, cavernous sinus, pterygomaxillary fissure, palate, skin and infratemporal fossa may produce symptoms such as proptosis, diplopia and epiphora, trismus, pain, oro-antral fistula, paraesthesia or other neurological deficits or a mass. # Introduction Tumours in the sinonasal region are rare, affecting less than 1 in 100 000 people per year. [bib_ref] Tumours of the nose, sinuses and nasopharynx, Lund [/bib_ref] They are histologically a diverse group of tumours and potentially pose significant management problems due to their close proximity to the orbit and intracranial cavity. Squamous cell carcinoma (SCC) is the most common malignant tumour, but tumours of every histological type can occur. The commoner epithelial tumours include adenocarcinoma, olfactory neuroblastoma, malignant melanoma and adenoid cystic carcinoma. Sarcomas, e.g. chondrosarcoma and rhabdomyosarcoma and haemoproliferative tumours, e.g. lymphoma may also occur. Benign tumours include inverted papilloma (IP), osteoma, juvenile angiofibroma (JA), haemangiopericytoma, haemangioma, schwannoma, pleomorphic adenoma and meningioma. All areas of the nasal cavity and paranasal sinuses can be affected, but the lateral wall, ethmoids and maxillary sinus are the most common primary sites. The frontal and sphenoid sinuses are rare primary sites for reasons that are unknown. ## Assessment and staging Investigation should include computed tomography (CT) and magnetic resonance imaging (MRI) which are complementary in the skull base, and biopsy [fig_ref] FIG. 1: Management algorithm for malignant sinonasal tumours [/fig_ref]. Computed tomography scans give excellent bony details and are helpful in determining whether a tumour remains confined within these natural boundaries or has eroded through the surrounding bone. They also provide details of the extent of local bony invasion and are useful in assessing the lamina papyracea, orbital floor, cribriform plate and pterygoid plates. Magnetic resonance imaging allows better distinction of tumour from adjacent soft tissues and retained mucus and is particularly useful for determining invasion of the orbital contents, dura, brain and cavernous sinus. An MRI may also be better for assessing carotid artery invasion. Positron emission tomography-computed tomography (PET-CT) imaging is utilised where the tumour could be an unusual metastatic site from a primary tumour elsewhere in the body, e.g. adenocarcinoma or occasionally where widespread metastatic disease is a clinical possibility, e.g. an aggressive sarcoma. shows the staging system for nasal and paranasal sinus malignancies. ## Recommendations - Sinonasal tumours are best treated de novo and unusual polyps should be imaged and biopsied prior to definitive surgery (G) - Treatment of sinonasal malignancy should be carefully planned and discussed at a specialist skull base multidisciplinary team (MDT) meeting with all relevant expertise (G) ## Management Discussion about management of these rare tumours should ideally occur in a specialist skull base MDT. ## Benign sinonasal tumours Sinonasal inverted papilloma. Sinonasal IP is the most common pathology and much of the literature on management of benign nasal tumours concerns itself with IP. [bib_ref] Sinonasal inverted papilloma: 84 patients treated by endoscopy and proposal for a..., Dragonetti [/bib_ref] It is a locally aggressive tumour, which usually arises in the nasal cavity. Inverted papilloma is associated with a risk of malignant transformation (about 2 per cent) and it is known to carry a high risk of post-treatment recurrence and/or residual disease if a subperiosteal resection is not undertaken. Expert histopathology review is essential as well differentiated SCC can easily be mistaken for IP. Juvenile angiofibroma. Juvenile angiofibroma is a slow growing highly vascular tumour which arises predominantly from the sphenopalatine region in adolescent and young adult males. The tumour is locally invasive and can cause life-threatening epistaxis. As with inverted papilloma this lesion can extend to involve Maxillary sinus T1 Tumour limited to the mucosa with no erosion or destruction of bone T2 Tumour causing bone erosion or destruction, including extension into hard palate and/or middle nasal meatus, except extension to posterior wall of maxillary sinus and pterygoid plates T3 Tumour invades any of the following: bone of posterior wall of maxillary sinus, subcutaneous tissues, floor or medial wall of orbit, pterygoid fossa, ethmoid sinuses T4a Tumour invades any of the following: anterior orbital contents, skin of cheek, pterygoid plates, infratemporal fossa, cribriform plate, sphenoid or frontal sinuses T4b Tumour invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other than maxillary division of trigeminal nerve V2, nasopharynx, clivus Nasal cavity and ethmoid sinus T1 Tumour restricted to one subsite of nasal cavity or ethmoid sinus, with or without bony invasion T2 Tumour involves two subsites in a single site or extends to involve an adjacent site within the nasoethmoidal complex, with or without bony invasion T3 Tumour extends to invade the medial wall or floor of the orbit, maxillary sinus, palate or cribriform plate T4a Tumour invades any of the following: anterior orbital contents, skin of nose or cheek, minimal extension to anterior cranial fossa, pterygoid plates, sphenoid or frontal sinuses T4b Tumour invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other than V2, nasopharynx, clivus the sinuses, orbits and intracranial space. The basisphenoid is the commonest site of residual disease usually due to invasion via the vidian canal. Treatment. Despite differences in tumour behaviour across the range of pathologies, all share the same basic treatment aims of complete surgical removal without damage to adjacent organs and with prevention of recurrence. The mid-facial degloving approach has been the mainstay for access if the frontal sinus or anterior ethmoids are not involved. Complex frontal tumours and those with intracranial extension have required use of osteoplastic flap and craniofacial approaches. In a large series of open surgery for inverted papilloma, an overall recurrence rate of 17 per cent is found. For juvenile angiofibroma, 'recurrence' rates fell from 21 to 2 per cent when drilling of the basisphenoid was employed during midfacial degloving. More recently, endoscopic surgery and endoscope assisted, minimal access surgery (see below) are more often employed, having been shown to be effective alternatives with equivalent results and reduced morbidity compared to open approaches. [bib_ref] Endoscopic surgery for juvenile angiofibroma: when and how, Nicolai [/bib_ref] Recent studies of endoscopic surgery for inverted papilloma suggest recurrence rates of around 14 per cent are achievable by experienced endoscopic surgeons. A similar recurrence rate has been reported for juvenile angiofibroma resected endoscopically though the series are relatively small. ## Recommendation - Complete surgical resection is the mainstay of treatment for inverted papilloma and juvenile angiofibroma (R) ## Malignant sinonasal tumours Surgical approaches Endoscopic resection of sinonasal tumours. The accepted method of resecting tumours of the anterior skull base is craniofacial resection. [bib_ref] Craniofacial resection for malignant paranasal sinus tumors: report of an international collaborative..., Ganly [/bib_ref] However, recent technological advances have facilitated endoscopic resection of malignant tumours of the lateral nasal wall and anterior skull base with safety and precision. [bib_ref] Endoscopic skull base surgery: principles of endonasal oncological surgery, Snyderman [/bib_ref] [bib_ref] European position paper on endoscopic management of the nose, paranasal sinuses and..., Lund [/bib_ref] [bib_ref] Endoscopic resection of malignant sinonasal tumors: an eighteen year experience, Lund [/bib_ref] [bib_ref] Endoscopic surgery for malignant tumors of the sinonasal tract and adjacent skull..., Nicolai [/bib_ref] In some cases, tumour resection may be entirely endoscopic, but the endoscope may also be combined to enhance surgical resection with craniotomy, midfacial degloving and lateral rhinotomy. Patients with sinonasal malignancy undergoing purely endonasal resection are reported to have outcomes as good as conventional external surgical techniques with the potential for lower morbidity and shorter hospital stays. Endoscopic resection of sinonasal tumours should be managed in units that have comprehensive skull base expertise that can manage all facets of the patient's care. ## Indications for endoscopic endonasal resection. Prior to undertaking this means of treatment, a clear operative plan must be considered by an MDT with the full range of expertise in the management of sinonasal malignancy. Surgeons undertaking endoscopic resection must be experienced in both endoscopic techniques and the full range of other surgical options with which they may be combined and must also be familiar with the natural history of the wide range of malignant sinonasal tumours. Once a decision has been made to treat a tumour surgically, the clinician should define whether this is with curative intent or palliation. Contraindications to endoscopic resection [fig_ref] TABLE II LIMITATIONS: OF ENDOSCOPIC SURGERY WITH CURATIVE INTENT 7 [/fig_ref] : Tumours invading facial soft tissues should not be attempted endoscopically. Tumours that are very vascular would pose a considerable problem if resected endoscopically. Embolisation within days of definitive surgery should be considered in these cases. Relative contraindications to endoscopic resection include extension to the orbital apex or laterally to the pterygomaxillary space and infratemporal fossa. Malignant tumour invasion of the cavernous and sagittal sinuses and brain parenchyma is difficult to clear endoscopically, but a decision to operate under these circumstances would mainly be for palliation rather than cure. Surgical considerations. Intra-operative computer assisted navigation should ideally be available. Some systems incorporate CT-MR fusion and three-dimensional CT angiography. Powered instruments should also include a microdebrider and high-speed drill systems with long diamond burrs and curved drills designed for intranasal use. Diathermy instruments designed for endoscopic intranasal use should be available, bipolar diathermy being preferable. Resecting tumours endoscopically is aided by having two surgeons using a 3-4 handed technique via both sides of the nose. This technique is facilitated by partial excision of the nasal septum. En bloc resection is usually not possible in the skull base. The most important principle is to obtain clearance of tumour usually by piecemeal resection, confirmed with frozen section when necessary. The extent of resection is determined by the histology: for olfactory neuroblastoma, the olfactory bulbs and tracts may be resected, but for high grade malignancy invading critical structures such as the cavernous sinus, complete resection is not possible. The incidence of positive tumour-margins is reported to be similar in patients with advanced anterior skull base disease undergoing either endoscopic resection or traditional craniofacial resection. Dura may be resected if invaded by tumour, but if extensive, an open approach may be more suitable. Reconstruction of the skull base defect is essential at the time of the primary surgery if the skull base or dura have been included in the resection. A multilayered technique is recommended and graft materials include autologous fascia, cartilage, fat, split calvarial bone and local mucosal flaps and grafts. Large pedicled septal mucosal flaps based on the sphenopalatine artery have been described, but are only suitable if the mucosa is not invaded by the tumour. ## Recommendations - Essential equipment is necessary and must be available prior to commencing endonasal resection of skull base malignancy (G) - Endoscopic skull base surgery may be facilitated by two surgeons working simultaneously, utilising both sides of the nose (G) - To ensure the optimum oncological results, the primary tumour must be completely removed and margins checked by frozen section if necessary (G) Results. Five-year disease-specific survival rates of 85 per cent after endoscopic resection of sinonasal malignancy are reported though selection bias needs to be taken into account. [bib_ref] Comparison of transnasal endoscopic and open craniofacial resection for malignant tumors of..., Eloy [/bib_ref] [bib_ref] Outcomes of minimally invasive endoscopic resection of anterior skull base neoplasms, Batra [/bib_ref] Encouraging results with good local control are reported following the endoscopic resection of olfactory neuroblastoma. [bib_ref] Treatment of esthesioneuroblastoma: a 16-year meta-analysis of 361 patients, Devaiah [/bib_ref] [bib_ref] Olfactory neuroblastoma -a 35 year experience and suggested followup protocol, Rimmer [/bib_ref] The overall survival of adenocarcinoma after endoscopic resection is reported at 92 per cent with a median follow-up of 30 months. The results following endoscopic resection of SCC are significantly worse. The outcome is dependent on the histology of the primary tumour as well as the presence of intracranial spread and positive surgical margins. With more recent larger series, survival is worse with increasing T-stage with the exception of malignant melanoma. 14 However, endoscopic resection of melanoma is associated with improved five-year survival (though not 10-year survival) irrespective of extent. Survival is best for patients who have not undergone previous surgery with incomplete resection. Maxillectomy. Maxillary tumours represent 3 per cent of all head and neck tumours. Of these tumours, 75 per cent are malignant. Of the malignant tumours, 80 per cent are of epithelial origin, with the remainder being most commonly salivary gland (adenoid cystic carcinoma > muco-epidermoid carcinoma > adenocarcinoma), malignant melanoma or sarcomas. There is a slight male preponderance, with most tumours occurring in the fifth and sixth decades. The five-year survival is between 30 and 50 per cent. Pre-operative planning It is important that a clear reconstructive plan is derived for the maxillectomy defect prior to surgery with a decision to either obturate the cavity with a prosthesis or perform some form of biological reconstruction. The latter includes local or regional flaps in addition to free-tissue transfer of a soft tissue only or composite nature. Ultimately the decision will depend on competing factors such as the site and size of the defect, available dentition after resection, concurrent comorbidity and prognosis. The reconstructive and prosthetic aspects of maxillectomy rehabilitation are dealt with in greater detail elsewhere in these guidelines. In summary, obturators have the advantage in that they reduce the length of surgery, impart no additional donor site morbidity, restore the dentition more immediately and theoretically retain the ability to inspect the post-ablative cavity, although in the era of PET-CT the latter argument is declining. However, obturators have their disadvantages. In the short term, this includes the need for frequent changes initially under general anaesthesia along with the requirement for repeated adjustment and refashioning as the maxillectomy cavity settles down. In the longer term, obturators impart more discomfort and demand patient compliance to remove and clean them. Studies that compare obturators with biological reconstruction demonstrate improved quality of life metrics for the latter group and as such the standard of care is to favour appropriate vascularised flap reconstruction as discussed elsewhere in these guidelines unless patient preferences or other contraindications exist. Surgical technique. Access to the maxilla may be transoral, transcutaneous or extended. The trans- Absolute When the following are required: Orbital exenteration Maxillectomy (except medial wall) Skin excision Anterior +/or lateral involvement of frontal sinus Dura or brain involvement lateral to mid orbital roof or lateral to optic nerve Brain parenchyma invasion Vascular invasion (internal carotid artery, cavernous sinus) Chiasm invasion V J LUND, P M CLARKE, A C SWIFT et al. oral route can be supplemented with a mid-facial degloving procedure. The transcutaneous incision (Weber-Ferguson) involves division of the upper lip and extension around the nasal vestibule and alar of the nose towards the medial canthus. Additional exposure of the ethmoid sinuses may be aided with a Lynch extension. Likewise access to the lateral and posterior-lateral maxilla may be improved with a transconjunctival, subciliary or infra-orbital extension. Skin flaps are raised in a submuscular plane to maintain blood supply and also minimise damage to the facial nerve. It is important to ensure adequate exposure by elevating skin flaps as far back as the posterior-lateral surface of the maxilla and under the surface of the zygoma in order to gain adequate access to the pterygopalatine fissure. Bony osteotomies are performed through tooth sockets or edentulous areas with either drills or saws. After the osteotomies are completed the specimen is delivered with division of the posterior soft tissue attachments. Care should be taken here to avoid bleeding from the palatine vessels and branches of the maxillary artery. The infra-orbital nerve can only be preserved if a low maxillectomy is performed. Management of the orbit is discussed below. If immediate obturation is to be carried out, it is imperative that the ablative cavity is adapted. Sharp spicules of bone should be removed, but undercuts retained to aid retention of the prosthesis. If obturation is to be performed, a simultaneous coronoidectomy should be carried out. Craniofacial resection. Approaches. Type 1 craniofacial or transorbital cranial facial uses the lateral rhinotomy incision extended up into a Lynch incision. There is no need to extend this incision around the nasal alar so avoiding any asymmetry of the alar base. Wide release of the orbital periosteum and lacrimal duct allows gentle lateral reflection of the orbital contents giving excellent exposure of the ethmoids and cribriform plate, lateral nasal wall, fronto-nasal recess, lamina papyracea and orbital periosteum all of which can be resected. Small areas of ethmoidal roof, cribriform plate and the olfactory bulb can be resected from below and dura resected and repaired as necessary. Type 2 craniofacial includes a shield shaped window craniotomy over the frontal sinus allowing excellent exposure of the superior surface of the cribriform plates allowing en bloc resection of dura, cribriform plate and early brain involvement. It allows robust repair of the dura under direct vision with fascia lata or pericranium. Type 3 craniofacial involves an approach to the ethmoids via a lateral rhinotomytype incision and a large frontal craniotomy approached by a bicoronal incision. This is only required for significant intracranial disease requiring neurosurgical input. Orbital management. An understanding of the anatomical barriers to the disease is very important. Both the dura and the orbital periosteum provide significant barriers. In particular the orbital periosteum may still be intact despite considerable intra-orbital tumour with proptosis. Although care must be taken to avoid attempting orbital preservation at the potential cost of decreased local disease control and survival, at present the most commonly performed approach with frozen section control is to resect involved orbital periosteum and preserve the orbital contents in cases where there is no invasion through the periosteum into orbital fat, orbital musculature or orbital apex. There does however remain some debate about the oncological basis for this. Although the loss of an eye psychologically is often very difficult for patients to consider, it must be remembered that preservation of a painful eye with diplopia and poor vision following RT is a significantly worse outcome than orbital clearance with an excellent prosthesis. Contraindications to surgery. Anatomical areas which preclude surgical intervention differ with the aggressiveness of the pathology. An aggressive tumour invading the cavernous sinus, particularly if it reaches the internal carotid artery or with massive intra-cranial extension, would be deemed incurable and the morbidity of surgical intervention would outweigh any potential benefits. These, however, are probably the only anatomical contraindications to surgery. With slower growing tumours quite significant intracranial disease may well still be amenable to surgical intervention with a hope of long-term survival. Significant involvement of both eyes or the loss of an only seeing eye is a devastating consequence of surgery and this would be a relative contraindication to any surgical resection. Regional nodes. Lymph node involvement at diagnosis is low. Rates are higher with increasing T stage, and squamous and undifferentiated histology. In T3-T4 SCC maxillary tumours elective nodal treatment of ipsilateral levels Ib and II has been advocated. In contrast, ethmoid sinus tumours have been associated with low rates of both lymph node involvement at diagnosis and nodal recurrence (approximately 2 and 7 per cent, respectively). Olfactory neuroblastoma can be associated with lymphatic spread, both uni-and bi-lateral in up to 25 per cent of cases. [bib_ref] When, how and why to treat the neck in patients with esthesioneuroblastoma:..., Zanation [/bib_ref] Results. Results from combined surgery and RT are very dependent on pathology and the anatomical areas involved by tumour with results if orbit and brain are involved being extremely poor. Involvement of the periorbita or dura also reduces survival. The following figures indicate published five years overall survival for common histological variants: SCC 30-55 per cent, adenocarcinoma 45-60 per cent and olfactory neuroblastoma approximately equal to 75 per cent. ## Radiation therapy Role of RT. Sino-nasal tumours are often advanced at presentation, invading adjacent structures and lie in close proximity to many organs at risk of damage from radiation (lens, retina, optic nerve and chiasm, brain tissue, pituitary gland). This makes irradiation to a radical dose difficult.The added numerous airtissue interfaces within the treated volume also make for inhomogeneous dose absorption and efforts should be made to eliminate these using tissue bolus techniques where possible. If orbital or brain invasion occurs, survival rates are extremely poor despite aggressive treatment. The most common management approach is surgery followed by post-operative RT, although some protocols have used chemotherapy alongside, where the tumour is recognised to be chemosensitive, e.g. SCC . Following surgery that involves a dural repair a longer interval before RT may be preferred to allow healing. The sequence of surgery and RT remains open to debate, with no significant differences in outcome found. Pre-operative (chemo) RT may allow for less extensive surgery in advanced tumours. The implementation of new advanced radiation techniques such as intensity modulated radiotherapy (IMRT) is especially attractive in sinus tumours as the dose distributions achieved with conventional techniques are rather inhomogeneous, with areas of low dose that can potentially contribute to local recurrence. [bib_ref] Intensity-modulated radiotherapy for sinonasal cancer: improved outcome compared to conventional radiotherapy, Dirix [/bib_ref] IMRT has demonstrated improved coverage of the tumour bed and potential sites of spread, whilst ensuring levels of radiation exposure are kept within the tolerance of adjacent neurological structures. Prospective studies with mature outcome data are not yet available. Dose escalation above conventional dose levels is achievable with IMRT and this will be an active area of future study to improve local control, since the majority of local failures occur within the radiation field. Patients with the most advanced tumours, previously thought to be suitable only for palliation, may then become treatable radically. Proton therapy is currently under evaluation and may have a role in treating small volume disease, e.g. low grade tumours at the skull base or close to radiosensitive structures, due to rapid dose fall off. It has been used in chondrosarcoma and olfactory neuroblastoma is included in the recommendations for specialised services in paediatric oncology. Sub-volumes may also be potentially treated using protons as a boost to residual tumour masses within a larger photon field as mixed plans. Radiation toxicity. Doses delivered with conventional RT are of the order of 60-70 Gy and are known to cause blindness in up to a third of patients, and too often sacrifice of the sight in one eye is unavoidable. [bib_ref] Postoperative radiotherapy for maxillary sinus cancer: long term outcomes and toxicities of..., Bristol [/bib_ref] Care must be taken to avoid a dry eye, caused by radiation injury from quite modest doses to the lacrimal gland (30 Gy), as optic pain, perforation and even enucleation may ensue. Brain radionecrosis is a potentially devastating complication of RT and the risk depends on the total dose, dose per fraction, overall treatment time and volume, with tolerance for partial volume irradiation set at 55-60 Gy/30 fraction equivalent dose. There is, however, very little information on the effect of irradiating large volumes of tissue to lower doses as occurs with IMRT, due to the multiple radiation portals. Conventional dose prescriptions include 60-70 Gy in 30-35# over 6 to 7 weeks for SCC, adenocarcinoma, undifferentiated carcinoma and olfactory neuroblastoma. Doses for lymphoma are approximately 40-50 Gy in 20-25# over 4 to 5 weeks. Accelerated, hyper and hypo-fractionated regimens remain investigational. ## Recommendations - The most common management approach is surgery followed by post-operative radiation therapy ideally within six weeks (R) - Radiation is given first if a response to radiation may lead to organ preservation (G) - Radiotherapy should be delivered within an accredited department using megavoltage photons from a linear accelerator (typical energies 4-6 MV) as an unbroken course (R) - Intensity modulated radiotherapy is the standard of care as it can improve target coverage, allow for dose escalation and facilitate organ sparing to reduce toxicity (R) Chemotherapy. Consensus statements are difficult due to the lack of adequately powered, randomised evidence. This is given either as a short course induction and/or neoadjuvant regime pre-RT or surgery for rapid symptom control, and/or concurrently as a radiation sensitiser. The neoadjuvant approach is not associated with improved overall outcomes, but is a practical solution to pre RT tumour shrinkage, as modern RT delivery relies on a static patient contour, to deliver dose accurately and safely. [bib_ref] Cisplatin-based neoadjuvant chemotherapy and combined resection for ethmoid sinus adenocarcinoma reaching and/or..., Brasnu [/bib_ref] This is usually cisplatin-based and in the phase II setting produces a response in about twothirds of patients. Concurrent use of chemotherapy with RT is associated with a small, but measurable improvement in survival for SCCs of the head and neck in general, with improved disease-free and overall survival at five years to approximately 70 and 67 per cent, respectively suggested. For the rarer tumour types of the sinus area, there is no strong randomised evidence currently to support its use routinely. Small-scale observational studies have reported on topical and intra-arterial chemotherapy, but are not recommended. Chemotherapy has also been reported to be of use in undifferentiated carcinomas, neuroendocrine and small cell carcinomas. Excellent local and distant control rates for olfactory neuroblastoma have been demonstrated with local therapy alone and chemotherapy in this setting is experimental, but often given in the presence of locally advanced disease. For sinonasal SCC, there is no randomised evidence in favour of the use of concomitant chemoradiation. Evidence supporting its use both in the primary and adjuvant setting can be extrapolated from other head and neck malignancies. Chemotherapy may improve quality of life and offer a modest survival benefit in the palliative setting, translating from benefit seen in other head and neck SCC sites. [bib_ref] Nasal and paranasal sinus carcinoma: how can we continue to make progress?, Dulguerov [/bib_ref] Molecular targeted treatments are under investigation, but none have proven benefit to date. The role of chemotherapy in paranasal sinus malignancy is limited to the following settings: as part of triple therapy, e.g. embryonal rhabdomyosarcoma, concurrently with radiation in locally advanced disease, e.g. SCC of maxilla, for disseminated lymphoproliferative malignancy and for palliation, e.g. poorly differentiated SCC with disseminated disease. Palliation. Some patients present with advanced disease where radical treatment is not appropriate. Surgery, RT and chemotherapy all have a potential role in palliation. Palliative RT treatment requires high doses to achieve any significant tumour control, and short fractionation regimes are associated with marked acute toxicity. Regimens that can be considered on an individual basis include 55 Gy in 20# over four weeks, 27 Gy in 6# over three weeks and 36 Gy in 12# over two-anda-half weeks. If the patient has a localised disease recurrence, then retreatment with IMRT or stereotactic RT may be considered especially if there has been a long disease-free interval. Follow-up. Follow-up is needed for detection of recurrence and to manage surgical sequelae (nasal crusting, epiphora, etc.). Follow-up should be lifelong as some tumours can recur many years after treatment and should include careful examination of the cavity with the endoscope and MRI scans. Imaging should include the neck in olfactory neuroblastoma (see below). ## Key points - Endoscopy and imaging (computed tomography and magnetic resonance imaging) are key to assessing tumour extent and planning surgical approach - Endoscopic techniques enable low morbidity and low recurrence rates to be achieved in suitable tumours and may be performed for curative or palliative reasons - A high level of expertise in endoscopic sinus surgery and skull base and/or dural reconstruction is a necessity before undertaking endoscopic resections - Neurosurgical support and neuronavigation should be routinely available in centres undertaking this surgery - Reconstruction and rehabilitation needs should be integrated into the treatment plan for patients undergoing open surgery - The majority of patients will require adjuvant radiotherapy - Diligent tumour surveillance with nasal endoscopy and interval magnetic resonance imaging scans is a necessity following treatment of sinonasal malignancy. [fig] FIG. 1: Management algorithm for malignant sinonasal tumours.7 [/fig] [table] TABLE II LIMITATIONS: OF ENDOSCOPIC SURGERY WITH CURATIVE INTENT 7 [/table]	None	https://www.cambridge.org/core/services/aop-cambridge-core/content/view/DB48A7DC75883C856553984CCAAAC227/S0022215116000530a.pdf/div-class-title-nose-and-paranasal-sinus-tumours-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. With only limited high-level evidence for management of nasal and paranasal sinus cancers owing to low incidence and diverse histology, this paper provides recommendations on the work up and management based on the existing evidence base. Recommendations • Sinonasal tumours are best treated de novo and unusual polyps should be imaged and biopsied prior to definitive surgery. (G) • Treatment of sinonasal malignancy should be carefully planned and discussed at a specialist skull base multidisciplinary team meeting with all relevant expertise. (G) • Complete surgical resection is the mainstay of treatment for inverted papilloma and juvenile angiofibroma. (R) • Essential equipment is necessary and must be available prior to commencing endonasal resection of skull base malignancy. (G) • Endoscopic skull base surgery may be facilitated by two surgeons working simultaneously, utilising both sides of the nose. (G) • To ensure the optimum oncological results, the primary tumour must be completely removed and margins checked by frozen section if necessary. (G) • The most common management approach is surgery followed by post-operative radiotherapy, ideally within six weeks. (R) • Radiation is given first if a response to radiation may lead to organ preservation. (G) • Radiotherapy should be delivered within an accredited department using megavoltage photons from a linear accelerator (typical energies 4–6 MV) as an unbroken course. (R)
45f6e63512600feccb9601f158a952273926ab30	pubmed	Recommendations for early diagnosis of Developmental Dysplasia of the Hip (DDH): working group intersociety consensus document	Recommendations for early diagnosis of Developmental Dysplasia of the Hip (DDH): working group intersociety consensus document This consensus document has been prepared by a multidisciplinary group of experts (Paediatricians, Radiologists, Paediatric Orthopaedics) and it is mainly aimed at paediatricians, hospitals and primary care providers. We provide recommendations for the early diagnosis and treatment of Developmental Dysplasia of the Hip (DDH) and indications on its management. # Introduction Developmental Dysplasia of the Hip (DDH) is the most common congenital disease of the musculoskeletal system in newborns. The disease ranges from a simple flattening of the acetabular cavity to the complete dislocation of the femoral head. If untreated, DDH can cause early hip osteoarthritis and, in the most severe forms, the presence of a limp with severe functional limitations, since walking age. An early diagnosis, which is essential for an early treatment, is the fundamental prerequisite in order to achieve the best treatment results and to reduce the possibility of hip osteoarthritis in young adults. The treatment effectiveness is maximized when it begins early, within the first month or, if possible, the first days of life. Paediatricians, radiologists, paediatric orthopedics worked together to design and write this document. The aim is to provide recommendations for early diagnosis and treatment of hip developmental dysplasia (DDH) and indications on its management. # Methods # Methodology used The document has been prepared according to the following steps: 1) identification of a multidisciplinary group of experts (Paediatricians, Radiologists, Paediatric Orthopaedics) with all the skills required to draft the document; 2) formulation, by the group of experts, of the most relevant scientific questions, with particular attention to the areas of major interest (opportunities for DDH screening, diagnostic tests, method of execution and timing of the tests, selective or universal ultrasound screening, operators' training, need for data registration); 3) review of the scientific literature according to a research strategy capable of identifying the best available scientific evidence relating to the questions raised; 4) evaluation and synthesis of the bibliography collected; 5) discussion and approval of the results' analysis with a consensus conference and formulation of recommendations based on the experts' advice; 6) drafting of the final shared document; 7) presentation and publication of the final version of the consensus 8) organization of a review in 3 years. ## Review of scientific literature From 1st of January 2000 to 31st of March 2019 a bibliographic research was performed by consulting Medline's databases through PubMed. Studies in English and Italian and articles in other languages have been included only if particularly significant. The members of the working group have identified keywords used for the research strategy. Articles taken from bibliographic references of the initially selected studies have also been considered. The references were periodically updated during the consensus drafting. Abstracts and articles were then evaluated by the working group, who selected the relevant articles favouring, where present, metaanalyses of clinical trials, systematic reviews, randomized controlled clinical trials, cohort studies and general interest articles. Additionally, a specific search was performed in order to identify guidelines and other national and international consensus documents already available. The articles considered most relevant according to the AGREE II methodology (1) ## Consensus Disease DDH is the most common congenital disease of the musculoskeletal system in newborns. The disease ranges from a simple flattening of the acetabular cavity to the complete dislocation of the femoral head. If untreated, DDH can cause early hip osteoarthritisand, in the most severe forms, the presence of a limp with severe functional limitations, since walking age. ## Ddh epidemiology The analysis of the literature does not allow a precise definition of DDH epidemiology due to the following reasons: the classification and definition of the disease have changed over time, in relation to the diagnostic methods used; the tools available for the diagnosis are characterized by a different accuracy (radiographic, clinical, ultrasound examination); DDH prevalence changes according to the children's age at the time of the study and their ethnicity. In the past, the incidence of severe forms of the disease (complete dislocation of the femoral head), without an early diagnosis program, was reported to be 0.13% of all newborns. The actual DDH frequency undoubtedly exceeds this value, since the disease includes not only complete dislocations but less severe clinical pictures, characterized by dysplasia of the acetabulum with the femoral head still in place, which are potentially responsible for early osteoarthritis of the hip; these features, detectable by ultrasound examination, are present in 1.6% of the general population. ## The natural history of ddh The femoral head must be positioned in a stable and entirely congruent manner within the acetabular cavity to ensure the healthy development of the child's hip. Children with a complete dislocation of the femoral head, if untreated, will maintain a dislocated hip and present a limp at the beginning of gait. The spontaneous evolution of the less severe forms of DDH has not yet been fully defined because of the objective ethical difficulty of performing a methodologically correct randomised clinical trials involving the comparison between the "treated" and the "untreated" groups. However, retrospective observational studies available in literature, report that DDH, if not detected and treated promptly, entails an increased risk of corrective surgery and hip replacement surgery. The clinical signs detectable in the first months of life may disappear overtime, differently from the pathological morphological patterns at the acetabulum level. According to Furnes, failure to treat these cases contributes to 29% of arthroplasty performed under the age of 60. ## Importance of early diagnosis of ddh An early diagnosis, which is essential for an early treatment, is the fundamental prerequisite in order to achieve the best treatment results and to reduce the possibility of hip osteoarthritis in young adults. The treatment effectiveness is maximized when it begins early, within the first month or, if possible, the first days of life. If a hip dislocation is present at birth, the anatomical alterations secondary to the dislocation of the femoral head are not yet consolidated; instead, they may be consolidated in delayed treatment, after the second or third month of life of the child. In the latter case, the reduction of the femoral head within the acetabular cavity is much more problematic and sometimes impossible with a closed approach. Furthermore, any minimal residual alteration of the acetabulum, most likely in late treatments, may lead to hip osteoarthritis in adulthood. There are studies which analysed the time limit within which the potential for acetabular growth, and therefore for the healing of dysplasia, is still high. The ideal time limit for diagnosis and treatment has been identified as the sixth week of life; beyond that age, a complete normalization of the acetabulum after treatment is not guaranteed. An essential role regarding the incidence of avascular necrosis of the femoral head, the most feared complication in DDH treatment, is determined by early diagnosis. Bradley, in patients treated with closed reduction and cast, reports an average incidence of avascular necrosis of 10%, with a progressively higher frequency of cases in relation to the age at which treatment is started. Also Senaranhighlights that treatment is more complex and lasts longer in cases of late diagnosis. ## Ddh diagnosis The examinations available for the diagnosis of the DDH are clinical, ultrasound and radiographic examinations. ## Clinical examination Clinical examination of the hips, at birth and in the first month of life, continues to play a fundamental role in the diagnosis of DDH, particularly in the severe forms of the disease. The correct clinical examination of the hips requires the evaluation of: i) the child's spontaneous posture; ii) a possible leg length discrepancy, in particular of the thighs (Galeazzi sign); iii) an asymmetry of the lateral profile of the pelvis; iv) a decreased hip range of motion during abduction of the thighs (not a very specific finding, as it is also present in healthy children who have maintained for a long time intrauterine postures with the lower limbs in adduction). Only after the above evaluations, will the examiner perform the Ortolani manoeuvrefollowed by the Barlow manoeuvre. When the femoral head is completely and permanently located outside the acetabulum, anatomical conditions can prevent reduction with the simple Ortolani manouvre; in these cases, we will not detect the "clunk", but only a severe limitation of the thighs abduction. Articular noises such as "clicks" or "creaks" should not be considered pathological findings. ## Ultrasound examination The introduction of the ultrasound technique for the study of childhood hip diseases is undoubtedly the most important novelty for the diagnosis of DDH in the past 30 years. Ultrasound examination allows to visualize with precision all the components, mineralized and not, of the infantile hip and to recognize any alteration of the hip joint from the first days of life. The main techniques proposed for the ultrasound study of the hip are: 1. Graf technique: initially used in Germanspeaking countries and in Italy, but now widespread throughout the world. This method of study is of rapid execution, well standardized and allows to identify with precision and in detail the morphology of all the joint components. By angle measurements of bony and cartilaginous components of the acetabulum, it allows the classification of normal and pathological images according to progressive severity criteria. 2. Harcke technique: it evaluates the femoral head stability at rest and under stress (method used mainly in the USA), by using different scans, longitudinal and coronal, and by extending or flexing the thigh at 90°with respect to the pelvis, 3. Morin-Terjesen technique: based on the calculation of the percentage of bone coverage of the femoral head (mainly used in Scandinavian countries). Regardless of the technique used, great attention should be paid to the training of sonographers and the periodic verification of their skills. All methods must be performed in strict compliance with the author's instructions. Diagnostic errors can be avoided by strictly adhering to the technique used; the accuracy of the examination, especially regarding specificity, is closely linked to the operator's technical skills. Only adequately trained and certified operators should perform the ultrasound examination in newborns; from a medical-legal point of view, according to the regulations in force in our Country, the hip ultrasound is to be considered a "medical act", thus constituting an assumption of professional responsibility (in terms of expertise, prudence and diligence) by the operator. ## Radiological examination Hip X-ray still plays a role in the diagnosis of DDH. However, the method is useful only from the 3rd -4th month of life of the child, when the skeletal structures reach a sufficient degree of mineralization and may be visualized by X-rays. The risks associated with radio exposure and the modest information that the examination provides in the first 3-4 months of life, have made this diagnostic tool no longer recommended as a screening test for DDH. Hip X-rays must be used as a second-level diagnostic investigation in order to: i) confirm a clinical or ultrasound suspicion of DDH; ii) as a follow-up the disease; iii) document the complete recovery of the most severe forms; iv) highlight the possible onset of complications. ## Comparison between the results of the clinical and the ultrasound examinations Studies comparing the results of clinical and ultrasound examinations have shown that the latter is more sensitive to detect all children with DDH. The concordance between clinical and ultrasound examinations is suitable in severe DDH cases (type III and IV according to Graf), but unsatisfactory for less severe cases (type IIc, D, IIb according to Graf). ## Ddh screening The need for DDH screening, aimed at an early diagnosis is now widely shared; the following points are still being debated: diagnostic tests to be used and data recording methods; necessary screening execution time; opportunity to follow a "universal" programme (aimed at all newborns) or a "selective" programme (for children with risk factors). Historically, X-ray screening of the hip at the age of 4-6 months has been recommended and implemented on the basis of the Health Authorities recommendations, especially in DDH endemic regions, such as Brianza and Emilia-Romagna. The need to reduce radio-exposure, while maintaining a high level of attention to this disease, suggested to consider as a significant progress the identification of any clinical sign that raised its suspicion. For many years, the screening for DDH "early" diagnosis has been performed in many parts of the world using the Ortolani manoeuvre, later associated to Barlow's. Many publications over the years have highlighted the limitations of the clinical screening. If it is true that in the presence of a positive sign of Ortolani the ultrasound examination always documents the presence of DDH, it is also true that the absence of such sign is not a guarantee of its absence. It should also be emphasized that a negative clinical sign does not always represent the normalization of an unstable hip, but sometimes a worsening of its morphological aspect, with an irreducibility of the dislocation. Indirect data that clinical screening has not allowed an early detection of all forms of DDH and the implementation of effective treatments are extractable from: Regional Register of Orthopaedic Prosthetic Implantology of the Emilia-Romagna Region (RIPO): DDH represents the second cause of arthroplasty, with an incidence of 10.9% between 2000 and 2011; the incidence rises up to 31.1% in patients operated on under 40 years of age; The Norwegian Arthroplasty Register: between 1987 and 2007, 163 of the 713 patients (22,86%) treated under 40 years of age with hip arthroplasty presented a DDH; out of these young adults 82% were females and 18% males and the average age at diagnosis was 4.4 years in the first and 22 years in the second. These data suggest that, although the Scandinavian countries and the Emilia-Romagna Region have always been aware of the importance of the disease and are in favour of carrying out a clinical examination as a tool for DDH screening, the problem of missed or late diagnosis has not been completely solved and the disease still represents a significant health concern. The ultrasound examination of the hips, introduced by the end of the 1980s, represented a major technological advance, initially as a useful tool for a more accurate diagnosis, then assuming the possible role of a screening test of DDH. In the first 10 years of 2000, most of the papers published on DDH ultrasound screening provided indications for a "selective" programme (clinical examination for all newborns and ultrasound examination only for patients with clinical or anamnestic risk factors). Data from more recent studies, in the last 10 years show that programs involving "selective" ultrasound screening have not significantly changed the number of late diagnoses of the disease and the number of children who undergo surgery. In patients without risk factors that escape selective screening, DDH diagnosis is late, thus leading to a higher incidence of complications. Interesting is the data of a review carried out by Sink: he examined patients who underwent surgery as the consequence of a late treatment of DDH: 85.3% of these did not meet the inclusion criteria for the selective screening, i.e. they did not present any risk factor. Broadhurstreports that in the United Kingdom there has not been a decrease in DDH late diagnoses since the introduction of selective ultrasound screening; in both authors' interpretation this is explained by the fact that many of the children with a late diagnosis had no risk factors at birth and escaped the selective ultrasound screening. The results of these studies indicate that selective ultrasound screening, aimed only at patients with risk factors, is doomed to fail due to the inability to identify those children affected by DDH, but without clinical and/or anamnestic risk factors. Conversely, the results obtained in countries that have introduced a "universal" ultrasound screening programme show a significant reduction in late diagnosis and number of children undergoing interventional treatment. Biedermannreports the results of a universal ultrasound screening conducted in Austria showing how early diagnosis has significantly reduced both open surgeries, to reduce the femoral head within the acetabular cavity (0.04 per thousand live births), and closed reduction interventions (0.86 per thousand live births). Moreover, similar results had already been reported by previous authors: Von indicated a reduction in surgery of 52%, while Thallingera reduction of 46% (from 1.3 per thousand to 0.7 per thousand of live births); Thalerin a comparison between two screening periods, namely 1978-1982 (clinical screening) and 1993-1997 (universal ultrasound screening) reported a reduction in surgery of 85%. In some Countries the application, of the ultrasound method as a universal screening tool for newborns has raised the problem of the higher percentage of "ultrasound" diagnosis of dysplasia compared to "clinical" diagnosis. Actually, if this doubt could arise in the first periods of application of the method, the data reported in subsequent years have reduced the problem, in particular, the fear of a possible "higher incidence of treated hips" (overtreatment). The technological progress of the equipment, together with the improvement of the knowledge resulting from the screening experience, has allowed refining the evaluation of DDH. In countries where the universal ultrasound screening has been implemented, the percentage of children treated for DDH decreased compared to the previous period when screening was carried out only by clinical examination. Thaleralso reports a 48% reduction in abduction treatment, while Thallingerindicates a 2.6% reduction in treated children. These percentages are in line with the 2.6% percentage reported in Central Europeand lower than that reported by the Norwegian register based on radiographic diagnosis, which is 3.3.%. Regarding the economic costs associated with the different DDH screening programmes, it has been demonstrated that universal ultrasound screening ensures a significant reduction in the health costs associated with the most invasive surgical treatments; by adding these costs to those necessary to organise set up a universal ultrasound screening programme, the overall economic costs of the different screening programmes are sustainable. ## Data collection Regardless of the technique used, any reliable DDH screening programme must include the systematic and computerised collection of data on the results of the health interventions implemented. The creation of a regional computerized registry for the collection of screening data and admissions with DRG related to DDH therapy is an essential tool to verify the results of the programme to prevent disease outcomes. Only through data analysis it will it be possible to assess the effectiveness of the programme, both in terms of health protection and costs, for the individual and the community. # Conclusions ➢ All newborns must undergo a clinical examination of their hips by a neonatologist or paediatrician at birth; the examination must be properly recorded. ➢ The clinical examination of the hips must be repeated during health assessments in the first 6 months of life by the family paediatrician, and properly recorded. ➢ All newborns who present a "clunk sign" at clinical examination must undergo an ultrasound examination of their hips before being discharged from the birth point or, in any case, within the first week of life; the examination must be properly recorded. It is crucial to organize a regional DDH screening program, including all newborns, with hip sonography at 4-6 weeks of life, and a registry for screening results and DDH treatments. ➢ All newborns, regardless of the presence of risk factors, must be included in a program of DDH screening that foresees the performance of an ultrasound examination of the hips between 4 and 6 weeks of life by certified operators and the creation of a computerized regional registry for the collection of screening data and DRG admissions related to DDH treatment. ➢ Health services should identify a local screening and care pathway, shared by paediatrician, orthopaedic and radiologist, for all cases with a positive dysplasia ultrasound examination (type IIb, IIc, D, III, IV image according to Graf's classification); type IIa hips should be monitored with ultrasound examination and treated only in the absence of signs of adequate maturation. ➢ Health services, with the collaboration of scientific societies, must: i) identify the centres suitable for carrying out the screening; ii) implement specific training programs for learning the clinical and ultrasound examination of the hips; iii) provide certification methods for the operators dedicated to the ultrasound examination; iv) verify the quality of the services provided.	None	https://ijponline.biomedcentral.com/track/pdf/10.1186/s13052-020-00908-2	None
0fd7ef41db94184ee4dac26d0bde3519a2b989ec	pubmed	Management of hyperkalemia in patients with kidney disease: a position paper endorsed by the Italian Society of Nephrology	Management of hyperkalemia in patients with kidney disease: a position paper endorsed by the Italian Society of Nephrology Hyperkalemia (HK) is the most common electrolyte disturbance observed in patients with kidney disease, particularly in those in whom diabetes and heart failure are present or are on treatment with renin-angiotensin-aldosterone system inhibitors (RAASIs). HK is recognised as a major risk of potentially life threatening cardiac arrhythmic complications. When an acute reduction of renal function manifests, both in patients with chronic kidney disease (CKD) and in those with previously normal renal function, HK is the main indication for the execution of urgent medical treatment and the recourse to extracorporeal replacement therapies. In patients with end-stage renal disease, the presence of HK not responsive to medical therapy is an indication at the beginning of chronic renal replacement therapy. HK can also be associated indirectly with the progression of CKD, because the finding of high potassium values leads to withdrawal of treatment with RAASIs, which constitute the first choice nephro-protective treatment. It is therefore essential to identify patients at risk of developing HK, and to implement therapeutic interventions aimed at preventing and treating this dangerous complication of kidney disease. Current strategies aimed at the prevention and treatment of HK are still unsatisfactory, as evidenced by the relatively high prevalence of HK also in patients under stable nephrology care, and even in the ideal setting of randomized clinical trials where optimal treatment and monitoring are mandatory. This position paper will review the main therapeutic interventions to be implemented for the prevention, detection and treatment of HK in patients with CKD on conservative care, in those on dialysis, in patients in whom renal disease is associated with diabetes, heart failure, resistant hypertension and who are on treatment with RAASIs, and finally in those presenting with severe acute HK. # Introduction HK is a common finding in patients with kidney disease, due to the effects of kidney dysfunction on potassium (K) homeostasis, and this condition strongly impacts upon the quality of life and prognosis of these patients. Low glomerular filtration rate (GFR) is the main driver for the increase of serum K (sK) above the normal range, the main co-determinants being metabolic acidosis, constipation, the typical comorbidities of CKD, diabetes mellitus (DM), heart failure (HF), and the use of RAASIs, the most prescribed cardio-nephroprotective drugs that per se increase sK. HK, besides being associated with fatigue and muscle weakness, remarkably increases the risk of sudden death due to fatal arrhythmias, and acts as major driver to start chronic dialysis therapy in patients with end-stage renal disease (ESRD). The true incidence and prevalence of HK is not known, but it has been estimated to be 2-3% in the general population and 1-10% among hospitalized patients. Individuals with CKD, HF, DM, and those taking RAASIs, as well as more than half of predialysis patients, have an estimated two to threefold higher risk for HK. As for advanced CKD, the prevalence of severe HK is relatively low. In fact, in patients with a GFR < 30 mL/ min/1.73 m 2 , severe HK was detected in 1.8% of a large cohort in the US, and in approximately 4-5% in a recent Italian study. However, the prevalence of sK > 6.0 mmol/L was reported as high as 34.5% in a recent epidemiological investigation. The clinical relevance of HK has recently been confirmed by a meta-analysis of 27 cohort studies, 10 in the general population, seven in individuals at high cardiovascular risk, 10 in CKD patients, including a total of 1,217,986 subjects followed for an average of 6.9 years. The study demonstrated that: (a) risk of HK onset increased proportionally to GFR decline, starting from GFR < 75 mL/min/1.73 m 2 , and in the presence of pathologic albuminuria (> 30 mg/g); (b) sK > 5.0 mmol/L was an independent predictor of death and ESRD. Despite the epidemiologic dimensions of HK and its negative effects on CKD outcome, current therapeutic strategies are far from optimal. A recent observational study from Italy has confirmed the limits of current approaches to HK even in the setting of renal clinics, i.e. the reference of care for overt CKD. This historical prospective study examined outcomes and determinants in as many as 2443 CKD patients referred to 46 Italian outpatient nephrology clinics. Patients were stratified into four groups by HK status (sK ≥ 5.0 mmol/L) over two visits, basal (referral) and visit after 12 months of nephrology care: "absent" (no-no), "resolving" (yes-no), "new onset" (no-yes), "persistent" (yes-yes). In this study, mean age was 65 ± 15 years, 58% males, 28% had diabetes, 36% cardiovascular disease, estimated GFR (eGFR) was 35 ± 17 mL/min/1.73 m 2 , proteinuria 0.40 (0.14-1.21) g/day, and RAASIs were prescribed in 79% of the patients. In either visit, mean sK was similar (4.8 ± 0.6 mmol/L) as the prevalence of HK (39% at visit 1 and 37% at visit 2). HK was mild to moderate in the vast majority of cases (sK > 6 mmol/L in less than 4% at either visit). Specifically, after 1 year of treatment in nephrology clinic sK was ≥ 5.0 mmol/L in 39%, > 5.0 mmol/L in 33% and ≥ 5.5 mmol/L in 14% in overt CKD (eGFR < 60 mL/ min/1.73 m 2 ). provides a gross estimate of the number of patients with HK followed in Italian nephrology clinics obtained when matching these data with the results of the National Health Survey 2008-2012 on CKD prevalence in Italy, the CARHES (Cardiovascular risk profile in Renal patients of the Italian Health Examination Survey) study. CARHES study disclosed that out of the total number of patients living in Italy with CKD stage 3-5 (n =861,835), only 18.4% (n =158,600) were aware of their kidney disease and therefore likely to be followed by a nephrologist. When examining the two visits with a 1 year-interval, HK was absent in 46%, resolving in 17%, new onset in 15% and persistent in 22%. Over a median follow up of 3.6 years, start of chronic dialysis and all-cause death occurred in 567 and 349 patients, respectively. The multivariate survival analysis revealed that compared with the reference group (absent), new onset or persistent HK independently increased the risk of dialysis by about 30%. In contrast to an unselected CKD population, mortality did not increase in these patients under stable nephrology care. This finding is expected if one considers the attitude of nephrologists starting dialysis in stage 5 when HK, even when of moderate degree, becomes refractory to medical therapy in order to prevent additional increments of sK potentially associated with fatal arrhythmias. The Estimated number of patients with CKD stage 3-5 by hyperkalemia severity followed in Italian nephrology clinics study therefore suggests that in outpatient nephrology clinics, HK of mild to moderate degree is common (37%) and increases by 30% the need for chronic dialytic treatment. An additional but important grey area in the management of HK is the treatment of this electrolyte abnormality in dialysis patients. In this setting, sK levels are higher than in non-dialysis CKD, with about 60% and 35% of patients experiencing sK > 5.5 and > 6.0 mmol/L, respectively. HK is more common during the long interdialytic interval and in patients treated with RAASIs to treat underlying cardiovascular disease as in those that need hypertonic dialysate because of poor intradialytic hemodynamic stability. In dialysis patients, the higher the sK values the worse is the prognosis (hospitalization, admission to emergency department and death). Finally, the optimal management of acute severe HK, which is a true nephrology emergency that requires prompt and efficacious intervention, still remains to be clarified. For the aforementioned reasons, the Italian Society of Nephrology has recently established a working group to develop practical recommendations on the clinical management of HK, in terms of monitoring and treatment. This position statement is the final output of the collaborative work and it is divided into four sections that address the main aspects of HK in CKD population: ## Hyperkalemia in non-dialytic chronic kidney disease ## Evaluation of the patient with chronic hk In-depth evaluation of the CKD patients with high sK is the key for graduating intensity of K-lowering treatment. The first objective is to correctly identify patients at high risk of developing more severe and potentially life threatening episodes of HK. Proper assessment is based not only on the exclusion of pseudohyperkalemia (spurious increases of sK usually due to hemolysis of blood samples caused by fist clenching or prolonged use of tourniquet during phlebotomy or delay in processing blood samples), but also on the decision of the correct timing of testing sK. Guidelines suggest measuring sK prior to first prescription or uptitration of RAASIs and in the first two subsequent weeks. Indeed, it is useful monitoring sK over time also independently from RAASIs therapy for three major reasons: (a) CKD per se is a risk factor of developing HK, (b) chance of revealing significant HK increases in parallel with the number of sK tests performed, and (c) HK status can change in even one-third of patients over 1-year observation, likely due to the different control of modifiable co-determinants of HK. # Position statement 1.1 1. Serum K levels must be measured at the first visit in the Nephrology Unit, as in all subsequent visits, independent of RAASIs prescription. 2. In the presence of elevated or increasing levels of sK, exclude pseudohyperkalemia, extend evaluation to all potential co-determinants of HK and anticipate control visit. ## Target levels of sk "Clinical normality" of sK can be defined by the range of levels that correspond to the nadir of cardiorenal events attributable to hyper-and hypo-kalemia, thus representing the goal of therapy. This definition must therefore take into account the effect of sK on the global prognosis of the CKD patient. Survival studies in CKD have shown that the relationship between sK and mortality is U-shaped, being significant for even mild degree of hypokalemia (sK < 4.0 mmol/L) and hyperkalemia (sK ≥ 5.0 mmol/L) and showing the best survival at sK 4.0-4.5 mmol/L. Therefore, even minimal sK abnormalities should call for attention, because they herald more important changes potentially associated with fatal arrhythmias. The observation is also relevant that in referred CKD, HK significantly increased ESRD risk despite being mild-to-moderate in 94% of cases. # Position statement 1.2 Serum K ≥ 5.0 mmol/L must be considered pathologic in CKD and require careful follow-up and implementation of preventive and therapeutic strategies aimed at maintaining sK in the optimal clinical range (4.0-4.5 mmol/L). ## Nutritional approach to chronic hk WHO recommends a daily potassium intake of at least 90 mmol or 3.5 g because a lower intake is associated with an increased risk of hypertension and cardiovascular events. These recommendations aimed for the general population may not hold true in CKD patients, due to the intrinsically higher risk of HK. Some studies, including patients with normal or only moderately reduced GFR, have shown a cardio-nephroprotective effect of higher levels of 24-h urine K excretion, that is proxy of daily K intake. Furthermore, fruit and vegetables, that contain higher amounts of K, also represent the major source of fiber that help in limiting the risk of constipation. This aspect is particularly important in CKD, where fecal loss of K increases with a decline in GFR, as a major compensatory mechanism. While waiting for more and solid evidence on K intake and outcome in mild-to-moderate CKD, it appears useful to maintain a nutritional approach, that is prudent but not restrictive in K intake a priori. On the contrary, patients with advanced CKD should be considered as those under chronic dialysis therapy, that is, they should restrict their daily dietary intake of K (see following paragraph and position statement 2.2). # Position statement 1.3 At variance with patients with advanced CKD, in nondialysis CKD of mild-to-moderate degree, restriction of K intake is not recommended unless sK levels are above 5.0 mmol/L in the absence of any other apparent cause; under these latter conditions, it is recommended to limit food with high K content, especially if poor in fibers, and pre-treat (soaking and boiling) before cooking to remove K. ## Pharmacological approach to mild-to-moderate chronic hk Treatment of mild-to-moderate chronic HK (sK 5.0-6.0 mmol/L) is essentially based on three interventions. The choice and timing of therapy must be tailored to the single patient by taking into account the clinical and laboratory scenario, and eventually integrated with diet modification and downtitration/withdrawal, at least temporarily, of RAASIs: (a) Oral supplementation of sodium bicarbonate (3-5 g/day) is indicated to achieve normokalemia in the presence of concurrent metabolic acidosis (HCO 3 < 22 mmol/L). However, bicarbonate appears less effective in reducing sK in patients with advanced CKD. (b) Loop diuretic therapy, either as add-on or uptitration, allows to enhance urinary K excretion. However, this measure is indicated exclusively in the presence of extracellular volume expansion. Indeed, intensive diuretic therapy in CKD requires careful monitoring of patient (body weight, blood pressure and GFR) to prevent hypovolemia and the consequent GFR decline that in turn increases sK. (c) Increase in fecal loss of K by the administration of intestinal K binders. Two binders are currently available, sodium polystyrene sulfonate (SPS) and calcium polystyrene sulfonate (CPS) that are however used in the acute setting and with no evidence on safety and efficacy over the long term, due to the absence of prospective studies or randomized controlled trials (RCTs) on their use as chronic therapy. Furthermore, these two binders must be withdrawn when sK levels drop below 5.0 mmol/L. This therapy therefore is not suitable to enable chronic cardio-nephroprotective therapy with RAASIs, and indeed the two mentioned binders are de facto poorly used in the real world. Two new potassium-binding drugs, namely patiromer and sodium-zyrconium cyclosilicate, not yet available in our country, have undergone extensive clinical testing recently in the setting of chronic hyperkalemia where they have been shown to be effective and relatively safe during long-term administration. # Position statement 1.4 The pharmacological approach to HK in to mild-moderate chronic CKD is multifactorial and must be based on the specific features of the single patient: (1) Sodium bicarbonate in the presence of metabolic acidosis, (2) Loop diuretics in the absence of euvolemia-hypovolemia and/or low blood pressure, (3) short therapeutic cycles with the two K binders today available (SPS and CPS). ## Hyperkalemia in dialysis patients ## Prevalence and target values of sk in dialysis Maintenance dialysis remains the main therapy to control K balance in patients with ESRD, especially in the absence of residual renal function. However, HK is quite frequent in the dialysis setting, more in hemodialysis (HD) than in peritoneal dialysis (PD) because of the continuous nature of the latter. The prevalence of HK, when defined as sK > 6 mmol/L, in HD ranges between 10 and 20% in the DOPPS (The Dialysis Outcomes and Practice Patterns Study) survey and DaVita data, while in PD it is about 7%, when defined as sK > 5.5 mmol/L. However, a recent study has shown that the overall percentage of HD patients experiencing HK anytime over a 2-year follow-up period can be as high as 74% for sK > 5.1 mmol/L, 58% for sK > 5.5 mmol/L and 35% for sK > 6 mmol/L. On the other hand, more than 25% PD patients have time-averaged sK < 4.0 mEq/L, a level that is associated with a significant increase in mortality risk in this population. Indeed, previous studies have suggested that 10-29% of PD patients require regular K supplements. Differences in reported rates of HK observed between clinical trials are mainly related to heterogeneity in HK definition and patient population, as well as the number of sK tests performed. K clearance in PD is about 15 ml/min. In patients undergoing 10 L of drainage per day, approximately 35-46 mmol of K is removed. Peritoneal fluids are potassium-free, and K balance is maintained by the continuous nature of the treatment, preserved residual kidney excretion, increased colonic secretion of K, decreased intake of K-rich foods, and transcellular shift driven by insulin release in response to the obligatory glucose absorption from the PD fluids. HK is the most important electrolyte abnormality in dialysis because it can cause cardiac arrhythmias. Nephrologists try to avoid rapid intradialytic changes of sK by using different models of K removal to limit K gradient between serum and dialysate. However, there is no solid evidence that these approaches improve survival. DOPPS data in HD showed that increased mortality was associated with sK > 5.6 mmol/L; these data have been confirmed in a study where it has been demonstrated that sK > 6.0 mmol/L was associated with an increased risk of morbidity and mortality. The lower mortality rates were observed in hemodialysis with pre-dialysis sK values ranging 4.6-5.3 mmol/L, and in PD with sK ranging 4.0-4.5 mmol/L. # Position statement 2.1 Serum K should be kept in the range 4.6-5.3 mmol/L before the beginning of the HD session and 4.0-4.5 mmol/L in PD. ## Management of hk in dialysis Although K is directly removed from plasma, the distribution of K between the plasma and interstitial fluid is nearly instantaneous; therefore, it is immediately removed from the extracellular fluid. The effect of dialysis on sK concentration depends on the rate of K removal from the extracellular fluid and the rate of K that is replenished from intracellular stores. About 80-140 mmol of K can be removed during a 4-h dialysis session, the amount removed depending on the plasma-to-dialysate concentration gradient, blood and dialysate flow rates, and total body K stores. Since replenishment from cellular stores continues when K removal stops, there is a substantial post-dialysis rebound of sK, ranging from 0.5 to 1.0 mmol/L; its concentration gradually rises to pre-dialysis levels within 24 h. Several factors influence dialysis K removal, namely dialysis modality, treatment time, frequency of sessions, residual diuresis, dietary intake, gastrointestinal loss, glycaemia and insulin fluctuations, metabolic acidosis, as well as the use of many drugs, mainly RAASIs. Several HD parameters may affect the magnitude of K removal, including dialysate concentrations of K, bicarbonate and glucose, as well as dialyzer blood flow. The lower the dialysate K concentration, the greater the amount removed, and the lower the final post-dialysis sK. However, the use of low K dialysate may expose patients to potential cardiac side effects. Low K concentration in dialysis bath could be associated with a prolongation of ventricular repolarisation time (expressed by the QT interval of ECG), particularly in presence of low calcium concentration in the dialysate (a). A severe prolongation of ventricular repolarisation time can cause early after-depolarizations that may "trigger" non sustained and sustained tachyarrhythmias, which can lead to ventricular fibrillation. Moreover, low dialysate K concentration is associated with higher intra-dialytic cardiac arrest incidence (b) and both total and sudden cardiac mortality are increased in HD patients with prolonged QT interval duration (c) . On the other hand, patients using dialysate with sK of 3 mmol/L need to be adequately monitored in order to avoid HK. Given that the kidneys are the major route for excretion of dietary K, limiting K intake is critical in functionally anephric dialysis patients. HD patients should restrict their daily dietary K to 2-3 g. Because HK is currently and frequently recognized in the dialysis setting, it is quite clear that current strategies do not allow the full control of HK. Inadequate dialysis, due to erroneous prescription, poor patient compliance or vascular access insufficiency, are additional common risk factors for HK. Therefore, in HK patients it is essential to evaluate dialysis efficiency (modality, dose, treatment time, session frequency, blood and dialysate flow, dialysate K concentration etc.). Generally, standard HD strategies do not allow optimizing HK control. Different schedules often need to be considered such as prolonged dialysis time, alternate-day or daily dialysis, or profiled hemodialysis K removal. The latter may be useful in order to avoid high and potentially harmful K gradient between serum and dialysate and post-dialysis K rebound, that are both related to arrhythmias and cardiac arrest. Therefore, we need an adequate mass balance while avoiding excessive changes in serum concentrations. Finally, an additional obstacle to consider in the chronic management of HK in patients on dialysis is the infrequent monitoring of serum K levels, which are generally measured monthly. # Position statement 2.2 1. When HK is repeatedly detected, dialysis prescription must be re-evaluated: dose, blood and dialysate flow, treatment time and frequency in hemodialysis schedule. 2. In PD: dialysis modality and dialysate volume dwells number. ## When to treat hyperkalemia in dialysis Opinions vary widely on what level of sK should define "severe" HK and what level constitutes a hyperkalemic emergency; inthe American Heart Association (AHA) criteria are reported. Hospital admission is often recommended for patients with sK > 6 mmol/L and electrocardiographic (ECG) monitoring and acute interventions for any patient with sK > 6.5 mmol/L. The ability of ECG features to predict hyperkalaemia of moderate severity is considered poor, since only half of patients with sK > 6.5 mmol/L display typical ECG changes, expecially in the dialysis setting. # Position statement 2.3 1. HD patients should restrict their daily dietary K intake to 2-3 g. 2. In dialysis patients HK must be treated independently of ECG changes. ## How to treat hyperkalemia in dialysis In dialysis patients, dialysis schedule, dietary intake and concomitant drugs need to be revised. If HK control is still inadequate, K binders need to be considered. Nowadays in Italy two cation exchange resins are available, SPS and CPS. SPS, which exchanges sodium for calcium, ammonium, and magnesium in addition to K, is available since 1950. It is most effective in binding K when it reaches the rectum, either by enema or by oral administration with cathartics. 1000 mg SPS exchanges bound Na for 110-135 mg of K, whereas 1000 mg CPS exchanges bound Ca for 53-71 mg of K. Therefore, the amount of K adsorbed with SPS is expected to be twice that of CPS. SPS exhibits an advantage over CPS because a smaller amount is sufficient to treat hyperkalemia (5-15 g/day). However, if a higher-dose ion-exchange resin is required, physicians should select the type and amount of resin according to the sodium and/or calcium load. Serious gastrointestinal complications from SPS, given with and without sorbitol, have been reported, including fatal colonic perforation and mortality being up to 33%. CKD and ESRD, post-operative or transplant status are the main risk factors. Moreover, when using SPS in dialysis the risk of volume overload needs to be taken into account. Beside being less effective than SPS, CPS also has relevant gastrointestinal side effects such as nausea, with limited tolerability. It is worth noting that these two K binders have not been tested for long-term efficacy and safety. # Position statement 2.4 Chronic HK in dialysis may be treated with short-term courses of both SPS or CPS. ## Hyperkalemia in patients with heart failure, diabetes and resistant hypertension on treatment with raas inhibitors ## Hyperkalemia in patients with diabetes In clinical practice, HK usually develops as an effect of combination of renal dysfunction and superimposed factors such as HF, high-potassium diet, use of medications inhibiting the RAAS and DM. DM is indeed associated with increased risk of chronic HK, due to blunted insulinemic response to hyperglycemia with reduced K switch to intracellular fluid, plasma hyperosmolality, with enhanced K switch to extracellular fluid, and hyporeninemic hypoaldosteronism, with impairment in K tubular secretion, which plays a major role, especially in type 2 DM. However, adaptation mechanisms may handle a K load and HK does not ensue in diabetic CKD (DKD) unless a reduction in renal function is present. Accordingly, chronic HK is highly prevalent in patients with DKD. In fact, the prevalence of chronic HK in DM ranges between 8 and 13%, but is reported as high as 28% in patients with stage 3 CKD. Also in DKD, the prevalence of chronic HK progressively increases along with increasing number of samplings. This highlights the need for multiple assessment of sK, especially in diabetics with reduced renal function, with the aim to identify subjects at high risk for HK. In most observational studies, together with impaired renal function, chronic use of RAASIs were observed to be independent predictors of the risk of HK in DKD. This is a matter of concern since chronic therapy with RAASIs is strongly recommended by currently available international guidelines for the management of albuminuric DKD at high risk of progression to ESRD, since albuminuria reduction was shown to be associated with a significant reduction in the risk of subsequent ESRD. Indeed, the incidence of HK reported in historical trials aimed at evaluating the impact of RAASIs on DKD progression toward ESRD ranged between 18 and 24% with even a 1-2% discontinuation rate from study protocols due to severe HK. Moreover, severe HK together with acute kidney injury (AKI) occurrence was the reason why two large trials exploring the effectiveness and safety of combined RAAS blockade in DKD were prematurely discontinued, thus leading to the recommendation of current guidelines not to adopt dual RAASIs therapy in DKD. Despite this, in several studies in DKD patients, the addition of a mineralcorticoid receptor antagonist (MRA) to angiotensin receptor blockers (ARBs) and/or angiotensin convertin enzyme inhibitors (ACEIs), i.e. an actual dual blockade of the RAAS, proved to be effective in reducing albuminuria. # Position statement 3.1 Perform more than one sampling annually for serum K assessment in patients with DKD, and even more frequently in patients administered RAASIs therapy. Interestingly, a systematic review of 50 RCTs on this topic showed no effectiveness of RAASIs on all-cause mortality in patients with DKD, unless the full or maximum tolerable dose was used, and confirmed that treatment with both ACEIs and ARBs resulted in a significant reduction in the risk of ESRD and of progression from micro-to macroalbuminuria with even a significant increase in regression from micro-to normoalbuminuria. However, current guidelines recommend not to offer RAASIs to CKD patients if their pre-treatment sK is greater than 5.0 mmol/L, and to withdraw therapy when sK increases to 6.0 mmol/L. In fact, HK is associated with increased mortality in the diabetic population and highest rates were observed when CKD coexists. Therefore, in clinical practice, ensuing HK is frequently associated with downtitration or even withdrawal of RAASIs therapy, even though this strategy seems to be associated with unfavorable clinical outcome. Interestingly, both submaximal doses of RAASIs and drug discontinuation were shown to be associated with greater incidence of adverse cardiovascular events and overall mortality in patients with DM, compared to subjects administered the full dose of those medications. Thus, the adequate administration of RAASIs therapy seems to be an important strategy in achieving significant clinical benefit in DKD. It appears that downtitration or even withdrawal of RAASIs for safety reasons (although controlling or even preventing chronic HK) misses the opportunity of offering DKD patients the best available renoprotective therapy. # Position statement 3.2 Full or maximum tolerable dose of RAASIs medication should be offered to patients with DKD, especially in those with reduced eGFR, in order to maximize nephro-and cardioprotective effects of these drugs. NICE (National Clinical Guideline Centre, UK) guidelines point out the importance of treatment, and eventually discontinuation of other factors or medications that can induce HK in CKD high risk patients taking RAASIs. They recommend the correction of metabolic acidosis by alkali administration, and adherence to low K diet, in an effort to prevent or offset HK in these high risk patients. Recently, new available agents, such as patiromer and sodium-zirconium cyclosilicate have shown to be effective in controlling HK in DKD patients, with good dose-response and safety profiles. Moreover, in HF patients with reduced renal function and DM, patiromer was effective in steadily maintaining normal sK values, avoiding RAASIs downtitrating and thus allowing full dose administration of spironolactone, aimed at achieving full cardioprotection. Last, new non-steroidal MRAs were shown to be effective in lowering albuminuria in DKD, with a lower incidence of HK, and can be considered a promising therapeutical tool for systematic use in DKD at risk of chronic HK. # Position statement 3.3 In order to offset chronic HK in patients on full or maximum-tolerable dose of RAASIs, it is important to adopt an adequate treatment and nutritional approach to reduce HK. It is also advisable to consider the use of new orally acting agents for chronic administration in DKD patients during effective RAASIs therapy. In conclusion, DKD is associated with an increased risk of HK, particularly in patients administered RAASIs, in whom more frequent sK assessment is recommended. Downtitration or even withdrawal of RAASIs is associated with worse clinical outcome. This suggests that all therapeutic strategies aimed at lowering sK should be adopted in an effort to improve in the management of this chronic electrolyte disorder mostly in high-risk patients, such as those with DKD, who may benefit from optimal treatment with RAASIs, as recommended by available international guidelines. ## Hyperkalemia in patients with heart failure Among patients with HF, the prevalence of CKD is high (approximately 41%) and associated with a 50% increase in risk of mortality compared to patients with HF and preserved renal function. The most recent data from the United States Renal Data Systemshow that, among CKD subjects, the percentage of patients with HF is 25.6% compared to a prevalence of 6.1% in the general population. In addition, 40% of patients undergoing HD, 28% of patients on PD and 14% of those undergoing renal transplantation suffer from HF. The 2-year survival of the population with CKD and HF is 65% vs. 75% in patients with HF alone, while ESRD patients with HF have a survival of 66% at 2 years vs. 83% in those without HF. These data underscore the importance of optimally treating CKD patients with HF to reduce the high incidence of mortality. In the presence of HF, European Cardiology Guidelinesrecommend ACEIs, along with beta blockers, as first-line drugs, with the addition of MRAs in symptomatic subjects, while ARBs are recommended as an alternative in patients intolerant to ACEIs. In the latest cardiology guidelines, the sacubitril/valsartan (ARNI) combination is recommended in symptomatic patients with HF and reduced ejection fraction. Indications similar to those of European Society of Cardiology (ESC) are those given by the AHAstating that the clinical strategy for the treatment of HF is the inhibition of the RAAS with ACEIs or ARBs or ARNI, in conjunction with beta blockers and with the addition of MRAs in selected patients. Even the US guidelines point out how in patients with HF and reduced ejection fraction ARNI significantly reduces cardiovascular death or HF hospitalization. Both European and US guidelines underline that ACEIs/ARBs should be given with caution to patients with CKD, or elevated serum potassium (> 5.0 mmol/L). The problem of the occurrence of HK is a crucial point for the treatment of HF in patients, both in the absence and in the presence of CKD. A survey by ESC conducted across 211 Cardiology Centers in 21 countries showed that the presence of HK was a contraindication to the use of ACEIs/ARBs in 8.5% of patients, and that 35% did not take MRAs for the same reason. A US study showed that in a large population of CKD patients with HF only 19% took the maximum dose of ACEIs, while 64% took a submaximum dose and 16% had discontinued the drug. 85% of these patients had at least one episode of HK. Patients taking submaximum doses or who discontinued ACEIs had worse outcomes than patients taking maximum doses of the drug. Similar outcomes were observed between those who were undertreated and those who discontinued the drug. Moreover, even if the AHA defines HK as a sK value > 5.1 mmol/L, a recent study examined the relationship between different levels of sK and mortality among patients with chronic HF and showed that sK above 4.8 mmol/L was also associated with increased mortality risk. If these data were confirmed, the number of HF patients with dangerous values of sK would increase by many units, particularly in the subgroup of subjects with HF and CKD. The problem of HK as a side effect of therapy in HF patients, already known, ignited after the publication of an important trial, the Randomized Aldactone Evaluation Study (RALES). The RALES showed that in patients with HF with reduced ejection fraction treated with an ACEI and a loop diuretic and randomized to spironolactone or placebo, there was 30% reduction in the risk of death and 35% reduction in the risk of hospitalization for HF among patients in the spironolactone group. This study excluded patients with a serum creatinine concentration > 2.5 mg/dl. An article published a few years later showed that publication of the RALES study was associated with an increase in the rate of spironolactone prescriptions and in hyperkalemia-associated morbidity and mortality. A post hoc analysis of RALES, aimed at investigating the influence of baseline eGFR and worsening renal function on the efficacy of spironolactone in RALES patients with CKD, showed similar reductions in all-cause of death and hospitalization in patients with a baseline GFR > 60 ml/min/1.73 m 2 compared to those with baseline GFR < 60 ml/min/1.73 m 2 . However, the risk of HK and renal failure was higher in those with worse baseline renal function, particularly in the spironolactone arm. After RALES, other RCTs demonstrated the efficacy of MRAs in reducing mortality and events in patients with HF. Moreover, in a large sample of hospitalized HF patients with a history of DM and/or CKD, a higher serum creatinine was associated with lower odds of MRAs use. MRAs therapy was associated with lower risk of long-term all-cause readmission, but greater risk of readmission for HK and acute renal failure. Recently, data from a sub-analysis of the TOPCAT study, a RCT aimed at evaluating the efficacy of spironolactone vs. placebo in a population of patients with HF and preserved ejection fraction were published. The authors evaluated the association between baseline renal function and the efficacy and safety of the drug over a 4-year follow-up period. Spironolactone was effective in reducing the incidence of death, aborted cardiac arrest and hospitalizations across three categories of eGFR (> 60, 45-60, < 45 ml/ min/1.73 m 2 ), but the drug was also associated with a higher risk of hyperkalaemia, worsening of renal function and drug discontinuation compared to placebo in the lower eGFR categories. The latest cardiology guidelines included for HF the treatment with an ARNI. The ARNI treatment was compared with enalapril in HF patients in addition to optimal therapy. Patients with an eGFR below 30 ml/min/1.73 m 2 were excluded and the mean creatinine plasma value was 1.1 mg/ dl for both arms. ARNI was superior to enalapril in reducing the risk of death and of hospitalization for HF. The rate of patients with elevated serum potassium (> 5.5 mmol/l) was similar with both therapies, while the rate of patients with serum potassium > 6.0 mmol/L was significantly higher in enalapril group. In conclusion, it is clear that even HF patients with CKD can benefit from the use of ACEIs, ARBs and MRAs. However, it is also evident that this population is more at risk for the occurence of HK, a potentially very dangerous complication in terms of hospitalization and mortality. Providing nephrologists with the necessary tools to enable them to control the onset of HK should significantly improve the prognosis of CKD patients with HF. Position statement 3.4. The drugs that the cardiology guidelines recommend for the treatment of patients with HF are effective in reducing adverse events, re-hospitalizations and mortality, even in patients with the simultaneous presence of HF and CKD. 2. Therefore, there should be no difference in the therapeutic approach in patients with HF with and without CKD. 3. ACEIs, ARBs and MRAs are among the drugs suggested by cardiology guidelines as first-line treatment. 4. All of these classes of drugs can lead to hyperkalemia, particularly in patients with reduced GFR and those experiencing a worsening of renal function. 5. In HF patients with CKD, special attention should be paid to the monitoring of sK and renal function. In these patients, all dietary and pharmacological measures should be implemented to prevent and control increases in sK, before reducing or discontinuing ongoing therapies. 6. In HF patients with CKD who are not taking RAASIs therapy because of high sK values, all dietary and pharmacological measures should be implemented to reduce sK and allow them to receive appropriate treatment for their cardiological disease. ## Hyperkalemia in patients with resistant hypertension Resistant hypertension (RH) is defined as hypertension when the recommended treatment (at least three drugs, including a diuretic) strategy fails to lower systolic (SBP) and diastolic blood pressure (DBP) values to < 140 mmHg and/ or < 90 mmHg and the inadequate control of BP is confirmed by ambulatory blood pressure and home blood pressure monitoring. Resistant hypertension is associated with a poor prognosis. The PATHWAY-2 randomized trial performed in 314 patients with RH assessed the role of plasma aldosterone, renin, and aldosterone-to-renin ratio (ARR) as predictors of home SBP and the effect of amiloride on lowering clinic SBP. The study demonstrated that SBP reduction by spironolactone was predicted by ARR and plasma renin values. Amiloride significantly reduced SBP, not different from spironolactone. The results suggest that RH is commonly a salt-retaining state, most likely due to inappropriate aldosterone secretion. In accordance with these findings, in recent years, an increasing body of evidence has shown benefit of MRAs, such as eplerenone and spironolactone, in improving BP control in patients with RH. A recent meta-analysis based on data from multiple RCTs evaluated the efficacy of add-on use of spironolactone in patients with RH. The antihypertensive effects were assessed in 869 patients included in four trials. The reduction in SBP and DBP in patients treated with spironolactone was greater than that observed in the placebo group. The rate of serious adverse effects or patient withdrawal from the trials tended to be higher in patients treated with spironolactone than placebo. CKD is often present in RH subjects. In a population of 37,061 presenting with uncontrolled hypertension despite taking ≥ 3 drugs, CKD was associated with a higher risk for RH. Data from 17,466 patients, 1576 of which had RH, showed a CKD prevalence of 20.4%. In a small sample (n =436) of hypertensive CKD patients, 22.9% (n =100) were classified as true resistantand in a larger population of RH patients (n =7436), 24.0% had CKD (eGFR < 60 ml/min/1.73 m 2 ). The use of MRAs for hypertension treatment is limited in patients with moderate-to-severe CKD, mainly due to the risk of HK. At present, only studies performed in a small number of patients evaluated the efficacy and safety of MRAs in CKD patients with RH. In 36 patients with stage 3 CKD MRAs induced a significant decrease in SBP and DBP. However, a concomitant significant increase in sK and serum creatinine was observed (one case of acute renal failure and three cases of significant hyperkalemia). In 41 patients with GFR between 25 and 50 mL/min and RH, randomly divided into two groups (placebo or spironolactone), there was a significant decrease in SBP and DBP after 6 and 12 weeks in the patients who received spironolactone, while there was no change in BP in the control group. HK occurred in one subject in the spironolactone group. Recently, the rationale and design of a RCT have been published that will evaluate if the potassium-binding patiromer used concomitantly with spironolactone could prevent HK and allow spironolactone use for the management of hypertension in CKD patients (eGFR 25 to 45 mL/ min/1.73 m 2 ) with RH. The endpoints are the differences in the proportion of patients remaining on spironolactone and in SBP values between the two groups (spironolactone and placebo) after 12 weeks of treatment. The latest guidelines from the European Society of Hypertensionestablished that, besides optimal doses or best-tolerated doses of an optimal therapy, typically including ACEIs or ARBs along with a calcium channel blockers and a thiazide diuretic, the fourth-line treatment should involve a blockade of aldosterone through the use of MRAs (spironolactone up to 50 mg/day). However, it is suggested that the use of spironolactone be restricted to patients with an eGFR > 45 mL/min/1.73 m 2 and a sK concentration < 4.5 mmol/L. The AHAstrongly suggests that the management of RH include lifestyle interventions, use of thiazide-like diuretics and the addition of a MRA. For these reasons, is important to provide the nephrologist with tools to allow them to apply the cardiology guidelines in patients with CKD and RH, at high risk of developing hyperkalemia, if simultaneously treated with RAASIs and a MRA. Position statement 3.5 In the presence of RH, the use of MRAs on top of antihypertensive therapy commonly including a calcium channel blocker, an ACEI/ARB, and a diuretic is indicated. Data on the use of MRA in CKD patients with RH are few, but suggest that even in patients with CKD MRAs reduce BP and urinary excretion of albumin. 2. Given the frequent occurrence of hyperkalemia, close monitoring of plasma potassium and renal function is important in patients with CKD and RH, particularly if they are simultaneously treated with ACEIs/ARBs and MRA. 3. Attention should be even greater in patients with an eGFR < 45 ml/min/1.73 m 2 . In these patients all dietary and pharmacological measures should be implemented to prevent and control increases in sK, before reducing or discontinuing ongoing therapies. 4. In RH patients with CKD and eGFR < 45 ml/ min/1.73 m 2 not taking ACEIs/ARBs and MRA, all dietary and pharmacological measures should be implemented to reduce plasma K values and allow them to receive appropriate treatment for their hypertensive disease. ## The treatment of severe hyperkalemia ## Relevance of the problem Severe HK is a potentially lethal condition, and represents a clinical emergency. With few exceptions (e.g., tumor lysis syndrome or rhabdomyolysis), it is associated with oliguria and low GFR, either in the setting of AKI or advanced CKD. Indeed, HK has been listed as one of the most common complications of AKI for several decades. In a recent retrospective study enrolling > 18,000 adults admitted to intensive care units, the frequency of HK increased from 8.8% in patients with AKI stage 1 to 32.2% in those with AKI stage 3. In a series of 923 consecutive hospitalized adult patients with at least one episode of severe HK (defined as a sK concentration of > 6.5 mmol/L), AKI was a coexisting condition in 22.2% of the patients with normal baseline function and in 51.8% of those with underlying CKD. HK is associated with increased mortality in both AKIand CKD. Moreover, 3-5% of deaths in patients with ESRD on routine HD may be attributed to HK. Severe bradyarrhythmias and complex ventricular tachyarrhythmias are life-threatening dangers associated with HK, especially if interfering drugs (e.g. digoxin) and/or severe acidosis are also present. ECG alterations are common in hyperkalemic patientsand are more frequently present when sK increases rapidly, ranging from peaked T-waves to QRS widening, disappearance of P-wave, and to advanced atrioventricular blocks, wide-QRS tachyarrhythmias and asystole in severe HK. Although there is a loose relationship between levels of sK and ECG changes in hyperkalemic patients, the ECG sensitivity does not exceed 34-43% as a unique tool to detect HK, and may also be misleading. Aspecific symptoms may be present with or without ECG changes, including gastrointestinal symptoms, paresthesias, decrease of deep tendon reflexes, and weakness progressing to paralysis. ## What are the treatment options? If HK is a casual laboratory finding and seems unjustified on clinical grounds in a given patient, pseudohyperkalemia should be ruled out before starting treatment. In all other cases, even if the patient is not clinically unstable, immediate evaluation of treatment options is mandatory. While the presence of serious ECG changes or arrhythmias are most relevant with respect to treatment approach, the absolute levels and rate of increase in sK, as well as urine output and potential hidden sources that maintain high sK, are also important factors that must be taken into account. If the patient is severely oliguric or anuric (e.g. in the setting of ESRD or AKI stage 3), there is ongoing K entry in the extracellular compartment (e.g. rhabdomyolysis or large hematomas), the patient is volume-overloaded and loop diuretics are unlikely to be effective, emergency dialysis should be performed. If the patient has ESRD and a functioning vascular access, dialysis should be started immediately, irrespective of the presence of ECG alterations. Whilst in this case the time interval between patient assessment and dialysis start is minimized, a variable delay is expected if a central venous catheter must be inserted in a patient with AKI. In this latter case, urgent treatment must be initiated to reduce the risk of life-threatening arrhythmias. # Position statement 4.1 1. If the patient is severely oliguric or anuric (e.g. in the setting of ESRD or AKI stage 3), there is ongoing K entry in the extracellular compartment (e.g. rhabdomyolysis or large hematomas), the patient is volume-overloaded and loop diuretics are unlikely to be effective, emergency dialysis should be performed. 2. If the patient has ESRD and a functioning vascular access, dialysis should be started immediately, irrespective of the presence of ECG alterations. ## If a central venous catheter must be inserted in a patient with AKI, urgent medical treatment must be initiated to reduce the risk of life-threatening arrhythmias. When dialysis is started, profiling of dialysate K concentration to maintain a constant gradient between K dialysate concentration and sK seems preferable, compared to a constantly low (i.e. < 2 mmol/L) K concentration in the dialysis bath. In fact, retrospective analyses suggest that low K dialysate concentration may be associated with sudden cardiac death [96], although there are no prospective data showing a favorable effect of changing K dialysate concentration on the incidence of sudden cardiac death. A rebound 0.1-1.0 mmol/L increase in sK after the end of the dialysis session should be taken into account. When electrocardiographic signs of HK are detected, the first treatment step is directed at stabilizing cell membrane potential. Immediate slow intravenous administration of calcium salts, either calcium gluconate or calcium chloride, must be performed to contrast the ongoing cell membrane depolarization. In fact, calcium re-establishes a larger transmembrane voltage gradient within a few minutes of intravenous administration, possibly via restoration of rapid sodium channel Nav1.5 functionality. Calcium chloride contains 13.6 mEq per 10 mL, whilst calcium gluconate contains 4.6 mEq per 10 mL. Calcium chloride may cause tissue necrosis on extravasation if given through a peripheral vein, and thus calcium gluconate is generally preferred, unless a central venous access is available, or the patient has cardiac arrest. One ampule of 10% calcium gluconate should be infused over 1-2 min, and can be repeated after 5 min if ECG does not improve. Calcium salts should be used with caution if digitalis toxicity is suspected. As the administration of calcium salts will not decrease sK, the following step to be undertaken is to force intracellular translocation of K. Stimulation of the Na/K ATPase activity and GLUT4 receptor recruitment by the intravenous administration of insulin and glucose is the most efficient way to induce transcellular K redistribution. While an intravenous bolus of 10 units of regular insulin together with an intravenosus bolus of 25-50 g of dextrose is indicated as a standard approach if serum glucose concentration is < 250 mg/dL, hypoglycemia may ensue, especially in patients with CKD. Thus, a reduced (i.e. 5 units vs. 10 units) dose of regular insulinor a weight-based intravenous insulin dose (0.1 units/Kg up to a maximum 10 units)have been advocated as preferential protocols to treat severe HK in patients with or without CKD/ESRD. The use of short-acting vs. regular insulin has also been investigated, but deserves further studies. A recent systematic review recommended either the continuous infusion of 20 units of regular insulin over 1 h with 60 g of dextrose or an intravenous 10 units regular insulin bolus together with 50 g of dextrose to reduce the risk of hypoglycemia in patients with severe HK. A treatment scheme with insulin/dextrose for severe HK is summarized in the. The administration of nebulized or intravenous salbutamol is another strategy to decrease sK in severely hyperkalemic patients, especially when this treatment is combined with insulin/dextrose. The salbutamol dose that promotes the intracellular translocation of K via stimulation of Na/K ATPase (i.e. 10-20 mg if given by nebulization, or 0.5-2.5 mg if given intravenously) is 4-8 times higher than that used to treat bronchospasm. Side effects (e.g. tremor, palpitations, anxiety) are usually mild and are more frequent with intravenous administration, but arrhythmias may develop in susceptible patients with heart disease. Moreover, efficacy may be reduced in patients treated with non-selective betablockers. The intravenous administration of sodium bicarbonate may theoretically cause transcellular K redistribution through the stimulation of transmembrane H/K exchange, Na/H exchange, sodium-bicarbonate cotransport and Na/K ATPase. However, the efficacy of sodium bicarbonate administration, particularly in the form of isotonic formulations or combinations with dextrose/insulin, is mainly seen in acidemic patients. The administration of large amounts of isotonic or hypertonic bicarbonate may also induce hypernatremia and fluid overload, and may increase pCO 2 in patients with respiratory insufficiency. Thus, the administration of sodium bicarbonate should not be advised as a first-line strategy in severe HK, and should be given preferentially as part of combination therapy in patients with metabolic acidosis. The intravenous administration of loop diuretics, possibly combined with thiazides or thiazide-like diuretics and acetazolamide, may be considered in hyperkalemic and hypervolemic patients with only moderately compromised renal function. Finally, the oral or rectal administration of SPS and CPS together with sorbitol can be performed with the aim of increasing K elimination in the distal colon, provided that bowel obstruction has been ruled out. However, the minimum 2-h time-lag before effect onset, variable efficacy, and the small though significant risk of colonic necrosisdo not support the administration of SPS as part of the treatment of patients with acute severe HK. New-K-binding drugs, namely patiromer and sodium-zyrconium cyclosilicate have undergone extensive clinical testing recently in the setting of chronic HK, and have proved to be effective and relatively safe in the short term. In particular, sodium-zyrconium cyclosilicate was shown to be able to decrease sK by 0.4 mmol/L at 1 h and 0.7 mmol/L at 4 h after the oral administration of a 10 g dose in 45 patients with baseline sK ranging between 6.1 and 7.2 mmol/L. Moreover, sK was < 6.0 mmol/L in 80% of the patients, and < 5.5 mmol/L in 52% by 4 h. While more data are awaited, sodium-zyrconium cyclosilicate may be interesting in the acute treatment of severe hyperkalemia, due to its rapid effect onset and K binding along the entire intestinal tract. An algorithm for the emergency treatment of severe HK is shown inPosition statement 4.2. If ECG signs of hyperkalemia are detected, the first treatment step is directed at stabilizing cell membrane potential. Immediate slow intravenous administration of calcium salts, either calcium gluconate or calcium chloride, must be performed to contrast the ongoing cell membrane depolarization. 2. As the administration of calcium salts will not decrease sK, the following step to be undertaken is to force intracellular translocation of potassium. The intravenous administration of insulin and glucose is the most efficient way to induce transcellular potassium redistribution. 3. The administration of nebulized or intravenous salbutamol is another strategy to decrease sK in severely hyperkalemic patients, especially when this treatment is combined with insulin/dextrose. 4. The intravenous administration of sodium bicarbonate may theoretically cause transcellular potassium redistribution. However, the efficacy of sodium bicarbonate administration, particularly in the form of isotonic formulations or combinations with dextrose/insulin, is seen mainly in acidemic patients. 5. The administration of large amounts of isotonic or hypertonic bicarbonate may also induce hypernatremia and fluid overload, and may increase pCO 2 in patients with respiratory insufficiency. Thus, the administration of sodium bicarbonate should not be advised as first-line strategy in severe hyperkalemia, and should be given preferentially as part of combination therapy in patients with metabolic acidosis. 6. If hemodialysis can be started immediately in a patient with a functioning vascular access (e.g., arteriovenous fistula or central venous catheter), pharmacologic strategies to force transcellular potassium redistribution should not delay dialysis start, and may be foregone as they may also, on theoretical grounds, decrease potassium removal by dialysis. 7. The intravenous administration of loop diuretics, possibly combined with thiazides or thiazide-like diuretics and acetazolamide, may be considered in hyperkalemic and hypervolemic patients with only moderately compromised renal function. 8. The oral or rectal administration of SPS or CPS together with sorbitol can be performed with the aim of increasing fecal potassium elimination in the distal colon, provided that bowel obstruction has been ruled out. However, the minimum 2-h time-lag before effect onset, variable efficacy, and the small though significant risk of colonic necrosis do not support the administration of SPS or CPS as part of the treatment of patients with acute severe hyperkalemia. # Conclusion The management of HK is a major yet unmet need in the Nephrology setting, in spite of the negative impact of this alteration on patient prognosis and the obvious high costs of hospitalization and dialysis. Although clinically challenging, the treatment of severe acute HK is sufficiently outlined, as in patients on dialysis. On the contrary, the treatment of chronic HK in patients with CKD still represents a therapeutic challenge, because its detection is often the cause of suboptimal medical treatment, responsible for faster progression of CKD, and an earlier recourse to renal replacement therapy. Thus, there is an important need for a well-tolerated and effective treatment, allowing the control of sK in a safe range, in patients with CKD or cardiovascular disease who require the therapeutic advantage of treatment with RAASIs, as in patients with ESRD still on conservative therapy. The Italian Society of Nephrology, being well aware of the clinical burden of HK and the limits of chronic therapy, suggest that nephrologists devote a high level of attention to patients with even a moderate increase in sK and suggest the prompt implementation of the two new K binders approved by Food and Drug Administration in US and the European Medicines Agency with efficacy and safety proven by controlled randomized trials in CKD. Indeed, both K binders (patiromer and sodium-zyrconium cyclosilicate) have demonstrated therapeutic efficacy in lowering sK, associated with a satisfactory tolerability and safety profile. Numerous clinical randomized trials have shown that the use of these drugs in patients with CKD, also in those with concomitant HF and/or DM, allows a longterm effective control of sK, allowing the maintenance of efficacious dosages of RAASIs, indicated with high level of evidence from the nephrology and cardiology guidelines as the most effective therapeutic strategy to slow the progression of CKD and to improve the prognosis of patients with heart failure. Funding No financial support was received in the preparation of this manuscript. ## Compliance with ethical standards Conflict of interest SB has no conflict of interest to declare. FA has received lecture fees from Amgen and Aferetica. LDN has received fees as scientific consultant/lecturer from Astellas, AstraZeneca, Janssen, and Vifor Fresenius. SG has received consultant fees from Astra Zeneca, Vifor Fresenius, Pfizer and Boston-Scientific. EP has received consultant fees from AbbVie, Bayer, Vifor Fresenius and Novartis. GR has received consultant fees from Astra Zeneca and Otsuka. Research involving human participants and/or animals For this type of study formal consent is not required. Ethical approval This article does not contain any studies with human participants performed by any of the authors. Informed consent Informed consent was not required since no patients participated the study. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.	None	https://link.springer.com/content/pdf/10.1007/s40620-019-00617-y.pdf	None
61732b5037518bae14a75488724b59d864ee7533	pubmed	International evidence-based guidelines on Point of Care Ultrasound (POCUS) for critically ill neonates and children issued by the POCUS Working Group of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC)	International evidence-based guidelines on Point of Care Ultrasound (POCUS) for critically ill neonates and children issued by the POCUS Working Group of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC) Background: Point-of-care ultrasound (POCUS) is nowadays an essential tool in critical care. Its role seems more important in neonates and children where other monitoring techniques may be unavailable. POCUS Working Group of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC) aimed to provide evidence-based clinical guidelines for the use of POCUS in critically ill neonates and children. Methods: Creation of an international Euro-American panel of paediatric and neonatal intensivists expert in POCUS and systematic review of relevant literature. A literature search was performed, and the level of evidence was assessed according to a GRADE method. Recommendations were developed through discussions managed following a Quaker-based consensus technique and evaluating appropriateness using a modified blind RAND/UCLA voting method. AGREE statement was followed to prepare this document. Results: Panellists agreed on 39 out of 41 recommendations for the use of cardiac, lung, vascular, cerebral and abdominal POCUS in critically ill neonates and children. Recommendations were mostly (28 out of 39) based on moderate quality of evidence (B and C). Conclusions: Evidence-based guidelines for the use of POCUS in critically ill neonates and children are now available. They will be useful to optimise the use of POCUS, training programs and further research, which are urgently needed given the weak quality of evidence available. # Introduction The incorporation of Point of Care Ultrasound (POCUS) has represented a transformative change in clinical practice, challenging the traditional diagnostic and procedural "art" of medicine, especially in acute care environments. It has emerged as "the new" clinical tool and it has displaced, in some way, the classical stethoscope. It is performed and interpreted by the bedside clinician with the intent of either answering a focused question or achieving a specific procedural goal. The use of POCUS by critical care providers has increased significantly in recent years and adult emergency medicine had pioneered this field with the publication of guidelines for implementation of structured POCUS training. These efforts were translated into paediatrics through emergency medicine. Since then, POCUS has gained popularity and expanded across many paediatric disciplines. However, unified guidelines on the use of POCUS and training do not exist yet for the paediatric and neonatal critical care. Bedside goal-directed echocardiography has been the first POCUS application in paediatric practice with guidelines for implementation. An expert statement was published in 2011, followed by the United Kingdom Expert Consensus Statement on Neonatologist Performed Echocardiography (NPE) and recommendations for NPE in Europe. The Australian Clinician Performed Ultrasound (CPU) programme is a well-established academic curriculum developed to train neonatologists in the use of POCUS, though applications are limited to the evaluation of the neonatal brain and heartand the training programme is restricted to neonatal physiology. Non-cardiac POCUS may carry more opportunities for use as well as a number of benefits for both patients and providers. However, the lack of guidelines is a barrier to widespread adoption. As more acute care providers invest in POCUS technology, it is critically important to define POCUS main purposes, establish formal training and develop accreditation guidelines, in order to maximise POCUS benefits and reducing risks. Therefore, the European Society for Paediatric and Neonatal Intensive Care (ESPNIC) assembled a group of international paediatric POCUS key opinion leaders to create evidence-based guidelines for the use of current and emerging POCUS applications in the neonatal (NICU) and paediatric intensive care units (PICU) by any clinician working in these units. # Methods Three lead authors, one neonatologist (YS), one paediatric intensivist (DDL) and one paediatric cardiologist (CT), identified expert colleagues who significantly contributed with publications in the POCUS field and/or have developed POCUS training courses in the last 10 years, similarly to what had been done with previous ESPNIC guidelines. Panellists selection was performed prior to the literature search and for logistic reasons, the number of participants was limited to a maximum of 20. These colleagues should have been fairly representative of all POCUS fields and both Europe and North America and include also non-ESPNIC members. Moreover, at least one co-author should have been an expert in guidelines development and supervised the whole methodology, while literature search was performed by each panellist for their sub-section. All invited experts agreed to participate. Details of the methods used to produce these guidelines are given in the additional file for online supplementary material (see Additional file 1). These guidelines followed relevant ESPNIC internal procedures for manuscript endorsement, and this included an external review by ESPNIC officers not included among the panellists. Guidelines have been prepared according to the international Appraisal of Guidelines, Research and Evaluation (AGREE). Each recommendation is intended to be applied both for paediatric and neonatal patients, unless otherwise specified. # Results A total of 41 recommendations on the use of POCUS in neonatal and paediatric critical care were discussed. There was strong agreement on 22 recommendations after first-round voting. Following the discussion in an in-person meeting among the experts (organised within the 2018 ESPNIC congress (Paris, France)), 19 recommendations were re-worded and re-voted in the second round. There was agreement on 17 recommendations and disagreement on 2 recommendations as summarised in. Conversely, a collapsed IVC may be suggestive of hypovolemia. Clinicians performing POCUS should be aware of its limitations especially in children on mechanical ventilation and neonates (especially when an umbilical central venous catheter is placed) in whom no validated normative data yet exist. Moreover, mechanical ventilation (especially with high mean airway pressure), spontaneous breathing effort and some concomitant conditions may reduce the reliability of IVC evaluation to predict fluid responsiveness. 3. POCUS may be helpful to assess fluid responsiveness in neonates and children-strong agreement (quality of evidence D). The variation of velocity-time integrals (VTIs) measured at the left ventricular outflow tract (LVOT), using pulse wave Doppler (PWD) in apical 5-chamber view, during inspiration and expiration has been reported to predict volume responsiveness. A variation of > 15% has been reported to have a high predictive value with a sensitivity and specificity exceeding 90%. This has been validated in several studies, including many studies involving mechanically ventilated children. Accurate measurement of VTI needs acquisition of apical 5-chamber view and good alignment of ultrasound beam with the across LVOT like any other Doppler assessment, which requires advanced ultrasonography skills. Hence this recommendation is particularly for neonatal/paediatric intensivists with advanced POCUS skills. 4. POCUS may be helpful for qualitative assessment of cardiac function on visual inspection in neonates and children-strong agreement (quality of evidence D). POCUS should be used for qualitative assessment of cardiac contractility ("eyeballing" assessment) in multiple views such as apical 4-chamber (A4C), parasternal long (PLAX) and short-axis (PSAX) and sub-costal short-axis views. Subcostal views may be very helpful in patients where parasternal or apical views impossible or sub-optimal, and in younger children or neonates where sub-costal views may provide even better image quality. 5. POCUS is helpful for semi-quantitative assessment of cardiac function in neonates and children [however, a detailed functional assessment should be performed by a person with advanced echocardiography training]-agreement (quality of evidence C). POCUS can be used to assess cardiac function semi-quantitatively by assessing ejection fraction (EF) and fraction shortening (FS). In experienced hands, POCUS can be used for further assessment of left and right ventricular function as summarised in[14, 15, 32-45]. However, a detailed assessment of cardiac function should be performed by a neonatologist/paediatric intensivist with advanced echocardiography training or a paediatric cardiologist. 6. POCUS is helpful for the assessment of pulmonary artery systolic pressure in pulmonary hypertension in neonates and children-strong agreement (quality of evidence B). In the presence of tricuspid regurgitation, pulmonary artery systolic pressure (PASP) can be reliably estimated using bedside POCUS. In the absence of right outflow tract obstruction, the regurgitation velocity represents the difference in pressure between the right atrium and the right ventricle. PASP is derived using a modified Bernoulli equation . 7. POCUS is helpful for semi-quantitative assessment of pulmonary hypertension in neonates and children-strong agreement (quality of evidence B). In the absence of tricuspid regurgitation, POCUS can be used for semi-quantitative assessment of pulmonary hypertension by evaluating the interventricular septal position and movement at the end of systole and by assessing flow direction and velocities across a patent ductus arteriosus and/or foramen ovale. In experienced hands, it may be used for hemodynamic evaluation of the ductus arteriosus.. The double lung point has been proposed as a pathognomonic findingbut it is debated, as it does not seem necessary for TTN diagnosis if normal lung areas are evident. High inter-observer agreement between physicians with different lung ultrasound (LUS) expertise has been reported, which makes the differential diagnosis between RDS and TTN reliable, irrespective of the operator. In preterm neonates with RDS, various studies showed that a semiquantitative ultrasound evaluation of. LUS has been reported to have higher diagnostic accuracy compared with chest X-rays for the diagnosis of pneumonia. However, there is no defined threshold for consolidation size or a consensual method of measurement. 3. POCUS is helpful to semi-quantitatively evaluate lung aeration and help the management of respiratory intervention in acute respiratory distress syndrome (ARDS) in neonates and children-agreement (quality of evidence B). LUS in neonatal and paediatric ARDS shows bilateral diffuse areas of reduced lung aeration with areas of the interstitial syndrome and consolidations, pleural line abnormalities and pleural effusion. Although current diagnostic criteria for ARDS do not yet include LUS, it represents a useful tool for its detection. Several LUS aeration scores are used to semi-quantitatively measure the effect of fluid restriction, alveolar recruitment and surfactant administration. Scores based on the main lung ultrasound semiology (including A lines, alveolar-interstitial pattern and presence of consolidations) should be preferred over the simple B lines count, as they describe better the lung aeration and have been validated with various techniques. 4. POCUS is helpful to recognise meconium aspiration syndrome (MAS)-agreement (quality of evidence C). MAS is now recognised as a cause of neonatal ARDSand shares the same LUS findings. However, this LUS pattern is dynamic and changes with the spread of meconium plugs during mechanical ventilation. 5. POCUS is helpful for descriptive purposes in viral bronchiolitis but cannot provide a differential aetiological diagnosis-strong agreement (quality of evidence C). LUS signs in viral bronchiolitis consist of pleural line irregularities, "sub-pleural" consolidations and areas with interstitial pattern. Good concordance between operators has been shown in wheezing infants. LUS findings in viral bronchiolitis are similar to those seen during influenza outbreaksbut it is not currently possible to differentiate between different forms of viral respiratory infections. 6. POCUS is helpful to accurately detect pneumothorax in neonates and children-strong agreement (quality of evidence B). In adults, LUS has a high diagnostic accuracy for the diagnosis of pneumothoraxand has been reported to be more sensitive than conventional radiology. Neonatal data confirm this high diagnostic performance for tension pneumothorax. 7. POCUS is helpful to insert chest tube or perform needle aspiration in neonatal tension pneumothorax-strong agreement (quality of evidence B). LUS should not only be used to diagnose pneumothorax but also to provide static guidance for pleurocentesis. Thus, POCUS should be used to identify lung margin, hemidiaphragm and sub-diaphragmatic organs throughout the respiratory cycle before needle or tube insertion to safely avoid them. 8. POCUS is helpful to detect pleural effusions in neonates and children-strong agreement (quality of evidence B). Policy statements in adults recommend the use of LUS for the detection of effusions and evaluation of pleural fluid volume to guide management. In children, LUS shows high accuracy in the diagnosis of pneumonia-related pleural effusion [47]. 9. POCUS is helpful to guide thoracentesis in neonates and children-strong agreement (quality of evidence B). Ultrasound-guided thoracentesis reduces the risk of complications and increases success rates. It should be used to identify lung margin, hemidiaphragm and sub-diaphragmatic organs throughout the respiratory cycle before needle or tube insertion to safely avoid them. 10. POCUS is helpful to evaluate lung oedema in neonates and children-agreement (quality of evidence C). Although LUS is accurate in detecting extra-vascular lung fluid, it cannot distinguish between cardiogenic and noncardiogenic oedema. LUS has been used in children to evaluate cardiogenic lung oedema, by assessing extravascular lung fluid counting numbers of B-lines after cardiac surgery. However, extravascular lung water may obviously be affected by the pressure delivered during mechanical ventilation. Thus, in these conditions, LUS globally evaluates the lung aeration rather than extravascular lung fluid.. Alterations in cerebral blood flow allow inferences to be made regarding brain pathology and raised intracranial pressure (ICP). Estimation of flow velocities and calculation of pulsatility (PI) and resistance indexes (RI) are useful tools for non-invasive monitoring of ICP. Age-dependent normal values of blood velocities in different vessels and indexes have been previously published. Paediatric data are not yet sufficient to support its use and caution must be taken when interpreting results. 2. POCUS should be used to detect germinal matrix and intraventricular haemorrhage (IVH) in neonates-strong agreement (quality of evidence A). Intraventricular haemorrhage and parenchymal bleeding remain a frequent and serious complication in extremely preterm infants. POCUS is a useful clinical tool to detect IVH and parenchymal changes, and assesses the severity according to Papile's classification. In environments where imaging resources are limited, brain POCUS should be used for the diagnosis of IVH which may aid in the redirection of care. 3. POCUS is helpful to detect cerebral blood flow patterns suggesting the presence of cerebral circulatory arrest in children with fused skull bones-agreement (quality of evidence C). Transcranial doppler has been used to establish the presence of cerebral circulatory arrestby evaluation of the middle cerebral (MCA) and basilar artery. The following patterns are compatible with cerebral circulatory arrest: (a) oscillating waveform or sustained reversal of diastolic flow, (b) small systolic spikes and disappearance of all intra-cranial flow, (c) no flow in MCA, (d) reversal of diastolic flow in extracranial Internal Carotid Artery (ICA) and (e) mean velocity in MCA less than 10 cm/s for more than 30 min. However, interpretation of this assessment must be done with caution. 4. POCUS is helpful to detect cerebral blood flow changes secondary to vasospasm in patients with traumatic brain injury and non-traumatic intracranial bleeding-agreement (quality of evidence C). Vasospasm of cerebral arteries results in increased flow velocities. The Lindegaard ratio (LR) is calculated by dividing mean velocity in MCA by mean velocity in ipsilateral extracranial ICA. As hyperaemia may also increase mean velocities, LR is useful to distinguish between hyperaemia and vasospasm (3:6 ratio is considered a sign of mild vasospasm, and > 6 a sign of severe vasospasm). 5. POCUS is helpful to detect changes in optic nerve sheath diameter (ONSD) indicative of raised ICP in children with fused skull bones-agreement (quality of evidence B). Measurement of the ONSD is suggestive of papilledema and increased ICP; however, data conflict on threshold measurementsand papilledema may persist despite normalisation of intracranial pressure. Therefore, it must be reminded that this technique may have relevant measurement errors because of the narrow margins that distinguish pathological from normal. 6. POCUS is helpful to detect cerebral midline shift (MLS) in neonates and children-agreement (quality of evidence C). Measurement of the distance from both temporal bones to the centre of the third ventricle through the temporal acoustic window determines the presence of MLS. Minimal shifts (less than 5 mm) in adults have proven to identify abnormal conditions. Yet, normative values for MLS identification in children have not been reported, and this may reduce the helpfulness of this application. E. Recommendations for abdominal POCUS 1. POCUS is helpful for the detection of free intraabdominal fluid in neonates and children-strong agreement (quality of evidence C). ## Pocus is helpful in detecting anaesthesiainduced atelectasis in neonates and children-a- Abdominal POCUS is widely used as a clinical tool for the management and diagnosis of patients with abdominal pathology. Evaluation of free fluid is particularly useful when sudden clinical deterioration and hypotension occur and may provide insight into the ongoing pathophysiologic processA renal ultrasound is useful to easily detect the presence of hydronephrosis even by novices. Urinary retention can be evaluated by POCUS assessing postvoid residual volumes. In the case of anuria, a simple obstruction requiring a urinary catheter placement can be ruled out. 4. POCUS may assess bowel peristalsis in neonates and children-agreement (quality of evidence D). Bowel POCUS may be used to assess peristalsisbut insufficient data yet exist correlating peristalsis with feeding tolerance. However, the presence of peristalsis has strong negative predictive value in adults for ileus and gut ischemia in adults. 5. POCUS may recognise hypertrophic pyloric stenosis [although for a definitive diagnosis a detailed assessment should be performed by a paediatric radiologist]-disagreement (quality of evidence D )[157] 6. POCUS may guide peritoneal drainage or aspiration of peritoneal fluid in neonates and children-strong agreement (quality of evidence D). A paracentesis may be required for either diagnostic or therapeutic purposes. POCUS should be used for pre-procedural planning, identification of epigastric vessels and real-time ultrasonographic guidance. In adult studies, the use of ultrasound has been shown to decrease both bleeding complications and the overall cost of care for patients undergoing in-hospital paracentesis. 7. POCUS is helpful to detect signs of necrotizing enterocolitis (NEC) [although for a definitive diagnosis a detailed assessment should be performed by a paediatric radiologist or a person with specific advanced ultrasound training]-agreement (quality of evidence C). Ultrasound may be a useful adjunct detecting changes consistent with NEC even when radiographs are inconclusive. Furthermore, radiographs have poor sensitivity in the diagnosis of NEC. POCUS can provide prognostic value identifying free fluid, bowel wall thickness, pneumatosis intestinalis, portal venous gas and vascular perfusion. The International Neonatal Consortium's NEC subgroup recently revisited the necrotizing enterocolitis (NEC) pathogenesis and new diagnostic criteria were proposed. These were based on the so-called 'two out of three' model which includes pneumatosis intestinalis or portal venous gas by abdominal X-rays and/or POCUS. POCUS was included since various studies demonstrated that it outperformed conventional radiology to this end. # Discussion POCUS is increasingly being utilised in neonatal and paediatric critical care as a valuable adjunct to clinical examination. The use of POCUS by the clinician is different than a complete diagnostic study by the specialist and its role is dynamic-the same provider can perform and interpret the study, rapidly integrate this information within the current clinical setting, and then repeat the study to identify changes associated with the intervention. POCUS involves a focused assessment to answer a specific question, and it provides anatomical and/ or physiological information to be integrated with clinical and laboratory data and make timely and accurate decisions possible. The statements on which panellists disagreed concerned two particular indications (endocarditis and hypertrophic pyloric stenosis), whose diagnosis should be done by a detailed ultrasonography in the hands of an expert paediatric cardiologist or radiologist. The role of POCUS (i.e., point-of-care ultrasound performed directly by neonatal/paediatric intensivists at the bedside) for these indications is not clear, while the role of ultrasound, in general, is indeed important. There remains a significant variation in clinical practice-in indications, training program and clinical governance. The application of POCUS in clinical practice is dependent on many factors including availability of ultrasound machines, providers, hospital setting, local patient population and specialty. Even within a unit, practice varies among clinicians and their expertise. We subdivided POCUS recommendations according to the estimated level of training required for their use, and this may be helpful for their implementation. Defining a scope of practice is fundamental for POCUS, and these ESPNIC guidelines have been developed for the targeted use of ultrasound in NICU and PICU by any neonatologist or paediatric intensivist. For most diagnostic (heart, lungs, brain and abdomen) and procedural (line placement and fluid drainage) POCUS applications, these guidelines can be used at all ages in children or neonates. However, while using cardiac POCUS in neonates, clinicians should be aware that undiagnosed critical congenital heart defects can present just during this period. They should acknowledge the limitations of skills, and it should not be used as a screening tool for diagnosing or excluding congenital heart defects. A patient with a suspected critical congenital heart defect should be quickly referred to a paediatric cardiologist, even if this implies out-ofhospital patient's transportation. However, in cases of suspicion of a non-critical defect or for patients with low pre-test probability a more expectative management can be provided. Moreover, the use of pulse-oximetry screening for congenital heart defects is useful and should be integrated into the clinical decision-making process, as internationally recommended. These guidelines may help in standardising clinical practice across acute care settings and physicians. It is not meant to be prescriptive, but rather to outline the important features of structured POCUS applications in clinical practice. The use of these guidelines often will not have any cost implication for the equipment, as ultrasound machine is almost always available in most neonatal and paediatric intensive care units. ESPNIC will promote the diffusion of these guidelines by appropriate advertisement, links and presentation in the society congresses and training events. These guidelines have strengths and limitations as any other. Strengths are represented by (1) the fairly subdivided multidisciplinary panellists' group (including both neonatologists and paediatric intensivists, expert in different POCUS areas and coming from different geographical regions), and (2) the use of a standardised methodology. In several fields, these recommendations are based upon a few studies with moderate/low evidence or based upon experts' opinions and this is a striking difference compared to similar guidelines in adult critical care. In fact, authors answered to following PICO questions: "Does point-of-care ultrasound for heart/lung/line placement/abdomen/brain provide any clinical advantage in neonatal or paediatric intensive care practice?" (supplementary methods). These questions were purposely quite general, as POCUS is not a therapeutic intervention, but rather a diagnostic and monitoring technique and we expected few randomised controlled trials or high-quality diagnostic accuracy studies about POCUS specifically aiming to improve any particular paediatric/neonatal outcome. Moreover, some of the POCUS applications may not be immediately used in all intensive care units as in ours, because of the specific expertise required in some particular contexts (such as the extremely preterm neonates or non-sedated and non-collaborative patients). However, the existence of formal guidelines may help to improve the local expertise and foster new studies to expand knowledge in this field and refine future recommendations. This is extremely important as further studies are warranted to demonstrate that POCUS actually improves patients' management and outcome, similar to what has been demonstrated in adult critical care. Another concern is that the clinicians involved are all enthusiastic users of POCUS and this may have theoretically contributed to have 'too positive' recommendations. The ESP-NIC POCUS Working Group recognises that there are emerging indications for POCUS outside of those listed here and needs for future research steps. Publication of new literature may require future revision and ESPNIC POCUS Working Group is willing to update guidelines accordingly every 3 years. These guidelines may provide a substrate to develop a POCUS curriculum and structured training programs, which are urgently needed for quality assurance. This guideline paper is not a training statement: requirements and methods of POCUS training should be a sensible follow-up article to this one. # Conclusions Despite the lack of published evidence-based guidelines specifically for its use in the neonatal and paediatric intensive care units, POCUS is increasingly being used. ESPNIC POCUS guidelines provide the substrate to optimise POCUS use in neonatal and paediatric critical care and guide future research steps according to currently unmet needs. Guidelines may help in making the clinical practice standardised and clinical governance robust. ## Supplementary information Supplementary information accompanies this paper at https://doi.org/10. 1186/s13054-020-2787-9. Authors' contributions YS, CT and DDL conceptualised and designed the development of the whole project. YS and CT wrote the first manuscript draft. DDL took care of the whole methodology and supervised the whole project. All authors performed literature search and analysis, interpreted the literature data with their specific expertise, participate in meetings discussions and voted on recommendations and manuscript preparation. Moreover, all authors critically reviewed the manuscript for important intellectual content, approved it in its final version and agreed to be accountable for all aspects of the work. The participation to the project did not entail any honorarium. All authors read and approved the final manuscript. # Funding This project has no funding. ESPNIC provided technical and secretarial assistance for free. ## Availability of data and materials Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. Ethics approval and consent to participate Not applicable. ## Consent for publication Not applicable. ## Competing interests The authors declare that they have no competing interests. ## Jain a, mohamed	None	https://ccforum.biomedcentral.com/track/pdf/10.1186/s13054-020-2787-9	None
be0302e320cf032d82cffe58b37d059f903f3549	pubmed	New scenarios in secondary hyperparathyroidism: etelcalcetide. Position paper of working group on CKD-MBD of the Italian Society of Nephrology	New scenarios in secondary hyperparathyroidism: etelcalcetide. Position paper of working group on CKD-MBD of the Italian Society of Nephrology Bone mineral abnormalities (defined as Chronic Kidney Disease Mineral Bone Disorder; CKD-MBD) are prevalent and associated with a substantial risk burden and poor prognosis in CKD population. Several lines of evidence support the notion that a large proportion of patients receiving maintenance dialysis experience a suboptimal biochemical control of CKD-MBD. Although no study has ever demonstrated conclusively that CKD-MBD control is associated with improved survival, an expanding therapeutic armamentarium is available to correct bone mineral abnormalities. In this position paper of Lombardy Nephrologists, a summary of the state of art of CKD-MBD as well as a summary of the unmet clinical needs will be provided. Furthermore, this position paper will focus on the potential and drawbacks of a new injectable calcimimetic, etelcalcetide, a drug available in Italy since few months ago. # Introduction Secondary hyperparathyroidism (SHPT) is a common, severe and costly complication of Chronic Kidney Disease (CKD), and it has an unfavorable impact on outcomes of patients, particularly in those undergoing hemodialysisThis manuscript is dedicated to the memory of our colleague Augusto Genderini, who suddenly passed away during the preparation of it. ## 3 (please refer tofor a complete list of abbreviations and acronyms). Although many treatment approaches are available, remarkable proportions of patients still present inappropriate serum levels of parathyroid hormone (PTH), phosphate and calcium, often reaching far beyond what is recommended by the guidelines for the treatment of Chronic Kidney Disease Mineral Bone Disorder (CKD-MBD). In the COSMOS study, a review of approximately 4500 subjects in 227 European dialysis centers, phosphate levels were higher than normal in 70% of dialysis patients, reaching values beyond 5.5 mg/dl in 41% of them. Similarly, only about one patient out of two in Italy present values of CKD-MBD parameters within the desired ranges. In the US, based on the data from the Dialysis Outcomes Practice Patterns Study (DOPPS), a survey performed in 2015, phosphate levels were higher than recommended by the guidelines for CKD-MBD management in more than 60% of prevalent patients undergoing hemodialysis treatment longer than 180 days. With regard to the plasma levels of PTH, according to DOPPS data, a progressive increase of median levels has been observed in the last years both in Europe and the US. In the 2012-2014 timeframe of the survey, in particular, more than 25% of patients treated in the US presented with poorly controlled SHPT (defined as PTH level > 500 pg/ml). In line with these observations, hyperparathyroidism was reported in a recently published study in as much as 29% of patients receiving chronic hemodialysis in Italy. In addition to such an assessment of the grade of appropriateness in the management of SHPT both in Italy and internationally, DOPPS data show that, in dialysis patients, there's an increase in the risk of cardiovascular mortality and all-cause mortality associated with serum calcium levels > 10 mg/dl, phosphate levels > 7 mg/dl, and PTH levels > 600 pg/ml, so as to highlight how much an appropriate control of SHPT and CKD-MBD is still an unmet clinical need. Current strategies for the medical treatment of SHPT are grounded in the following criteria: lower the intake of phosphate by careful avoiding food and beverages with "masked" phosphorus content (many preserved foods and alcohol-free beverages); privilege the intake of proteins of vegetal origin which, due to higher content in fiber, cause lower intake of phosphorus so as to reduce animal proteins while avoiding malnutrition; use phosphate binders; use vitamin D analogs; ensuring dialysis appropriateness in dialysis patients, with particular regard to duration; use of calcimimetics. The latter are chemical agents which activate calcium sensing receptor (CaSR) and suppress PTH secretion from the parathyroid glands. Parathyroidectomy is usually the last resort treatment and is only performed after evidence of failure of drug therapy , and a careful evaluation of all potential complications of such surgery procedure. The goal of the treatment is to maintain calcium, phosphate and serum PTH below the levels advised by the guidelines for CKD-MBD management. However, partly because of the limitations of the current therapeutic options for SHPT, a large proportion of patients on chronic replacement therapy do not reach target levels of PTH. It is not thus surprising that the research in this field is still ongoing with the aim of developing molecules able to offer new therapeutic solutions for clinicians to cure bone mineral disorders. In this "Position Paper", we are going to present the updates of the guidelines for CKD-MBD management issued by Kidney Disease Improving Global Outcomes (KDIGO) and the evidence available on etelcalcetide, a novel calcimimetic agent administered intravenously, which a few months ago entered the therapeutic armamentarium of nephrologists who are struggling with the management of SHPT. ## Kdigo guidelines on ckd-mbd management: new updates The updates of the guidelines for diagnosis, evaluation, prevention and treatment of CKD-MBD in patients with chronic kidney disease were released in August 2017at the end of a long internal review process. In fact, the changes from previous 2009 guidelines are modest, particularly with regard to management and therapy of SHPT. Among the new recommendations, the importance of serial assessments of phosphate, calcium, and PTH levels considered together, is reiterated under point 4.1.1 of the guidelines. When deciding or modifying the treatment of CKD-MBD, it is indeed important to consider the set of these biochemical markers as a whole, and to also take into account their trends in time, an aspect that is often neglected by clinicians. In patients in dialysis (CKD-G5D) it is suggested to maintain phosphate levels in the normal range, avoid hypercalcemia, and use a dialysate calcium concentration between 1.25 and 1.50 mmol/l (grade and strength of the recommendations: 2C). Concerning management and adjustment of PTH levels, the recommendation (under point 4.2.3, grade and strength 2C) is unchanged from year 2009, i.e. it is suggested to maintain PTH levels in the range of 2-9 times the upper normal limit reported by the lab and, importantly, to initiate or change therapy in case of progressive changes in PTH levels, even if still within the suggested range. This recommendation applies for either increased or decreased PTH levels, in order to avoid both hypercorrection and suboptimal treatment of SHPT. As it is shown in, many drugs are available to improve SHPT, and guidelines suggest to use calcimimetics, calcitriol, vitamin D analogs or a combination of these in patients in dialysis (point 4.2.4, 2B). The choice of the treatment and the assessment of the best therapeutic strategy are up to the physician in charge of the single patient, based on his/ her biochemical pattern, as it is reported under the above mentioned point 4.1.1 of the guidelines. Among the working group who reviewed the KDIGO 2017 guidelines there was no consensus as to the indication for the use of calcimimetics as first line treatment in CKD-G5D and SHPT patients . Several studies show superior efficacy of cinacalcet as compared to active vitamin D or its analogs for the simultaneous control of both PTH and the other bone mineral metabolism markers (serum calcium, serum phosphate, FGF23). Therefore, in our opinion calcimimetics should be seen as first line drugs to control SHPT in patients with moderately to severely elevated serum calcium levels and elevated levels of phosphate, while active vitamin D or its analogs should be used as first choice in patients with hypocalcemia. However, it is necessary to remind that in most cases the best control of SHPT is achieved in the later phase using a balanced combination of calcimimetics and low doses of active vitamin D or its analogs. Indeed, several randomized clinical trials have proven that combined therapy with cinacalcet and low doses of active vitamin D might achieve better control of SHPT in comparison with solely using active analogs of vitamin D. In a study by Urena et al.conducted in 300 incident patients undergoing hemodialysis, combined therapy with cinacalcet and low doses of active vitamin D (average weekly dose of paricalcitol 4.5 mcg) achieved greater reduction of PTH levels, along with lower average levels of serum calcium and phosphate (8.7 vs. 9.3 mg/dl and 5.1 vs. 5.5 mg/dl respectively) as compared with monotherapy with paricalcitol (average weekly dose 11.7 mcg). In the IMPACT study, the control of PTH levels was similar between subjects treated with cinacalcet and low doses of vitamin D and those who were treated with monotherapy either with paricalcitol or analogs of vitamin D. However, in comparing study-end and baseline serum levels, a trend was observed toward a decrease in phosphate, calcium and FGF23 among patients treated with cinacalcet, while the same markers were increased by the use of intravenous or oral paricalcitol. Furthermore, in around 11% of patients treated with paricalcitol, hypercalcemia (defined as serum calcium over 11 mg/dl) was detected. Also the PARADIGM study, conducted in 312 dialysis patients, showed comparable control of PTH levels between the group treated with cinacalcet (median daily dose at 52 weeks 85 mg) and the one treated with paricalcitol (median weekly dose at 52 weeks 21 mcg). However, serum calcium, phosphate and FGF23 were significantly reduced in patients treated with cinacalcet, while the same markers were increased in the paricalcitol group. According to the "Evidence based medicine", the EVOLVE study (Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events), the largest placebo-controlled double-blind clinical trial ever conducted in dialysis patients with SHPT, was not able to prove superiority of cinacalcet over placebo in achieving the more ambitious composite primary end-point of all-cause mortality, myocardial infarction, unstable angina requiring hospitalization, heart failure or peripheral vascular disease. The statistical inconclusive significance of the study is due to the reduction of its statistical power from 90% to 54%, as a consequence of both the decision of the physicians in charge to treat placebo patients with a calcimimetic, and the sideeffects drop-out rate from the calcimimetic drug, mainly due to gastrointestinal events. Therefore, on the one hand clinical trials using surrogate endpoints like biochemical markers control have proven a specific pattern achieved by the calcimimetic; on the other, the EVOLVE studycould not prove an impact of CaSR modulation on hard endpoints. In fact, at the end of the 64-month treatment period, the reduction of the composite risk of all-cause mortality, myocardial infarction, unstable angina requiring hospitalization, heart failure or peripheral vascular disease was proven non-significant (Hazard Ratio 0.93; 95% Confidence Interval 0.85-1.02; p = 0.11). Nevertheless, in the EVOLVE study the risk of developing severe and unremitting hyperparathyroidism and undergo parathyroidectomy was shown to be lower in the cinacalcet group than in controls (who were treated with active vitamin D and/or phosphate binders). This observation, however, is based on secondary or post hoc analysis and it requires further evidence. Other interesting findings from the EVOLVE study are listed in. Treatment with cinacalcet was more beneficial in individuals of age over 65 years as compared to the younger ones. In general, the risk of calciphylaxis, non-atherosclerotic Main messages arising from the latest KDIGO review of the guidelines on CKD-MBD managementKDIGO guidelines It is important to evaluate the set of biochemical markers as a whole and their trends in time Hypercalcemia should be avoided Calcimimetics are among first choice options to consider in stage-5D CKD patients cardiovascular events, calcifications, and bone fracturesseemed to be lower when CKD-MBD therapy included the use of a CaSR modulator. In summary, the current clinical evidence does not allow to draw clear indications on which therapy of SHPT should be chosen as first line, but it actually suggests that the treatment strategy should be tailored to the biochemical pattern of each patient, leaving physicians free to make the clinical choices they deem appropriate for their patients. Clinical common sense tells us we should follow the suggestions here above. ## When and how to start drug treatment of shpt? The KDIGO guidelines include only very general advices about when to initiate treatment with drugs able to reduce the levels of PTH. At point 4.2.3, among other things, the KDIGO guidelinessuggest to start treatment when repeated increases of PTH levels are observed, even within the suggested range, in order to avoid progression of the condition of SHPT. In clinical practice, however, such suggestion does not seem to be much followed. The latest DOPPS data show that SHPT treatment is generally started late, namely, when PTH has exceeded the recommended target. In contrast with the increase of the average levels of PTH observed during the study period, prescription of active vitamin D was frequent (around 80% of patients were treated with vitamin D) but it remained stable. Changes were not seen either in the prescription of cinacalcet, that remained stable and limited to around 20% of white and 37% of black patients. Although cinacalcet use has been associated with parathyroid gland volume reduction even in patients with marked parathyroid hyperplasia, there are physiopathological and clinical considerations that should push to start treating SHPT as early as possible, with the aim of achieving optimal and simultaneous control of multiple mineral metabolism markers and slow and/or contain the progression of SHPT. In detail, it is thought that chronic and abnormal stimulation of the parathyroid glands to release PTH might lead to structural changes of the glands themselves which, with time, become progressively less sensitive to mechanisms regulating PTH production and therefore also to medical therapy (unremitting SHPT). Delaying treatment of SHPT might therefore mean to jeopardize its efficacy. There are substantial differences, though, among classes of drugs able to control PTH. When deciding the treatment for CKD-MBD, it is important to take these differences into account. In particular, the effect of the administration of vitamin D on calcium and phosphate balance can be very different from that of a CaSR modulator. We know that, in dialysis patients, serum levels of calcium and phosphate do not only depend on dietary intake and intestinal absorption but also on dialysis balance and bone resorption of these elements. Protein intake being equal, for example, the risk of hyperphosphatemia increases with PTH levels. In detail, in patients with protein intake from0.8 to 1.2 g/kg/day the risk of hyperphosphatemia increases significantly when levels of PTH are > 300 pg/ml (as compared to the population with PTH levels from 150 to 300 pg/ ml). In another study conducted in more than 100,000 patients undergoing maintenance dialysis treatment, the risk of hyperphosphatemia (defined as serum phosphate levels > 5.5 mg/dl), hypercalcemia (defined as serum calcium levels > 10.2 mg/dl) and elevated alkaline phosphatase (> 120 U/L) increased progressively with PTH levels, thus showing an important role of bone turnover in determining serum levels of these elements. As compared to active analogs of vitamin D, cinacalcet does not increase the intestinal absorption of phosphate and is effective in reducing elevated bone turnover. The action on bone turnover might indeed explain the finding of serum levels of calcium and phosphate generally lower in patients treated with a CaSR modulator than in those treated with vitamin D or its analogs. Based on the available evidence and the physiopathological arguments discussed above, it seems reasonable to initiate treatment before the condition of unremitting SHPT is reached, using one or more drugs enabling the control of multiple biochemical markers at the same time. ## Calcimimetics: when and how to use these molecules? suggestions from the working group As it was discussed above, calcimimetics are a first line therapeutic option for the treatment of SHPT in patients with moderately to severely elevated serum calcium levels and elevated levels of phosphate, who are receiving renal replacement therapy. Drugs belonging to this class bind and allosterically activate CaSR (allosteric agonists). So far cinacalcet has been the only drug in this class available for therapy. Since few months ago also etelcalcetide is available in Italy; as compared to cinacalcet, the new drug has a different administration route (intravenous) and a different mechanism of CaSR activation. Furthermore, other molecules are under clinical development or are ready to enter the market. Unlike vitamin D and its analogs, calcimimetics are effective in reducing PTH without increasing the intestinal absorption of calcium and phosphate. Clinical studies have shown that treatment of SHPT with cinacalcet significantly reduces circulating levels of PTH. After 26 weeks of treatment with cinacalcet or placebo, levels of iPTH ≤ 250 pg/ml were achieved in a remarkable proportion of patients treated with the drug (43%) as compared to placebo (5%), and also better control of serum calcium and phosphate, in association with higher suppression of PTH, were observed. Further studies have confirmed the efficacy of PTH suppression with cinacalcet, in combination with vitamin D or vitamin D analogs, as compared to monotherapy with calcitriol. In the ACHIEVE study, PTH levels were reduced by at least 30% from baseline in 68% of patients receiving cinacalcet and only in 36% of patients receiving active vitamin D as monotherapy. In another open-label 16-week study, 71% of patients treated with active vitamin D in combination with a low dose of cinacalcet reached levels of PTH ≤ 300 pg/ml as compared to 22% of patients treated with vitamin D only. In all these studies mild to moderate hypocalcemia was common but easily manageable. Hypocalcemia is a side effect attributed to CaSR modulation and likely to a reduction of bone calcium mobilization due to stricter control of PTH. Lastly, the EVOLVE study has confirmed that achieving target levels is easier in CKD-MBD patients who are treated with cinacalcet than in the ones treated with placebo. As we already discussed, despite the primary endpoint of the study (all-cause mortality, myocardial infarction, unstable angina requiring hospitalization, heart failure or peripheral vascular disease) was not reached, serum levels of iPTH, calcium, phosphate and FGF-23 were better controlled among patients assigned to the cinacalcet treatment group. As compared to the placebo group, the most common side effects related to treatment with calcimimetics were nausea, vomiting and hypocalcemia; the prevalence of hypocalcemia was 12% in the cinacalcet group and 2% in the placebo group. These side effects likely contributed to the higher discontinuation rate due to adverse events (16% in the cinacalcet group versus 12% in the placebo group). Activation of CaSR can have beneficial effects through the control of serum biochemical markers. Although inconclusive, the ADVANCE study, a phase 4 randomized clinical trial, showed a trend towards slower progression of cardiovascular calcifications in subjects treated with cinacalcet and low doses of active vitamin D, as compared to subjects treated with varying doses of vitamin D as monotherapy. Following analyses showed that patients who were adherent to therapy or presented with large coronary and/or heart valve calcifications, seemed to benefit more greatly from this combined therapy. In a post hoc analysis, subjects with aortic valve calcification treated with CaSR modulators showed a 74% reduction in the risk of progression of CAC (Odds Ratio 0.26; 95% CI 0.10-0.64). Also in the ADVANCE study, the most common side effects reported by subjects assigned to treatment with cinacalcet were gastrointestinal disorders and hypocalcemia, which occurred in 21% and 7%, respectively, of patients treated with this drug. Although the activation of CaSR is an effective therapeutic strategy to control SHPT, further studies are needed to clarify the effect of potential interactions with various drugs commonly used to control CKD-MBD. According to a recent post hoc analysis of the INDEPENDENT study data, the concomitant administration of cinacalcet and Sevelamer significantly modulated the impact of these drugs on mortality (p = 0.006): treatment with cinacalcet, with or without Sevelamer, yielded longer survival (Hazard Ratio 0.34, 95% CI 0.14-0.81, p = 0.01) than the combined treatment of cinacalcet and calcium-based phosphate binders (Hazard Ratio 1.28, 95% CI 0.82-2.00, p = 0.26). Although further verification is required, these data suggest that the activation of CaSR might modulate balance of calciumand affect survival of patients with CKD. Overall, however, the scientific evidence accumulated so far points to the need of a careful selection of the appropriate therapeutic strategy in SHPT. ## Ckd-mbd, a field of intense research: new scenarios On the date of January 26th 2018, 160 trials in SHPT were reported in the clinical trials register (www.clini caltr ials. gov; keyword: secondary hyperparathyroidism); 143 were completed or early terminated, and 17 were actively ongoing. Of these, 16 were interventional studies (four in phase 1, one in phase 2, three in phase 3, three in phase 4, and five unclassified), and one was listed as an observational study. Such numbers show that treatments and interventions targeting the mechanisms of development and progression of SHPT are a current area of interest. Etelcalcetide (formerly denominated AMG 416) is a new prolonged-action drug, whose molecule is composed by a linear chain of seven amino acids, with the ability to activate CaSR (calcimimetic). Etelcalcetide binds directly to CaSR, inhibiting the production and secretion of PTH by parathyroid glands. Such action is due to the formation of a disulfide bridge between d-cysteine in the etelcalcetide molecule and l-cysteine in CaSR, resulting in a fast activation of receptors. Many scientific articles have been published in the last 2 years concerning pharmacokinetics, biotransformation and excretion of the drug both in animal models and in CKD patients undergoing hemodialysis treatment. A summary of the main characteristics of etelcalcetide compared with cinacalcet is reported in . Biotransformation of circulating etelcalcetide mainly yields a covalent conjugate with serum albumin (SAPC). The process of biotransformation in the human bloodstream is reversible, but the rate of formation of SAPC from etelcalcetide is faster than the inverse process. These properties account for reduced extrarenal elimination and longer blood half-life of the drug. When etelcalcetide was intravenously administered to CKD patients under chronic replacement therapy, the drug predominant clearance route was the dialysis treatment itself. Around 60% of the dosage was indeed found in the dialysate. Based on these considerations, etelcalcetide should be given after the dialysis session in order to avoid the elimination of a substantial fraction of the administered dose and achieve long duration of action of the drug. Similarly, due to elimination of a substantial fraction of the administered etelcalcetide dose in the presence of a significant residual renal function, together with the route (intravenous) and frequency (three times per week) of administration make this drug not suitable for treating hyperparathyroidism in peritoneal dialysis patients. The efficacy of etelcalcetide was tested in several clinical trials versus placebo or cinacalcet in patients with CKD-G5D Summary of the differences in clinical and pharmacological properties between etelcalcetide (AMG 416) and cinacalcet a In the study comparing the drugs, 52.4% of patients treated with etelcalcetide showed a reduction of at least 50% in PTH levels at the end of a 26-week period of treatment vs. 40.2% of patients treated with cinacalcet (difference 10.2%, p = 0.001)and SHPT. In one of the first phase 2 dose-finding clinical trials, SHPT patients under hemodialysis treatment were randomized by Bell and colleagues to one of three different study treatment regimens: etelcalcetide 5 mg or placebo for 2 weeks (cohort 1); etelcalcetide 10 mg or placebo for 4 weeks (cohort 2); and etelcalcetide 5 mg or placebo for 4 weeks (cohort 3). Mean percent change of PTH from baseline was statistically significant (p < 0.05) and dose-dependent, reaching − 49% and + 29% in subjects treated with etelcalcetide 10 mg and placebo, respectively, in cohort 2, and − 33% and + 2% for etelcalcetide 5 mg and placebo, respectively, in cohort 3. The proportions of patients who achieved a 30% reduction in PTH levels from baseline were 76% in the etelcalcetide 10 mg group versus 10% in the placebo group (p < 0.0001). The proportion was lower in the etelcalcetide 5 mg group, equaling 54% versus 15% in the placebo group. Finally, the numbers of patients achieving PTH levels below 300 pg/ml at the end of the study were 67% in the etelcalcetide 10 mg group and 46% in the etelcalcetide 5 mg group. A second study conducted in Japan confirmed these findings even expanding them, as it suggested that the dosedependent reduction of PTH levels might be associated with a corresponding effect on markers of bone neo-formation (bone-specific alkaline phosphatase) and bone resorption (tartrate-resistant acid phosphatase 5b). In the two phase 3 studies versus placebo, etelcalcetide was given three times weekly to 508 patients with moderate to severe SHPT as compared to 515 patients who were given placebo. At the end of the 26-week study duration, active treatment significantly reduced the levels of PTH (75% versus 9% in the placebo group) and of FGF-23 (70% versus 30% in the placebo group), and it also improved other bone mineral metabolism markers. A post hoc analysis of the placebo-controlled studyevaluated the efficacy of etelcalcetide in achieving levels of PTH below 300 pg/ml according to specific baseline PTH levels. The results show that 69.2% of patients with baseline PTH < 600 pg/ml succeeded in achieving levels of PTH ≤ 300 pg/ml in the efficacy evaluation period; such proportion is reduced to as low as 48,9% and 29,5% for patients with baseline PTH from 600 to 1000 pg/ml and > 1000 pg/ml, respectively. These data are resulting from a symmetrical decrease of PTH levels compared to baseline by 54.2%, 58.2% and 55.5% in the three categories of patients with baseline PTH < 600 pg/ml, from 600 to 1000 pg/ml, and > 1000 pg/ml, respectively. The phase 3 study recently published by Block and colleaguesshowed that etelcalcetide was both non-inferior and superior to cinacalcet in controlling serum levels of PTH. A total of 683 patients from dialysis centers in Europe and the US were enrolled in this double-blind, doubledummy study, of whom 340 were treated with intravenous etelcalcetide and 343 with oral cinacalcet. At the end of the 26-week follow-up period, etelcalcetide was shown to be non-inferior to cinacalcet with regard to the proportion of subjects whose PTH levels were reduced at least by 30% from baseline (68.2% vs. 57.7% of patients treated with etelcalcetide and cinacalcet, respectively, non-inferiority p value < 0.001)and superior to cinacalcet with regard to the proportion of patients whose PTH levels were reduced at least by 50% (52.4% vs. 40.2% of patients treated with etelcalcetide and cinacalcet, respectively, p = 0.001). It has to be noted that all patient subgroups in which the efficacy of etelcalcetide was tested have shown the same effect of the new drug on PTH control. A summary of key results from phase 3 studies is shown in. The safety profile of etelcalcetide appears to be comparable to the one reported for cinacalcet. Adverse events reported during the treatment with etelcalcetide in clinical trials seem to be for the most part correlated to the mechanism of action of calcimimetic drugs. The most important risk for etelcalcetide is the induction of hypocalcemia or events that might occur as a consequence of a decrease in serum calcium (for example, prolongation of QTc interval). The rate of these adverse events, in particular hypocalcemia or decrease of serum calcium to levels that are not considered as true hypocalcemia, is slightly higher than with cinacalcet. This is likely due to the higher potency of the new drug. During phase 2 and phase 3 clinical trials, a total of 1655 subjects received at least one dose of etelcalcetide, and 499 of these received etelcalcetide for more than 1 year. In placebo-controlled trials, the most common adverse event was asymptomatic hypocalcemia (occurring in 63.8% of patients treated with etelcalcetide vs. 10.1% of patients treated with placebo). Based on Kaplan-Meier estimates, the median time to the onset of the first event of hypocalcemia is around 9.6 weeks. The tolerability profile of etelcalcetide was basically comparable to that of cinacalcet. The most commonly reported adverse events were asymptomatic hypocalcemia and gastrointestinal disorders. In particular, asymptomatic hypocalcemia was reported in 68.9% of patients treated with etelcalcetide and in 59.8%. Although intravenous administration bypasses the gastrointestinal tract, etelcalcetide only partially reduced gastrointestinal adverse events (nausea and diarrhea)observed with the use of cinacalcet. These effects are likely due to the systemic activation of CaSR, rather than at the level of the gastrointestinal mucosa. Nevertheless, these symptoms are generally mild in severity and improve with etelcalcetide dose reduction or drug interruption. In placebo-controlled clinical trials, prolongation of QT interval (500 ms) secondary to hypocalcemia was observed in 4.8% of patients treated with etelcalcetide and 1.9% of subjects on placebo. Close monitoring of calcium levels is thus needed in patients with risk factors like congenital long QT syndrome, previous history of QT prolongation, familial anamnesis of long QT syndrome, sudden cardiac death and other medical conditions (data from European Medicines Agency (EMA): Parsabiv summary of product characteristics. Available from: http://www.ema.europ a.eu, accessed November 30, 2016) or dugs (metoclopramide, antibiotics, etc.) that can predispose to QT interval prolongation. Also, caution should be exerted in the context of potential drugto-drug interactions that can displace etelcalcetide from albumin binding and potentially worsen hypocalcemia or hypoglycemia when etelcalcetide is administered in diabetic patients with SHPT. In dialysis patients, who undergo dialysis sessions three times weekly, regular monitoring of electrolytes and CKD-MBD biochemical markers seems sufficient to prevent the occurrence of severe adverse events. In this regard, the open label one-year extension of the three previously described phase 3 studies further corroborates the risk-to-benefit profile of etelcalcetide, without raising any additional safety concerns associated with longer-term exposure to the drug. Etelcalcetide was associated with greater-than-placebo reductions in bone mineral metabolism markers (bone alkaline phosphatase and type 1 collagen C-terminal telopeptide) and fibroblast growth factor 23 (exploratory endpoints) at the end of the study (week 27) in placebo-controlled registration trials as well. ## Closing remarks Pharmacological treatment of SHPT has made progress in the last years. The introduction of targeted therapies like VDR and CaSR selective modulators is offering more chances for an appropriate control of serum PTH levels, in particular in patients with CKD undergoing dialysis treatment. Emerging intravenous therapies for SHPT like etelcalcetide (AMG 416) might improve patients' therapeutic compliance, reduce the number of drugs to take orally at home so as to simplify dosing schedules, and increase the likelihood to reach treatment goals suggested by the guidelines for the management of CKD-MBD. The question remains unanswered whether emerging SHPT treatments will prove they can reduce the risk of cardiovascular morbidity and mortality in CKD-G5D. Emerging therapies seem effective in reducing PTH, restoring mineral homeostasis, improving therapeutic compliance, and they might help create prerequisite conditions to improve long-term outcomes in dialysis patients with SHPT. However, the final answer to such a question can only come from randomized clinical trials on the new drugs, like etelcalcetide.	None	https://link.springer.com/content/pdf/10.1007/s40620-019-00677-0.pdf	None
6558179ef42c91a26719c8753360d9366624be88	pubmed	Recommendations for accurate CT diagnosis of suspected acute aortic syndrome (AAS)—on behalf of the British Society of Cardiovascular Imaging (BSCI)/British Society of Cardiovascular CT (BSCCT)	Recommendations for accurate CT diagnosis of suspected acute aortic syndrome (AAS)—on behalf of the British Society of Cardiovascular Imaging (BSCI)/British Society of Cardiovascular CT (BSCCT) # Introduction Timely and accurate assessment of suspected acute aortic syndrome (AAS) is vital in this potentially life-threatening condition with significant pre-hospital and in-hospital mortality rates of up to 20% and 30%, respectively. [bib_ref] Thoracic aortic aneurysm and dissection: increasing prevalence and improved outcomes reported in..., Olsson [/bib_ref] There are many definitions of AAS; however, for the purpose of this document, AAS is defined as aortic dissection, intramural haematoma and the complications arising from penetrating atherosclerotic aortic ulcer. [bib_ref] A pictorial review of acute aortic syndrome: discriminating and overlapping features as..., Ueda [/bib_ref] [bib_ref] Nontraumatic acute aortic emergencies: Part 1, Acute aortic syndrome, Maddu [/bib_ref] [bib_ref] Acute aortic syndrome, Vilacosta [/bib_ref] These are not mutually exclusive and may represent variations on the same disease spectrum. [bib_ref] Acute aortic syndrome, Vilacosta [/bib_ref] [bib_ref] Imaging modalities for the early diagnosis of acute aortic syndrome, Evangelista [/bib_ref] [bib_ref] Don't get in a flap!: a case report of progression through the..., Choong [/bib_ref] [bib_ref] Acute aortic syndrome, Sheikh [/bib_ref] Different classifications of aortic dissection exist, [bib_ref] Acute aortic syndrome: CT findings, Chiu [/bib_ref] [bib_ref] Acute aortic syndrome: CT findings, Das [/bib_ref] but to avoid confusion, we recommend using the most recently proposed classification of defining dissection as follows: Type A, involving the ascending aorta; Type B, limited to aorta portion distal to left subclavian artery; and Type B with aortic arch involvement, involving the arch (between the innominate and left subclavian arteries) but not involving the ascending aorta. [bib_ref] Aortic arch dissection: a controversy of classification, Lempel [/bib_ref] The classification reflects the current management approach, which supports that Type B dissection can be managed conservatively. With recent advances in CT scanning technology and increasing expertise in cardiovascular CT, the purpose of these recommendations are to outline the best practice for the investigation of suspected AAS so that unequivocal diagnosis can be made based on imaging. Specifically, accurate motion-free imaging is vital to eliminate the possibility of false-positive diagnoses, needless patient transfer and potentially disastrous unnecessary surgery, all of which have been reported. [bib_ref] Motion artifact resulting in a false positive CT angiogram for a presumed..., Karras [/bib_ref] [bib_ref] Prevalence and factors associated with false positive suspicion of acute aortic syndrome:..., Raymond [/bib_ref] [bib_ref] Pitfalls in the diagnosis of thoracic aortic dissection at CT angiography, Batra [/bib_ref] [bib_ref] Transfer of patients with suspected acute aortic syndrome, Aggarwal [/bib_ref] [bib_ref] Transfer metrics in patients with suspected acute aortic syndrome, Aggarwal [/bib_ref] Assessment of pre-test likelihood Recommendation 1 Assessment of pre-test clinical probability of AAS should be performed using American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guidance. [bib_ref] American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines;..., Hiratzka [/bib_ref] Initial evaluation of AAS should be based upon careful history and clinical examination (i.e. assessing for peripheral pulse deficits and potential end organ damage secondary to dissection) resulting in the ability to determine a pre-test likelihood of AAS. A summary of pre-test likelihood is shown in [fig_ref] Figure 1: Risk stratification for acute aortic syndrome and appropriate management strategy [/fig_ref] which categorizes patients into low, intermediate or high likelihood of AAS. 17 ## Recommendation 2 Patients deemed to have intermediate or high risk should proceed to have imaging to establish a definitive diagnosis. In patients with low clinical risk, an alternative diagnosis should be considered but definitive imaging may also be required. Patients with high-risk conditions such as those with increased wall stress (e.g. hypertension, phaeochromocytoma, cocaine use) and aortic medial abnormalities (e.g. Marfan, Loeys-Dietz, Ehlers-Danlos, Turner syndromes, inflammatory vasculitides) have increased risks of developing thoracic aortic aneurysm and dissection. [bib_ref] Familial thoracic aortic aneurysms and dissectionsincidence, modes of inheritance, and phenotypic patterns, Albornoz [/bib_ref] [bib_ref] Emergency repair of type A aortic dissection in type IV Ehlers-Danlos syndrome, Ascione [/bib_ref] [bib_ref] Clinical and genetic features of vascular Ehlers-Danlos syndrome, Germain [/bib_ref] [bib_ref] Imaging of cardiovascular risk in patients with Turner's syndrome, Marin [/bib_ref] [bib_ref] Treatment of aortic disease in patients with Marfan syndrome, Milewicz [/bib_ref] [bib_ref] Aortic dissection in children and adolescents with Turner syndrome: risk factors and..., Turtle [/bib_ref] High-risk clinical features and examinations should also be borne in mind, allowing for appropriate patient selection for imaging. Pre-test likelihood assessment should be performed to exclude other causes and select appropriate patients for timely imaging. ## Imaging modality and technique recommendation 3 When imaging is deemed appropriate, CT scan is the imaging modality of choice in acute scenario. Transthoracic echocardiography Transthoracic echocardiography usually allows adequate assessment of the aorta and can often diagnose involvement of the aortic root and proximal ascending aorta. However, other segments (e.g. the aortic arch, proximal descending aorta and abdominal aorta) are sometimes difficult to see owing to inadequate acoustic window. The value of transthoracic echocardiography is further limited in non-standard patients (e.g. abnormal chest wall configuration, obesity, pre-existing pulmonary emphysema, or patients on mechanical ventilation). Transoesophageal echocardiography The proximity of the oesophagus to the aorta allows high-quality images of the aorta to be obtained. The high accuracy of transoesophageal echocardiography for the diagnosis of aortic dissection has been reported previously. [bib_ref] Comparative diagnostic value of transesophageal echocardiography and retrograde aortography in the evaluation..., Chirillo [/bib_ref] [bib_ref] Accuracy of biplane and multiplane transesophageal echocardiography in diagnosis of typical acute..., Keren [/bib_ref] The largest series examining ascending aortic dissection shows a sensitivity and specificity of 96.8% and 100%, respectively. [bib_ref] Diagnosis of ascending aortic dissection by transesophageal echocardiography: utility of M-mode in..., Evangelista [/bib_ref] The main drawbacks of transoesophageal echocardiography are sedation requirement and access to appropriate expertise. CT The accuracy of CT in the diagnosis of aortic dissection is high with sensitivity and specificity ranging around 98-100%. As per evidence based on the International Registry of Acute Aortic Dissection registry 27 and the Spanish Registry of Acute Aortic Syndromes, [bib_ref] Better diagnosis is not reflected in reduced mortality, Evangelista [/bib_ref] CT is already the preferred imaging modality and was used in 74% and 77% of patients in each registry, respectively. One of the major drawbacks of CT is the pulsation artefact which is addressed in this article. MRI MRI has very high sensitivity (97-100%) and specificity (94-100%) for the diagnosis of aortic dissection. [bib_ref] Aortic dissection: a comparative study of diagnosis with spiral CT, multiplanar transesophageal..., Sommer [/bib_ref] [bib_ref] Diagnosis of thoracic aortic dissection. Magnetic resonance imaging versus transesophageal echocardiography, Nienaber [/bib_ref] MRI is free from ionizing radiation, but limitations are low availability and time taken for examination (even in experienced sites, imaging time can be 20-30 min) means lack of suitability in acute setting. Given the available evidence, CT is recommended as the imaging modality of choice in the acute scenario because of accuracy, ease of access and relatively quick examination time. [bib_ref] Imaging modalities for the early diagnosis of acute aortic syndrome, Evangelista [/bib_ref] [bib_ref] Management of acute aortic syndrome, Clough [/bib_ref] Once AAS is confirmed, in addition, echocardiography may be used to assess complications such as aortic valve dysfunction, pericardial tamponade, or wall motion abnormalities, but this should not delay definite surgical management. In equivocal cases of acute intramural haematoma, a characteristic ''echo-free space or echolucent area'' within the thickened aortic wall that may be sought in supportive of diagnosis. [bib_ref] Management of acute aortic syndrome, Clough [/bib_ref] [bib_ref] Update in acute aortic syndrome: intramural hematoma and incomplete dissection as new..., Song [/bib_ref] [bib_ref] Transesophageal echocardiographic and clinical features of aortic intramural hematoma, Harris [/bib_ref] [bib_ref] Clinical significance of echo-free space detected by transesophageal echocardiography in patients with..., Song [/bib_ref] MRI/MR angiogram is not recommended in acute scenario but is useful in the context of follow-up of known aortic dissections, particularly in young patients [bib_ref] Imaging of aortic aneurysms and dissection: CT and MRI, Hartnell [/bib_ref] in line with the as low as reasonably practical principle of radiation dose optimization. ## Recommendation 4 All CT scans should be performed with the aim of producing motion-free images of the aortic root, which is prone to pulsation artefact [fig_ref] Figure 2: Ungated CT angiogram of the aorta demonstrating pulsation artefact [/fig_ref]. In systems with 64-detector-row arrays (or 80-detector-row arrays-these systems may be configured as 128 or 160 slices per rotation systems depending upon technical details of reconstruction), this should involve routine use of electrocardiogram (ECG) synchronization. [bib_ref] Multi-detector row computed tomography: imaging in acute aortic syndrome, Manghat [/bib_ref] [bib_ref] Thoracic aorta: motion artifact reduction with retrospective and prospective electrocardiography-assisted multi-detector row..., Roos [/bib_ref] Prospective triggering should be used where possible in order to reduce radiation dose. Retrospective gating usually incurs a penalty of significantly higher radiation dose. A dose-length product (DLP) for retrospective thoracic CT angiogram can be as high as 2547 mGy cm 21 , 38 although there are specific instances where this may have to be performed (see Specific protocol examples section). Broad detector array systems, e.g. 128 detector rows (e.g. Philips iCT; Philips, Andover, MA), 256 detector rows (e.g. GE Revolution; General Electrics, Milwaukee, WI) or 320 detector rows (e.g. Toshiba Aquilion One; Toshiba, Irvine, CA) or dual-source systems, should be optimized to allow motion-free imaging which may not require ECG synchronization if temporal resolution is rapid enough, but this depends upon scanner capabilities. ## Recommendation 5 A non-contrast ECG synchronization CT scan should be performed to look for a rim of hyper-attenuation around the aortic wall [fig_ref] Figure 3: Non-contrast CT demonstrating typical appearance of a hyperattenuating crescentic ring that can... [/fig_ref]. This should be performed prior to the contrast-enhanced study. The use of a non-contrast scan may reduce the likelihood of false-negative diagnosis on contrast studies in cases of isolated subtle intramural haematoma. Incidences vary but range from 6% to 30%. [bib_ref] American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines;..., Hiratzka [/bib_ref] [bib_ref] Acute aortic intramural hematoma: an analysis from the International Registry of Acute..., Harris [/bib_ref] [bib_ref] Diagnostic errors in the evaluation of nontraumatic aortic emergencies, Souza [/bib_ref] [bib_ref] Diagnostic utility of unenhanced computed tomography for acute aortic syndrome, Kurabayashi [/bib_ref] In addition, a non-contrast scan may enable the visualization of acute haemorrhagic content within the aortic wall that can be associated with the other forms of AAS 2 and also localized rupture into the pericardium. Where possible, a low-dose setting should be utilized. The non-contrast scan does not need to encompass the whole aorta and can be limited to covering from aortic arch to diaphragmatic sulcus. ## Coverage ## Recommendation 6 Coverage should be limited to thorax from aortic arch to diaphragmatic sulcus in the first instance, unless the patient is deemed high risk or has known disease. Initial coverage should be as for a CT Thorax (covering aortic arch to diaphragmatic sulcus). As the diagnostic rate for positive findings may be as low as 2.7%, [bib_ref] Suspected aortic dissection and other aortic disorders: multi-detector row CT in 373..., Hayter [/bib_ref] [bib_ref] Preliminary development of a clinical decision rule for acute aortic syndromes, Lovy [/bib_ref] coverage should be limited in the first instance in patients with intermediate pre-test probability in order to avoid unnecessary radiation dose. If the scan proves positive, then a repeat scan can be performed with extended coverage to the common femoral arteries to allow for endovascular access planning and to fully delineate the full extent of the dissection. In those patients deemed "high risk" for dissection following risk assessment, particularly with abdominal and/or lower limb symptoms/signs, it is reasonable to perform complete coverage of the entire aorta and to include the iliofemoral arteries from the outset. In addition, in situations where there is known aortic dissection, extended coverage is mandatory. ## Premedication In the acute setting, we do not advocate the use of beta-blocker medication to slow the heart rate (HR). ## Patient size Patient size or body mass index (BMI)-adjusted tube current/ voltage should be employed for maximum dose optimization. As a general rule, lower BMI will allow for the use of flow tube voltage (kVp) and provided that tube current is also optimized, dose can be reduced. Lowering kVp will affect image contrast and will allow for the use of less iodine intravenous contrast (see Recommendation 8 section). ## Scan initiation and contrast regime recommendation 7 A dedicated injection protocol should be used, taking into account the speed of scan acquisition and coverage with the aim to achieve adequate contrast concentration of at least 250 HU in the aorta. There are three distinct methods of scan initiation that may be used. (a) Fixed delay: this must take into account the contrast injection rate, contrast concentration, table feed speed, scanner detector width and perceived patient cardiac output. This is effectively a prediction and is not recommended. (b) Test bolus: this technique will allow homogeneous contrast enhancement and takes into account the patient's haemodynamic status. However, a disadvantage is that it requires a small increase in the overall contrast medium dose for the test bolus (usually #20 ml). [bib_ref] Intravenous contrast medium administration at 128 multidetector row CT pulmonary angiography: bolus..., Rodrigues [/bib_ref] Lower tube voltage protocols for test bolus imaging can be used to reduce radiation further. 45 (c) Bolus tracking: with a region of interest placed in the ascending thoracic aorta, the scan is commenced once a predetermined threshold Hounsfield unit has been reached. It should be noted that in AAS, there is a risk that if the region of interest is incorrectly placed (e.g. as can occur in the false lumen of a dissected aorta), inappropriate triggering may occur. The operator should be aware that manual initiation may be required in this instance. The contrast injection should be given via the right arm to eliminate the streak artefacts that might be caused by injection from the left side, obscuring assessment of head and neck vessels that may potentially be involved. The amount of contrast and rate of injection depends upon the speed of scan acquisition, tube voltage, patient size and z-axis coverage, as well as the iodine concentration used and whether a saline bolus chaser is used. The aim is to achieve adequate contrast concentration of at least 250 HU in the aorta. [bib_ref] Cardiothoracic CT angiography: current contrast medium delivery strategies, Weininger [/bib_ref] The use of a saline flush is recommended as this produces a higher contrast peak opacification for any given iodine flux and makes most efficient use of administered contrast. [bib_ref] Saline flush effect for enhancement of aorta and coronary arteries at multidetector..., Kim [/bib_ref] On the most recent generation of CT scanners, it is now feasible to use low tube voltage for routine imaging of the aorta, even in large-sized patients (often in conjunction with iterative reconstruction techniques). Owing to the greater photon absorption of iodinated contrast at energies nearer 70 kVp, this results in greater relative vascular enhancement. This in turn allows for smaller volumes of contrast to be used at lower flow rates (iodine delivery rates of 1.3-1.5 g s 21 ). Similarly, the use of high-pitch dual-source systems need less iodine delivery rate but owing to acquisition speed, adjustment of the acquisition delay may be required. Biphasic or triphasic injections should be considered to reduce contrast dose, produce a uniform enhancement pattern without affecting the maximal enhancement and also minimize artefacts from dense contrast material within the superior vena cava. Patient-specific protocols can also be employed and may achieve more uniform contrast enhancement. 49 ## Recommendation 8 The key to adequate contrast opacification is to achieve an iodine delivery rate of at least 1.6 g s 21 (ideally up to 2 g s 21 ) when using a tube voltage of 120 kVp. The two factors to consider when calculating iodine flux are the iodine concentration of the contrast media and the injection rate, i.e. 300 mg of iodine per millilitre injected at 6.7 ml s 21 vs contrast media of 400 mg of iodine per millilitre injected at 5 ml s 21 . It is worth noting that patient factors also affect iodine delivery rate (i.e. cardiac output and weight). Therefore, it is recommended that contrast volume should be determined based on the patient's weight, usually delivering at least 300-mg iodine per kilogram for examinations of the whole aorta with 64-detector row systems. However, advanced broad detector array or dual-source systems may permit lower volumes in view of their increased speed of acquisition. 48 If using a 64-detector-row CT for the entirety of the aorta, a decrease in aortic enhancement in the descending aorta may be observed when using a biphasic protocol. However, the decrease in aortic enhancement usually does not fall below diagnostic acceptability and often remains above the 250 HU. [bib_ref] Effect of different saline chaser volumes and flow rates on intravascular contrast..., Behrendt [/bib_ref] Whilst the aim is to get uniform enhancement throughout the entire aorta, but in the descending and abdominal aorta, this may on occasion be difficult to achieve. However, in most cases, the abdominal aorta can be delineated sufficiently to visualize the dissection and the perfusion of the mesenteric and renal arteries without a need for a repeat examination. Moreover, intramural haematoma and penetrating atherosclerotic ulcer are relatively rare in the abdominal aorta. Multiphase injection protocols may enable more uniform vascular enhancement throughout the entire aorta, and if available should be considered. [bib_ref] Uniform vascular contrast enhancement and reduced contrast medium volume achieved by using..., Bae [/bib_ref] Optimizing CT parameters Although diagnosis of AAS can be made using non-gated CT techniques, image quality at the aortic root is often suboptimal owing to motion artefact. This limits the diagnostic confidence and may on occasion mimic aortic dissection, leading to unnecessary further investigation and treatment, including sternotomy/thoracotomy. The prevalence of aortic motion artefacts with non-gated CT has been reported to be high as 57-93% in some series. [bib_ref] Motion artifacts of the aorta simulating aortic dissection on spiral CT, Qanadli [/bib_ref] [bib_ref] A case report of a normal aorta misdiagnosed as type A dissection..., Hamilton [/bib_ref] [bib_ref] Effects of heart rate on motion artifacts of the aorta on non-ECGassisted..., Ko [/bib_ref] With ECG synchronization, the occurrence of this artefact is less common, allowing motionfree visualization of the aortic root and proximal coronary arteries in almost all cases. [bib_ref] Thoracic aorta at multidetector row CT: motion artifact with various reconstruction windows, Morgan-Hughes [/bib_ref] [bib_ref] Electrocardiographically gated 16-section CT of the thorax: cardiac motion suppression, Hofmann [/bib_ref] To allow for prospective acquisition of the aorta, systems with detector coverage of at least 32 mm in the z-axis are recommended to make breath-holding possible during the whole scan acquisition. ECG synchronization must be available to allow co-registration with heart rhythm. Scanners with $64 detector rows should be used in conjunction with narrow reconstructed slice thickness (,1 mm) in order to provide adequate multiplanar reformats, preferably with isotropic resolution utilizing small voxel size through the use of a small field of view tailored to the aorta. ## Specific protocol examples For each scanner type, it is important that dedicated protocols are used and optimized. The protocols outlined below should be used as a guide, and variations may exist depending on differing parameters as outlined above. These protocols are advocated based upon expert British Society of Cardiovascular Imaging user recommendations and in collaboration with UK application specialists. ## Basic concept For a 64-detector-row system (including "128-slice" scanners and similar), prospective ("step-and-shoot") acquisition should be employed where possible with phase selection based on HR. This is because the phase with minimal motion of the aortic root varies with HR. At HR ,65 beats per minute (bpm), this is usually the end-diastolic phase. With HR .65 bpm, this is usually end-systolic phase. [bib_ref] Thoracic aorta at multidetector row CT: motion artifact with various reconstruction windows, Morgan-Hughes [/bib_ref] Where phase selection is not adjustable (e.g. on a scanner with prospective helical acquisition with diastolic phase acquisition only for slow HRs), then a retrospective protocol may need to be employed for patients with faster HRs. Retrospectively gated acquisitions can be used but should be only employed where no prospectively triggering alternative exists. Iterative reconstruction algorithms should be used where deemed appropriate to allow reduced radiation dose. [bib_ref] Effects of model-based iterative reconstruction on image quality for low-dose computed tomographic..., Caywood [/bib_ref] [bib_ref] High-pitch, low-voltage and lowiodine-concentration CT angiography of aorta: assessment of image quality..., Shen [/bib_ref] [bib_ref] Impact of Adaptive Statistical Iterative Reconstruction (ASIR) on radiation dose and image..., Cornfeld [/bib_ref] For larger detector array or high-pitch dual-source systems, ECG synchronization may not be necessary for motionfree imaging of the aorta. A summary of all the protocols can be seen in [fig_ref] Table 1: Summary of scanning parameters for different types of CT scannersNon-gated helical acquisition... [/fig_ref]. Further discussions are as follows. Single-source systems: standard detector coverage-64and 80-detector row scanners (including "128and 160-slice" systems) Although, step artefact may be problematic in coronary imaging, this does not affect diagnostic confidence in the visualization of the aorta. The advantage of adopting prospective triggering is a significant reduction in radiation dose compared with nongated and retrospectively gated acquisitions. There may be a role for retrospective gating when the HR is fast (i.e. .100 bpm) or in systems where the threshold for prospective triggering under a pre-defined HR cannot be overridden [fig_ref] Table 1: Summary of scanning parameters for different types of CT scannersNon-gated helical acquisition... [/fig_ref]. When retrospective acquisition is used, dose modulation outside the 30-80% cardiac cycle should be applied. [bib_ref] Prospective and retrospective ECG gating for thoracic CT angiography: a comparative study, Wu [/bib_ref] Prospective triggering is recommended with phase selection taking into account the patient's HR. [bib_ref] Thoracic aorta at multidetector row CT: motion artifact with various reconstruction windows, Morgan-Hughes [/bib_ref] [bib_ref] Comparison of sequential and helical scanning for radiation dose and image quality:..., Bischoff [/bib_ref] [bib_ref] Prospective ECGtriggered CT angiography of the thoracic aorta in patients with atrial..., Blanke [/bib_ref] Regular HR ,65 bpm: prospective with end-diastolic triggering. HR .65 bpm or irregular HR: prospective with end-systolic triggering. For scanners that cannot utilize prospective triggering in a "stepand-shoot" manner at HR .65 bpm, the following protocol should is recommended. Regular HR ,65 bpm: prospective with end-diastolic triggering. HR .65 bpm or irregular heart rate: retrospective gating with dose modulation. For scanners that have a retrospective mode with adaptive dose modulation, this may be used as an alternative for fast HRs. This mode can be used to automatically tighten the dose modulation during retrospective acquisition. However, it is worth noting that the use of this mode should be performed with caution in irregular/variable HRs, where scanner may widen the modulation window and dose may increase significantly. In addition, dose modulation outside the acquisition window should be set at the lowest possible value if adjustable (this is vendor-specific but ranges from 4% to 20%), therefore lowering overall dose further in retrospective acquisition. For scanner types that only use prospective helical scanning during diastolic phase at HR ,65 bpm, retrospective gating should be used above this threshold. In this setting, the following protocol is recommended. Regular HR ,65 bpm: prospective helical scanning with enddiastolic triggering. HR .65 bpm or irregular HR: retrospective gating with dose modulation. Where a variable helical pitch function is available, this allows seamless switching to non-gated scanning with increased pitch outside the coverage for the heart. For example, for thorax only, one would scan variable helical pitch caudocranially. ECG synchronization only used within the heart, followed by ungated acquisition for the rest of the thorax to the apices. If extended coverage of whole aorta is required, scan can be performed craniocaudally, using ECG synchronization in the thoracic portion, and then changing pitch and switching to ungated acquisition for the remaining abdominal and pelvic coverage. Single-source systems: broad detector coverage-128-, 256-or 320-detector-row scanners (including "256and 640-slice" systems) For large detectors systems with increased z-axis coverage, the scanning time can be reduced. 128-detector-row scanners usually have a detector width of 8 cm. Imaging the entire thoracic aorta therefore requires more than one transverse section (and often 3-4 sections). It is recommended that a prospectively triggered approach is used, as with the 64-slice scanners. Recommendations are as follows: Where the ability to switch from gated to non-gated scan acquisition is available, this should also be utilized to minimize dose. 320-detector systems have a detector width of 16 cm; this coverage may be adequate to image the thoracic aorta in 1-2 rotations, and with this rapid acquisition, ECG synchronization may not be required. Non-gated helical acquisition with the middle 8-cm coverage (160 3 0.5 mm) can be used to image the thoracic aorta in 1-2 heartbeats with motion-free imaging of the aorta. However, if dedicated coronary assessment is also required (e.g. in the context of known AAS or a high pre-test probability), then prospectively triggered ECG synchronization (HR ,65 bpm 70-80% single pulse per volume, HR .65 bpm 30-80% single pulse per volume) covering the entire thoracic aorta should be performed. This will require 2 volumes of 16 cm (320 3 0.5 mm) for adequate coverage. Several investigators have reported similar protocols previously. [bib_ref] Initial experience with a chest pain protocol using 320-slice volume MDCT, Hein [/bib_ref] [bib_ref] Prospective ECG-gated 320-row CT angiography of the whole aorta and coronary arteries, Li [/bib_ref] Dual-source systems Dual-source systems have improved temporal resolution and thus allow higher tolerance for accelerated HRs. If temporal resolution ,100 ms can be achieved, HR-dependent prospectively ECG-synchronization protocols can be applied. For example, if the HR is ,65 bpm, the optimum phase is at end diastole. For HRs .65 bpm, the optimum phase is at end systole. [bib_ref] Robustness of end-systolic reconstructions in coronary dual-source CT angiography for high heart..., Adler [/bib_ref] [bib_ref] Optimal systolic and diastolic reconstruction windows for coronary CT angiography using dualsource..., Seifarth [/bib_ref] In a system that allows for high-pitch acquisition in conjunction with wide detector arrays, traditional ECG synchronization may not be required. [bib_ref] Lowdose, 128-slice, dual-source CT coronary angiography: accuracy and radiation dose of the..., Alkadhi [/bib_ref] [bib_ref] High-pitch dual-source CT angiography of the whole aorta without ECG synchronisation: initial..., Beeres [/bib_ref] [bib_ref] Thoracic aorta: prospective electrocardiographically triggered CT angiography with dual-source CT-feasibility, image quality,..., Blanke [/bib_ref] [bib_ref] High-pitch dual-source CT angiography of the aortic valve-aortic root complex without ECGsynchronization, Karlo [/bib_ref] [bib_ref] Dual source multidetector CT-angiography before transcatheter aortic valve implantation (TAVI) using a..., Wuest [/bib_ref] For example, using a pitch of .3 and gantry rotation time 0.28 s permits coverage of 9.6-11.6 cm s 21 with reduced radiation dose. [bib_ref] High-pitch dual-source CT angiography of the whole aorta without ECG synchronisation: initial..., Beeres [/bib_ref] [bib_ref] High-pitch dual-source CT angiography of the aortic valve-aortic root complex without ECGsynchronization, Karlo [/bib_ref] [bib_ref] Dual-source spiral CT with pitch up to 3.2 and 75 ms temporal..., Flohr [/bib_ref] CONCLUSION This document outlines the different methods of scan acquisition with an emphasis on the importance of performing motionfree imaging of the aorta in suspected AAS in order to provide accurate diagnosis. This is by no mean an exhaustive coverage of the multiple scanners available but should encompass most scanners being used routinely in UK practices. It serves to outline the basic principle of motion-free aortic imaging using the currently available evidence and expert opinions of the BSCI/BSCCT. With continuing rapid advancement of CT technologies and the need to standardize image acquisition coupled with an obligation for dose optimization, these recommendations should allow centres to adopt protocols specific to their scanners for timely and accurate assessment using the basic principles outlined in this document. Acquisition is only one aspect of the scan and to properly implement this imaging strategy, centres must also adopt appropriate reporting facilities (e.g. picture archiving and communication system must be able to manage ECG-gating data sets, including handling of multiphasic reconstruction of retrospective acquisition), radiographer's training, as well as reporting expertise. In terms of implementation, it has been shown that application of ECG gating by adequately trained staff has no impact on the workflow of the CT examination in acute setting. [bib_ref] Comparison of retrospectively ECG-gated and nongated MDCT of the chest in an..., Schertler [/bib_ref] We envisage that definitive diagnosis of ascending aortic pathology, eliminating false-positive scans, should become routine practice and that no patient should undergo sternotomy/ thoracotomy or other intervention without an optimal AAS CT scan. [fig] Figure 1: Risk stratification for acute aortic syndrome and appropriate management strategy. [/fig] [fig] Figure 2: Ungated CT angiogram of the aorta demonstrating pulsation artefact (arrows). [/fig] [fig] Figure 3: Non-contrast CT demonstrating typical appearance of a hyperattenuating crescentic ring that can be seen in acute intramural haematoma (arrowheads). [/fig] [table] Table 1: Summary of scanning parameters for different types of CT scannersNon-gated helical acquisition with the middle 8-cm coverage (160 3 0.5 mm) can be used to image the thoracic aorta in 1-2 heartbeats with motion-free imaging of the aortaExceptionIf dedicated coronary assessment is required (e.g. in the context of known AAS or a high pre-test probability), then use followingHR , 65 Prospectively triggered ECG synchronization with 70-80% single pulse per volume HR . 65 Prospectively triggered ECG synchronization with 30-80% single pulse per volume Dual source HR-dependent HR-dependent prospectively ECG-synchronization protocols can be applied similar to the systems above HR , 65 Prospective gating with end-diastolic acquisition HR . 65 Prospective gating with end-systolic acquisition In a system that allows for high-pitch acquisition in conjunction with wide detector arrays, traditional ECG synchronization may not be required e.g. a pitch of .3 and gantry rotation time 0.28 s permit coverage of 9.6-11.6 cm s 21 AAS, acute aortic syndrome; ECG, electrocardiogram; HR, heart rate. Regular HR ,75 bpm: prospective with end-diastolic triggering. HR .75 bpm or irregular HR: prospective with end-systolic triggering. [/table]	None	None	Accurate and timely assessment of suspected acute aortic syndrome is crucial in this life-threatening condition. Imaging with CT plays a central role in the diagnosis to allow expedited management. Diagnosis can be made using locally available expertise with optimized scanning parameters, making full use of recent advances in CT technology. Each imaging centre must optimize their protocols to allow accurate diagnosis, to optimize radiation dose and in particular to reduce the risk of false-positive diagnosis that may simulate disease. This document outlines the principles for the acquisition of motion-free imaging of the aorta in this context.
7fba2c74f6b40429b257fc1b76b3e322ddd73af0	pubmed	Universal Hepatitis B Vaccination in Adults Aged 19–59 Years: Updated Recommendations of the Advisory Committee on Immunization Practices — United States, 2022	Universal Hepatitis B Vaccination in Adults Aged 19–59 Years: Updated Recommendations of the Advisory Committee on Immunization Practices — United States, 2022 [bib_ref] Prevention of hepatitis B virus infection in the United States: recommendations of..., Schillie [/bib_ref] # Background Hepatitis B is a vaccine-preventable, communicable disease of the liver caused by HBV. HBV is transmitted through percutaneous (i.e., puncture through the skin) or mucosal (i.e., direct contact with mucous membranes) exposure to infectious blood or body fluids. Since HepB vaccine was introduced in 1982, the number of reported hepatitis B cases has declined substantially. However, despite reductions in hepatitis B incidence during the past 4 decades, which were achieved through incremental expansion of groups for whom HepB vaccination is recommended, progress in recent years on further reducing acute hepatitis B cases has stalled (3). Incident hepatitis B declined from 26,654 reported cases (172,700 estimated actual cases) in 1985 to a low of 2,791 reported cases (18,100 estimated actual cases) in 2014 [bib_ref] Estimating acute viral hepatitis infections from nationally reported cases, Klevens [/bib_ref]. In 2019, a total of 3,192 cases of acute hepatitis B were reported to CDC, corresponding to 20,700 estimated acute infections (95% CI . The most commonly reported risk behaviors and exposures were injection drug use (35%), multiple sex partners (23%), and surgery (10%), followed by other sexual and bloodborne risk behaviors; risk behavior and exposure information were missing for 37.1% of cases. There are an estimated 880,000 (95% CI = 580,000-1,170,000) prevalent chronic HBV infections in the United States based on 2013-2018 National Health and Nutrition Examination Survey data, with a modeled estimate of 1.89 million (range = 1.49-2.40 million) that accounts for potential underrepresentation of the non-U.S.-born population [bib_ref] An updated assessment of chronic hepatitis B prevalence among foreign-born persons living..., Wong [/bib_ref]. In 2018, the reported HepB vaccination coverage (≥3 doses) was 30.0% among adults aged ≥19 years, only a small increase over the past 4 decades (7). # Methods During September 2019-October 2021, the ACIP* Hepatitis Work Group † (Work Group) held monthly conference calls to review and discuss scientific evidence relevant to the use of HepB vaccines in a universal adult vaccination recommendation. The Work Group identified the following outcomes of interest for evaluation: incidence of hepatitis B, morbidity related to hepatitis B, mortality related to hepatitis B, and vaccine-related serious adverse events. Data on universal HepB vaccination outcomes and safety were summarized based on findings from a systematic review of the literature completed on ## Summary of key findings The scientific literature was searched through a systematic review using PubMed, Medline, Embase, CINAHL, and Cochrane Library databases from January 1, 2006, through September 10, 2020. Search terms included "hepatitis b vaccines," "adult," "routine," and "universal." To qualify as a candidate for inclusion in the review, a study had to discuss adult HepB vaccination. Studies were excluded if they did not address the adult population, were non-English language, discussed HepB vaccines not licensed in the United States, or if data could not be abstracted. The search identified 3,226 studies, 263 of which were deemed eligible and informed this review. Rates of reported acute hepatitis B have not notably decreased for over 1 decade, with 20,700 estimated infections in . None of the identified studies reported hepatitis B incidence, morbidity, and mortality when comparing universal and risk-based adult HepB vaccination. The safety of single-antigen 3-dose HepB vaccines has been established [bib_ref] Prevention of hepatitis B virus infection in the United States: recommendations of..., Schillie [/bib_ref]. PreHevbrio was approved by FDA in 2021 and recommended by ACIP in 2022. Little or no difference in seroprotection or occurrence of serious adverse events or mild adverse events (GRADE evidence type 3; low certainty evidence) was found for PreHevbrio in comparison with a 3-dose, singleantigen vaccine (Engerix-B), and serious adverse events were rare for both vaccines. The 2-dose HepB vaccine (Heplisav-B) was approved by FDA in 2017 and recommended by ACIP in 2018. No difference in occurrence of serious adverse events (GRADE evidence type 1; high certainty evidence) was found for Heplisav-B compared with a 3-dose vaccine (Engerix-B), and serious adverse events were rare for both vaccines [bib_ref] Recommendations of the Advisory Committee on Immunization Practices for use of a..., Schillie [/bib_ref]. ## Rationale for recommendations Approximately one half of acute hepatitis B cases reported in 2019 occurred among persons aged 30-49 years . The number of cases of acute hepatitis B has increased among adults aged ≥40 years, particularly among those aged 40-49 years, for whom the rate of reported cases increased from 1.9 per 100,000 population in 2011 to 2.7 per 100,000 population in 2019 . The rate among adults aged 50-59 years increased 45.5% during the same period (from 1.1 to 1.6 per 100,000 population) and accounted for 22.2% of reported cases in 2019. Acute HBV infections among adults leads to chronic hepatitis B disease in an estimated 2%-6% of cases. HepB vaccination coverage among adults aged ≥19 years is low. In 2018, self-reported HepB vaccination coverage (≥3 doses) among adults aged ≥19 years was 30.0% (7). HepB vaccination coverage (≥3 doses) was 40.3% for adults aged 19-49 years and 19.1% for adults aged ≥50 years. During 2013-2018, 21.4% (95% CI = 20.2%-22.6%) of adults aged ≥25 years had vaccine-induced immunity to hepatitis B (5). HepB vaccination coverage among adults with risk factors has been suboptimal. In 2018, self-reported coverage (≥3 doses) was 33.0% among adults with chronic liver disease, 38.9% among travelers to countries where HBV infections have been endemic since 1995, 33.0% among adults with diabetes aged 19-59 years, and 67.2% among health care personnel (7). In a national survey of 433 family medicine physicians and 420 internal medicine physicians to assess their barriers to adult HepB vaccination, 68% of physicians cited patients' nondisclosure of risk factors as a barrier, and 44% felt there was inadequate time to routinely assess patients for risk factors [bib_ref] Physician practices regarding adult hepatitis B vaccination: a national survey, Daley [/bib_ref]. A universal recommendation for HepB vaccination could increase the number of persons who receive vaccination before the onset of chronic liver disease and other comorbidities (e.g., obesity or diabetes) that might make vaccination less effective. For example, patients with chronic liver disease are known to have decreased immune response to HepB vaccination [bib_ref] Safety and efficacy of hepatitis B vaccination in cirrhosis of liver, Roni [/bib_ref]. Among the 3,192 case reports of acute hepatitis B received by CDC for 2019, risk behavior and exposure data were missing for 1,183 (37.1%). Risk factors assessed under prior recommendations for HepB vaccination include potential criminal or stigmatizing behavior (e.g., injection-drug use, incarceration, or multiple sex partners), limiting the effectiveness of provider risk assessment [bib_ref] Hepatitis B vaccination uptake in hard-to-reach populations in London: a cross-sectional study, Taylor [/bib_ref] [bib_ref] A blind spot? Confronting the stigma of hepatitis B virus (HBV) infection-a..., Mokaya [/bib_ref]. A universal vaccination recommendation eliminates the need for risk assessment before vaccination. Racial and ethnic disparities exist among those who become infected with HBV. In 2005, acute hepatitis B incidence among non-Hispanic Black Americans was approximately twice that among several other racial and ethnic populations (3). In 2019, the rate of HBV infection among non-Hispanic Black adults was triple that of Asian or Pacific Islander adults and approximately twice that of Hispanic adults (3). Rates of hepatitis B among children and adolescents of all races and ethnicities converged to a lower rate after a universal vaccination strategy was implemented for this age group (3). ## Resource use An economic model was used to estimate the health improvements that are expected to result from universal adult HepB vaccination [bib_ref] Assessing the cost-utility of universal hepatitis B vaccination among adults, Hall [/bib_ref]. One measure of cost-effectiveness, the incremental cost-effectiveness ratio (ICER), was calculated at $153,000 per quality-adjusted life-year (QALY) gained for all adults aged ≥19 years. A sub-analysis performed for adults aged 19-59 years yielded an ICER of $117,000 per QALY gained. § Increased vaccination coverage resulting from the modeled vaccination intervention strategies resulted in better § https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-11-2-3/02-HepWG-weng-508.pdf health outcomes; the average QALYs gained, life-years gained, number of acute HBV infections averted, and number of hepatitis B-related deaths averted all increased as vaccination coverage in the intervention strategy increased [bib_ref] Assessing the cost-utility of universal hepatitis B vaccination among adults, Hall [/bib_ref]. Among the cohort aged ≥60 years, hepatitis B incidence is markedly lower (0.6 cases per 100,000 population in 2019); thus, the number of preventable HBV infections in that age group is lower than for those aged 19-59 years. ## Recommendations HepB vaccination is recommended for adults aged 19-59 years and adults aged ≥60 years with risk factors for hepatitis B. Adults aged ≥60 years without known risk factors for hepatitis B may also receive HepB vaccines (Box). Infants and all other persons aged <19 years are already recommended to receive HepB vaccines (2). ## Clinical guidance ACIP recommends that adults aged 19-59 years and adults aged ≥60 years with risk factors for hepatitis B should receive HepB vaccines, and that adults aged ≥60 years without known risk factors for hepatitis B may receive HepB vaccines. In previous HepB vaccine recommendations, providers were advised to administer HepB vaccine to all patients who requested it. The new language for adults aged ≥60 years without known risk factors is intended to prompt all providers to offer HepB vaccination to patients in that cohort, rather than wait for a patient to request vaccination, thus shifting the responsibility of initiating the consideration of HepB vaccination from the patient to the provider. Persons who have completed a HepB vaccination series at any point or who have a history of HBV infection should not receive additional HepB vaccination, although there is no evidence that receiving additional vaccine doses is harmful. ¶ However, there are cases where revaccination might be indicated as specified in the 2018 ACIP recommendation (e.g., nonresponder infants born to persons testing positive for hepatitis B surface antigen [HBsAg], health care providers, and persons on hemodialysis) [bib_ref] Prevention of hepatitis B virus infection in the United States: recommendations of..., Schillie [/bib_ref]. Providers should only accept dated records as evidence of HepB vaccination. Vaccination of persons immune to HBV infection because of current or previous infection or HepB vaccination does not increase the risk for adverse events. However, in settings in which the patient population has a high rate of previous HBV infection, prevaccination testing, which may be performed concomitantly with administration of the first dose of vaccine, might reduce costs by avoiding complete vaccination of persons who are ¶ https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html https://cdafound.org/polaris/ (Accessed November 19, 2021). ## Box. persons recommended to receive hepatitis b vaccination ## All infants ## Persons aged <19 years ## Adults aged 19-59 years Adults aged ≥60 years with risk factors for hepatitis B: - Persons at risk for infection by sexual exposure ï Sex partners of persons testing positive for HBsAg ï Sexually active persons who are not in a long-term, mutually monogamous relationship (e.g., persons with more than one sex partner during the previous 6 months) ï Persons seeking evaluation or treatment for a sexually transmitted infection ï Men who have sex with men - Persons at risk for infection by percutaneous or mucosal exposure to blood ï Persons with current or recent injection drug use ï Household contacts of persons testing positive for HBsAg ï Residents and staff members of facilities for persons with developmental disabilities ï Health care and public safety personnel with reasonably anticipated risk for exposure to blood or blood-contaminated body fluids ï Persons on maintenance dialysis, including incenter or home hemodialysis and peritoneal dialysis, and persons who are predialysis ï Persons with diabetes at the discretion of the treating clinician - Others ï International travelers to countries with high or intermediate levels of endemic hepatitis B virus infection (HBsAg prevalence of ≥2%) ï Persons with hepatitis C virus infection ï Persons with chronic liver disease (including, but not limited to, persons with cirrhosis, fatty liver disease, alcoholic liver disease, autoimmune hepatitis, and an alanine aminotransferase or aspartate aminotransferase level greater than twice the upper limit of normal) ï Persons with HIV infection ï Persons who are incarcerated ## Adults aged ≥60 years without known risk factors for hepatitis b may receive hepatitis b vaccines Abbreviation: HBsAg = hepatitis B surface antigen. ## Summary What is already known about this topic? Vaccination with hepatitis B (HepB) vaccines shows wellestablished safety and efficacy. However, because of risk factor-based approaches of previous vaccination recommendations, coverage among adults has been suboptimal. What is added by this report? In addition to groups for whom HepB vaccination is already recommended, the Advisory Committee on Immunization Practices recommends that all adults aged 19-59 years should receive HepB vaccines. What are the implications for public health practice? Universal adult HepB vaccination through age 59 years removes the need for risk factor screening and disclosure and could increase vaccination coverage and decrease hepatitis B cases. already immune. Prevaccination testing consists of testing for HBsAg, antibody to HBsAg (anti-HBs), and antibody to hepatitis B core antigen (anti-HBc). The presence of HBsAg indicates current HBV infection. The presence of anti-HBs is generally interpreted as indicating immunity, either from HepB vaccination after a complete series or after recovery from HBV infection. The presence of total anti-HBc indicates previous or ongoing infection with HBV. Detailed interpretations of serologic markers for HBV infection are available [bib_ref] Prevention of hepatitis B virus infection in the United States: recommendations of..., Schillie [/bib_ref]. Lack of access to serologic testing should not be a barrier to vaccination of susceptible persons, especially in populations that are difficult to reach. Testing is not a requirement for vaccination, and in settings where testing is not feasible, vaccination of persons recommended to receive the vaccine should continue [bib_ref] Prevention of hepatitis B virus infection in the United States: recommendations of..., Schillie [/bib_ref]. The safety and effectiveness of Heplisav-B and PreHevbrio have not been established in adults on hemodialysis . Data are not available to assess the effects of Heplisav-B and PreHevbrio on the breastfed infant or on milk production and excretion. Data on Heplisav-B and PreHevbrio are currently insufficient to inform vaccine-associated risks in pregnancy. Thus, providers should vaccinate pregnant women needing HepB vaccination with Engerix-B, Recombivax HB, or Twinrix. Abbreviations: ACIP = Advisory Committee on Immunization Practices; HepA = hepatitis A; HepB = hepatitis B. * If the HepB vaccination schedule is interrupted, the series does not need to be restarted. If a 3-dose series is interrupted after the first dose, the second dose should be administered as soon as possible; the second and third doses should be separated by an interval of ≥8 weeks. If only the third dose has been delayed, it should be administered as soon as possible. The final dose of a 3-dose series must be administered ≥8 weeks after the second dose and ≥16 weeks after the first dose; the minimum interval between the first and second doses is 4 weeks. Inadequate doses of hepatitis B vaccine or doses received after a shorter-than-recommended dosing interval should be readministered, using the correct dosage or schedule. Vaccine doses administered ≤4 days before the minimum interval or age are considered valid. Because of the unique accelerated schedule for Twinrix (https://www.fda.gov/media/119351/download), the 4-day guideline does not apply to the first 3 doses of this vaccine when administered on a 0-day, 7-day, 21-30-day, and 12-month schedule. PreHevbrio (https://www.fda.gov/media/154561/download) is a three-antigen HepB vaccine approved by the Food and Drug Administration in 2021 and recommended by ACIP in 2022. † A 2-dose schedule of Recombivax HB adult formulation (10 μg) (https://www.fda.gov/media/74274/download) is licensed for children and adolescents aged 11-15 years. When scheduled to receive the second dose, persons aged ≥16 years should be switched to a 3-dose series, with doses 2 and 3 consisting of the pediatric formulation administered on an appropriate schedule. § Engerix-B (https://www.fda.gov/media/119403/download) for adults on hemodialysis and is administered as a series of 4 doses (2 mL each) as a single 2-mL dose or as two 1-mL doses on a 0-, 1-, 2-, and 6-month schedule. Recombivax HB for adults on dialysis is a 3-dose series. ¶ The safety and effectiveness of Heplisav-B and PreHevbrio have not been established in adults on hemodialysis. Data are not available to assess the effects of Heplisav-B and PreHevbrio on breastfed infants or on maternal milk production and excretion. Data on Heplisav-B (https://www.fda.gov/media/108745/download) and PreHevbrio are currently insufficient to inform vaccine-associated risks in pregnancy. Thus, providers should vaccinate pregnant persons needing HepB vaccination with Engerix-B, Recombivax HB, or Twinrix. [fig] FIGURE.: Rates of reported acute hepatitis B virus infection, by age group -United States, 2004Source: https://www.cdc.gov/hepatitis/statistics/2019surveillance/Figure2.4.htm [/fig] [table] TABLE: Recommended doses and schedules of hepatitis B vaccine for adults aged ≥18 years and persons aged 11-19 years, by vaccine type and age group* HepB vaccine*/Age group, yrsDose (μg) Volume (mL) Schedule [/table]	None	http://www.amjtransplant.org/article/S1600613522082533/pdf	Hepatitis B (HepB) vaccines have demonstrated safety, immunogenicity, and efficacy during the past 4 decades (1,2). However, vaccination coverage among adults has been suboptimal, limiting further reduction in hepatitis B virus (HBV) infections in the United States. This Advisory Committee on Immunization Practices (ACIP) recommendation expands the indicated age range for universal HepB vaccination to now include adults aged 19-59 years. Removing the risk factor assessment previously recommended to determine vaccine eligibility in this adult age group (2) could increase vaccination coverage and decrease hepatitis B cases.
58ba2a1af94be26401d7ca477bb43c3158fade18	pubmed	The Permanent Vegetative State	The Permanent Vegetative State ## He permanent vegetative state (pvs) Apatient in a continuing vegetative state will enter a Permanent vegetative state when the diagnosis of irreversibility can be established with a high degree of clinical certainty. It is a diagnosis which is not absolute hut based on probabilities. Nevertheless, it may reasonably be made when a patient has been in a continuing vegetative state following head injury for more than 12 Months or following other causes of brain damage for more than six months. There shall be an established cause for the condition. It may be due to acute cerebral injury, degenerative conditions, metabolic disorders or developmental malformations. ## ? The persisting effects of sedative, anaesthetic or neuromuscular blocking drugs shall be excluded. It is recognised that drugs may have been the original cause of an acute cerebral injury, usually hypoxic, but their continuing direct effect must be excluded either by passage of time or by appropriate analysis of body fluids. Reversible metabolic causes shall be corrected or excluded as the cause. Metabolic disturbance may occur during the course of a vegetative state and are an inevitable consequence of the terminal stage but should have been ruled out as causative. Clinical criteria 1 There shall be no evidence of awareness of self or environment at any time. There shall be no volitional response to visual, auditory, tactile or noxious stimuli. There shall be no evidence of language comprehension or expression. 2 There shall be the presence of cycles of eye closure and eye opening which may simulate sleep and waking. 3 There shall be sufficiently preserved hypothalamic and brain stem function to ensure the maintenance of respiration and circulation. These three clinical requirements shall all be fulfilled for the diagnosis to be considered. Other clinical features are: ? There will be incontinence of bladder and bowel, spontaneous blinking and usually retained pupillary responses and corneal responses. The response to ice water caloric testing will be a tonic eye movement which can be conjugate or dysconjugate. ? There will not be nystagmus in response to ice water caloric testing, the patient will not have visual fixation, be able to track moving objects with the eyes or show a 'menace' response. ? There may be occasional movements of the head and eyes towards a peripheral sound or movement Journal of the Royal College of Physicians of London Vol. 30 No. 2 March/April 1996 and there may be movement of the trunk and limbs in a purposeless way; some patients may appear to smile and the eyes may water, there may be a 'grimace' to painful stimuli. There may be startle myoclonus. These motor activities shall be inconsistent, non-purposeful and explicable as a reflex response to external stimuli. Deep tendon reflexes may be present and reduced, normal or brisk; plantar responses may be flexor or extensor; there may be clonus and other signs of spasticity. There may be roving eye movements. Differential diagnosis [fig_ref] Table 1: Differentiation of vegetative state from other conditions [/fig_ref] It is essential to distinguish the vegetative state from brain stem death, coma and the locked-in syndrome. The differentiation of these conditions is on clinical grounds; there is no evidence at present that electroencephalography, evoked potentials, computed tomography (CT) of the cranium or magnetic resonance imaging (MRI) of the cerebrum improve upon the clinical diagnosis. Patients who are in a permanent vegetative state may show changes of cortical atrophy and hydrocephalus on CT head scan, and positron emission tomography (PET) will show a reduction in cerebral metabolism; but neither finding is diagnostic of the permanent vegetative state. ## The time course There is evidence that the factors which influence the prognosis of patients in a continuing vegetative state are the cause of the condition and the length of time for which it has continued. In patients who are in a continuing vegetative state following causes other than head injury there is very little hope of recovery of sentience after three months and none after six months. In patients who are in a continuing vegetative state after head injury the chances of recovery after six months are extremely low and, after 12 months non-existent. It is suggested that, whenever head injury is present, even when there is additional severe trauma, the longer of these time intervals be taken before the continuing vegetative state is termed 'permanent'. Thus, the diagnosis of the permanent vegetative state should not be made before six months following non-head injury brain damage or 12 months following head injury. The management of the patient in a vegetative state Medical care Prior to the diagnosis of a permanent vegetative state it is imperative that patients have a high quality of care with appropriate nursing or home care and that oxygenation, circulation and nutrition are maintained and complicating factors such as hypoglycaemia and infection corrected. Until there is firm scientific evidence that treatment, in terms of specific medical, physiotherapeutic or rehabilitative activities improves the outcome of patients in a continuing vegetative state it is a matter of clinical judgement as to the most appropriate measures, their application and the length of time they should be pursued. The medical staff must advise the relatives and carers of the situation during the continuing vegetative state. Examination When the diagnosis of a permanent vegetative state is being considered it is obligatory that the patient should be examined by two medical practitioners experienced in assessing disturbances of consciousness. They should undertake their own assessment separately and should write clearly the details of that assessment and their conclusion in the notes. They must ask medical and other clinical staff and relatives or carers about the reactions and responses of the patient and it is important that the assessors shall take into account the descriptions and comments given by relatives, carers and nursing staff who spend most time with the patient. The medical practitioners shall separately perform a formal neurological examination and consider the results of those investigations which have been undertaken to identify the cause of the condition. It is helpful for nursing staff and relatives to be present during the examination; their role as responsible witnesses who spend a much longer time with the patient than can the medical practitioners must be recognised. Re-assessment It is to be emphasised that there is no urgency in making the diagnosis of the permanent vegetative state. If there is any uncertainty in the mind of the assessor then the diagnosis shall not be made and a reassessment undertaken after further time has elapsed. The most important role of the medical practitioner in making the diagnosis is to ensure that the patient is not sentient and, in this respect, the views of nursing staff, relatives and carers are of considerable importance and help. Final definitive diagnosis and decisions concerning life support When the diagnosis of a permanent vegetative state has been established by (a) identification of the cause for the syndrome; (b) the clinical state of the patient; and (c) the lapse of time, recovery cannot be achieved and further therapy is futile. It merely prolongs an insentient life for the patient and a hopeless vigil for relatives and carers. The clinical team of doctors and nurses, augmented when necessary by colleagues, should formally review the clinical evidence. The decision, when made on full evidence that the situation is, in lay terms, 'hopeless' should be communicated sensitively to the relatives who are then given time to consider the implications, including the possibility of withdrawing artificial means of administering food and fluid. At present the courts require, as a matter of practice, that the decision to withdraw nutrition and hydration, resulting in the inevitable death of the patient, should be referred to the court before any action is taken [bib_ref] The persistent vegetative state: information on prognosis allows decisions to be made..., Howard [/bib_ref]. A decision to withdraw other life sustaining medication such as insulin for diabetes may also need to be referred to the courts because the legal position on this is uncertain. By contrast, decisions not to intervene with cardio-pulmonary resuscitation or to prescribe antibiotics, dialysis and insulin are clinical decisions. Further, those responsible for the patient's care must take account of, and respect, the patient's own views when known, whether these are formally recorded in a written document (or advance directive) ?r not [bib_ref] Advanced directives: like a will, everybody should have one, Doyal [/bib_ref]. When the medical team is agreed on the course to be taken the relatives should be counselled and their views sought, but (subject to court involvement) the decision is for those professionals who have the responsibility for the care of the patient. [table] Table 1: Differentiation of vegetative state from other conditions [/table]	None	None	None
16e3c146c3d3e51946d82885c95bee3f67bf8ad4	pubmed	Clinical practice guideline for breast-conserving surgery in patients with early-stage breast cancer: Chinese Society of Breast Surgery (CSBrS) practice guidelines 2021	Clinical practice guideline for breast-conserving surgery in patients with early-stage breast cancer: Chinese Society of Breast Surgery (CSBrS) practice guidelines 2021 ## 1.1 Patient wishes to preserve her breast I # Discussion A considerable amount of evidence from the scientific literature supports the safety and efficacy of combining BCS with radiotherapy in the early stages of breast cancer. In the National Surgical Adjuvant Breast and Bowel Project B-06 trial, a total of 1851 patients diagnosed with Stage I or II breast cancer were randomly allocated to three study arms, namely total mastectomy, BCS, and BCS with radiotherapy. According to results of the long-term followup that lasted 20 years, it was found that disease-free survival, metastasis-free survival, and overall survival did not differ significantly between the three arms.During the same period, in the Milan I trial, seven hundred and one patients with <T2 breast cancers (tumor size measuring <2 cm) were randomized to two arms: radical mastectomy and BCS with radiotherapy. The 20-year follow-up results indicated that there was no significant difference between the overall survival of the two arms. However, the cumulative recurrence rate was higher in the BCS + radiation arm (8.8%) when compared with the mastectomy arm (2.3%).A short-term follow-up study of 95 Chinese patients by Li et alrevealed that, after an average follow-up of 17 months, the 2-year local recurrence rate of Stage I or II breast cancer after BCS was only 1.4%, with no metastases or deaths. Chen et alused propensity-score matching to compare the clinical outcomes after a median follow-up of 67 months of 2866 patients with early-stage breast cancer who had undergone BCS or mastectomy in China; they confirmed the safety and efficacy of BCS. Recently, BCS has been recommended internationally as the standard surgical treatment for eligible breast cancer patients in the early stages.The panel members agreed that, provided acceptable cosmetic outcomes could be expected, BCS is suitable for patients with clinical Stage I or II disease or T2 tumors who wish to preserve their breasts. ## The result of early breast cancer trialists' collaborative Group meta-analysis revealed that neoadjuvant chemotherapy can significantly increase the BCS rate. The 10year cumulative local recurrence rate was slightly, but not significantly, higher in the neoadjuvant chemotherapy than in the untreated group (15.1% vs. 11.9%, P = 0.10). No significant differences were observed in the 10-year cumulative rates of breast cancer-related deaths between patients who did and did not receive neoadjuvant chemotherapy (27.5% vs. 24.8%, P = 0.15).Therefore, for patients who were clinically diagnosed with Stage III breast cancer or >T2 tumors, it is possible to administer neoadjuvant chemotherapy to downstage the tumor, and thus increase the chances of being eligible for BCS. The panel members considered that, in clinical practice, it is not always easy to accurately measure the degree of shrinkage of a tumor after neoadjuvant chemotherapy. Thus, there was a lack of consensus in the panel regarding the optimal extent of surgery in patients with breast cancer who have received neoadjuvant chemotherapy. However, there was agreement that achieving negative surgical margins is mandatory in this situation. The panel considered that the following factors are potential risk factors for local recurrence after BCS: breast cancer located in the central portion; bloody discharge from the nipple; large tumor (eg, >T2); multifocal breast cancer; multicentric breast cancer; young age (<35 years); and radiotherapy contraindicated (eg, active connective tissue disease). However, there is no high level evidence that the abovementioned factors are contraindications to BCS. Achieving negative surgical margins is mandatory for successful BCS. There is evidence that positive surgical margins are closely associated with local recurrence. Intra-operative gross inspection,imprint cytology,intra-operative specimen imaging,and novel devicescan also reportedly reduce the rates of positive margins. However, the panel does not recommend these approaches because of the lack of high-level evidence. Intra-operative frozen section analysis (FSA) is reportedly capable of reducing the rates of margin positivity and second surgeries.The panel considers that FSA is widely used in clinical practice in China and supports its use for intra-operative margin assessment. The panel take a cautious attitude toward performing margin assessment only by post-operative formalin-fixed, paraffin-embedded examination. Both lumpectomy margins and cavity margins are suitable for the margin assessment of BCS. Lumpectomy margins are assessed on the surface of the tumor-containing specimen. There are two techniques that can be used for margin assessment: the perpendicular inked and tangential shaved techniques.Cavity margins are assessed by performing a biopsy (tissue sampling) of the residual cavity (or the wall of the tumor bed) after tumor removal. Well-designed studies suggesting that cavity margin assessment alone is capable of achieving excellent local control have been published.A meta-analysis has demonstrated that the "no-ink on tumor" is significantly associated with a reduced local recurrence rate and that wider surgical margins do not further improve the local control rate.Furthermore, the increased risk of local recurrence associated with positive surgical margins is not nullified by post-operative radiotherapy. There is no evidence that different margin widths should be considered for patients of different ages or with different molecular subtypes. A real-world study (CSBrS-005) conducted by the CSBrS in 2019 revealed that 88.2% (1530/1734) of patients who had undergone BCS had margin widths >5 mm.Others have reached consensus on diagnosing negative surgical margins for infiltrating ductal carcinoma and ductal carcinoma in situ by "no-ink on tumor" and "≥2 mm," respectively.The panel considered these standards inappropriate for China and has not recommended them for routine use. The panel agreed that whole-breast irradiation (RT) is necessary after BCS. However, the CALGB9493 trial showed a small improvement of locoregional recurrence rate in BCS patients who received RT (RT: 2% (95% confidence interval [CI]: 1% to 4%) vs. no-RT: 10% (95% CI: 7% to 15%) ), but no statistically significant differences in 10-year distant metastasis and overall survival between patients with low-risk BCS who did and did not undergo RT.In contrast, the PRIME II trial showed that, in patients aged ≥65 years with early-stage and hormone receptor-positive disease who underwent BCS, the 5-year ipsilateral recurrence rates were 4.1% and 1.3% (P = 0.0002) in the no-RT and RT groups, respectively.Although this difference is statistically significant, the benefit is not clinically important. The panel suggested that RT might be forgone after BCS in certain situations related to the patients' preferences and comorbidities. The International Breast Cancer Study Group VI-VII trialThe CO-HO-RT trialrevealed that the risk of developing grade ≥2 radiation-induced subcutaneous fibrosis is similar in patients who receive concurrent vs. sequential RT and endocrine therapy, suggesting that concurrent use of these treatment modalities is safe. According to the 3.7-year follow-up data of the N9831 trial,concurrent use of RT and trastuzumab did not significantly increase cardiotoxicity, supporting the feasibility of the concurrent use of RT and anti-human epidermal growth factor receptor 2 (HER2) treatments. The panel recommended the concurrent use of RT and endocrine therapy, as well as anti-HER2 therapy if indicated. 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.	None	None	Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Department of Breast Surgery, Yat-sen Breast Tumor Hospital, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China; Department of Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
24f928cc3ffb147142889867590a2d44ca90da5a	pubmed	Clinical Guidelines for Diagnosis and Treatment of Botulism, 2021	Clinical Guidelines for Diagnosis and Treatment of Botulism, 2021 # Introduction background These evidence-based guidelines provide health care personnel with recommended best practices for diagnosing, monitoring, and treating botulism in the settings of conventional, contingency, and crisis standards of care. The following syndromes are described: foodborne botulism (exposure to botulinum neurotoxin in food), wound botulism (exposure to botulinum neurotoxin from a wound colonized with the bacteria), inhalational botulism (exposure to aerosolized botulinum neurotoxin, which could be caused intentionally), and iatrogenic botulism (exposure to botulinum neurotoxin by injection of high-concentration botulinum toxin for cosmetic or therapeutic purposes). These guidelines do not address syndromes of botulism caused by intestinal colonization by botulinum-toxin-producing Clostridia species (i.e., infant botulism and adult colonization botulism), which are inherently sporadic and have not occurred in outbreaks. Therefore, throughout the text, terms such as "botulism" and "patient with suspected botulism" refer to syndromes other than intestinal colonization. Contamination of foods with botulinum neurotoxin can occur unintentionally when botulinum spores germinate under appropriate conditions and produce toxin, or intentionally, when toxin is added directly to foods. Foodborne botulism outbreaks usually affect few persons. However, because large outbreaks are possible ("epidemic potential"), foodborne botulism is a public health emergency. Contamination of wounds with Clostridium botulinum and subsequent in situ botulinum toxin production is typically (in the United States) caused by unsanitary injection of a particular type of heroin (black tar heroin) subcutaneously or subdermally; although common-source heroin containing clostridial spores might affect groups of injectors, wound botulism does not have the epidemic potential of foodborne botulism. Purified botulinum toxin, produced and weaponized by military biological warfare programs of various countries, could be dispersed as an aerosol and cause inhalational botulism. This form of botulism, which does not occur naturally and has been reported once in a laboratory worker, could affect many persons. Diagnosis of botulism depends on high clinical suspicion and a thorough neurologic examination. The timeliness of diagnosis is crucial to successful treatment because botulinum antitoxin, the only specific therapy for botulism, must be administered to patients as quickly as possible. In the United States, botulinum antitoxin (to treat suspected botulism, other than infant botulism) is available emergently and free of charge from the federal government. Health departments and CDC provide emergency clinical consultations 24 hours per day and facilitate rapid antitoxin delivery for treatment of suspected botulism, other than infant botulism. For suspected cases of infant botulism, the California Department of Public Health Infant Botulism Treatment and Prevention Program provides clinical consultation and access to the specific antitoxin licensed for treatment of infant botulism. The recommendations in these guidelines address the conventional standard of care, in which medical resources are not limited, as well as settings of contingency and crisis standards of care, with limited medical resources. These guidelines focus on clinical management in the acute phase of illness and do not address long-term care, epidemiologic investigations, antitoxin for postexposure prophylaxis, and management of routine medical issues that are not specific to botulism. Clinicians, hospital administrators, state and local health officials, and planners can use the recommendations in these guidelines to assist in developing crisis protocols for national preparedness for botulism events ranging from sporadic (single) cases to large outbreaks. ## Pathophysiology of botulism Botulism is caused by toxins formed by the anaerobic, gram-positive bacterium C. botulinum and, rarely, by strains of closely related species (C. baratii and C. butyricum). These organisms form spores that are ubiquitous in the environment and capable of indefinitely surviving most naturally occurring conditions as well as boiling and other routine cooking practices. Spores are routinely ingested by humans but do not normally germinate in the intestine. Toxin is produced only when the spores germinate; this occurs under a rare confluence of circumstances that include anaerobic conditions, low acidity (pH >4.5), low salt and sugar content, and temperatures of 37°F-99°F (3°C-37°C), depending on the serotype. Botulinum toxins are the most potent biologic toxins known. Although the precise lethal dose for humans is unknown, extrapolations have been made from primate studies. The lethal doses for purified crystalline botulinum toxin type A for a 154-lb man are estimated to be 70 μg when introduced orally and 0.80-0.90 μg when inhaled. Lower doses were proposed in older studies. Seven antigenically distinct botulinum toxins have been identified (A, B, C, D, E, F, and G), all during ; most strains of C. botulinum produce only a single toxin, although strains producing two toxin types have been identified. In addition, two novel botulinum-toxin-like proteins have been identified from gene sequences and assembled: one from a C. botulinum isolate and one from an Enterococcus faecium isolate. All botulinum toxin types share a similar structure, consisting of a zinc-endopeptidase protein formed by a heavy chain of approximately 100,000 daltons and a light chain of approximately 50,000 daltons. Botulinum neurotoxin enters the vascular circulation (through ingestion, absorption from colonized wound or intestine, inhalation, or injection) and is transported to peripheral cholinergic nerve terminals, including neuromuscular junctions, postganglionic parasympathetic nerve endings, and peripheral ganglia. All toxin types produce a similar clinical syndrome of cranial nerve palsies followed by descending symmetric flaccid paralysis of variable severity and extent through similar pharmacological mechanisms at the neuromuscular junction. The sequence of botulinum neurotoxin activity at the neuromuscular junction includes heavy-chain binding to a neuronal cell followed by internalization by means of receptor-mediated endocytosis, translocation to the cytosol, and cleavage of the proteins (specific for each serotype) involved in the release of the neurotransmitter acetylcholine. The characteristic flaccid paralysis results from blocking acetylcholine transmission across the neuromuscular junction by inhibition of acetylcholine release from the presynaptic motor neuron terminal. The large molecular size of the botulinum toxin likely precludes its crossing the bloodbrain barrier to the central nervous system. Botulinum toxin might be transported to the central nervous system axonally, similar to tetanus toxin, which it resembles, although direct effects on the central nervous system have not been documented in humans. Recovery, which takes weeks to months, occurs after sprouting of new nerve terminals. Toxin serotypes A, B, E, and (more rarely) F cause human disease. Toxin type A produces the most severe syndrome, with the highest proportion of patients requiring mechanical ventilation. Toxin type B usually causes milder disease than type A. Only two cases of illness in humans from toxin type C and one outbreak caused by toxin type D have been reported, all in the 1950s. Although toxin type C blocks neuromuscular transmission in human tissue in laboratory experiments, this toxin type might not be absorbed in the human gastrointestinal tract. In studies of human tissue, toxin type D has been reported not to block neuromuscular transmission. No cases in humans have been reported from toxin type G (3). Toxin type E, usually associated with consumption of foods of aquatic origin, produces a syndrome of variable severity, which frequently includes gastrointestinal symptoms. Type F cases are rare and characterized by rapid progression, extensive paralysis, and respiratory failure but with earlier recovery. All toxin types readily produce botulism in experimental animal models. US Department of Health and Human Services/Centers for Disease Control and Prevention # Methods In 2015, CDC established a technical development group with experts in the clinical, epidemiologic, and laboratory aspects of botulism and related fields. To oversee and guide development of the guidelines, CDC also established an internal agency guideline steering committee comprising clinical, preparedness, and response experts. Together, the technical development group and the guidelines steering committee prioritized topic areas and determined the scope of the guidelines. Priorities included characterizing the clinical features of botulism, determining optimal monitoring of patients with suspected botulism, and establishing the efficacy and safety of botulinum antitoxin. Children and pregnant women were considered specifically. How botulism might uniquely affect these populations was considered throughout the process, including through systematic reviews on pediatric botulism and botulism in pregnant women, as well as presentations during two forums and a workshop. A committee comprising representatives from federal agencies, including the Assistant Secretary for Preparedness and Response, the Biomedical Advanced Research and Development Agency, the U.S. Department of Homeland Security, the U.S. Department of Defense, the Food and Drug Administration (FDA), and the National Institutes of Health, was briefed throughout the process of developing the guidelines. Physicians from CDC and academia conducted six systematic reviews on the clinical features of botulism, pediatric botulism, botulism in pregnancy, epidemiology of botulism outbreaks, botulinum antitoxin efficacy, and allergic reactions to botulinum antitoxin. The systematic reviews were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (http://www.prisma-statement. org) and registered with the International Prospective Register of Systematic Reviews . The antitoxin efficacy systematic review included animal studies that reported controlled toxin exposure and antitoxin treatment. The pediatric and pregnancy systematic reviews included non-English-language articles that were professionally translated; the other systematic reviews included only English-language articles. The six systematic reviews were published, along with nine other manuscripts on various botulism topics, including clinical characteristics and ancillary test results among patients with botulism and clinical criteria to trigger suspicion for botulism, that also informed these guidelines. In addition, an analysis of detailed abstractions of medical records from 99 hospitalized patients with laboratory-confirmed botulism provided data on presence and progression of signs and symptoms . In partnership with the National Association of County and City Health Officials, CDC organized two forums conducted during January-May 2016 to elicit the individual input of experts in botulism, crisis standards of care, and clinical medicine. One forum focused on the diagnosis and management of botulism (10 teleconferences with 16 experts) and the other on the treatment of botulism (11 teleconferences with 21 experts). Data from the systematic and other reviews, individual published and unpublished studies, CDC investigations, and the relevant botulism, pharmacologic, respiratory, neurologic, and critical care literature were presented to the experts in each of the forums. Experts represented themselves and provided their own input on various topics, including botulism pathophysiology, infectious diseases, antitoxin use, emergency and critical care medicine, crisis standards of care, electrodiagnostic testing, public health, obstetrics and gynecology, and pediatrics. CDC used input from the two forums to generate preliminary recommendations for a 2-day botulism workshop in June 2016. A total of 72 experts, including the technical development group, steering committee, most of the expert forum participants, and other invited participants, provided their own input on targeted questions posed by CDC about the diagnosis and management of botulism. Participants included physicians who have treated patients with botulism, representatives from professional societies (e.g., the American College of Emergency Physicians), state and federal public health officials, and botulism subject matter experts. Participants provided their own input in response to CDC solicitation throughout the process. CDC staff and other participants presented the evidence compiled from the systematic reviews and forums and gave presentations on various topics, including crisis standards of care, pathophysiology of botulism, caring for patients with botulism during an outbreak, ethical considerations in the management of botulism, antitoxin safety and effectiveness, and considerations for vulnerable populations. Of note, the peer-reviewed scientific literature on clinical aspects of botulism consists largely of case series and case reports. CDC asked participants to declare any potential conflict of interest. Two experts reported such potential conflicts. CDC reviewed these potential conflicts of interest and determined that they did not preclude these persons from participating. The authors of the guidelines have no financial interests in or other competing interests with the manufacturers of commercial products or suppliers of commercial services related to botulism. After the workshop, the authors wrote a draft of the guidelines based on the systematic reviews and forum and workshop discussions. The draft was reviewed by selected members of the technical development group and steering committee and then sent to workshop participants for their individual review. The recommendations presented in this report reflect the synthesis and analysis of evidence obtained from systematic reviews conducted by CDC scientists and input from subject matter experts. These guidelines will be updated when substantive new evidence is available regarding the diagnosis, monitoring, and treatment of foodborne, wound, inhalational, or iatrogenic botulism. ## Standards of care: conventional, contingency, and crisis The acute onset of neuromuscular weakness in patients with botulism, frequently progressing to respiratory failure, typically requires high acuity emergency and inpatient care. Therefore, a sudden influx of severely ill patients with botulism might stress the ability of a single hospital or a hospital network to provide appropriate care. To prepare for potentially catastrophic events such as botulism outbreaks, the Institute of Medicine (National Academies of Medicine) recommends that officials from state and local governments (e.g., public health and emergency management), emergency medical services, and health care organizations establish disaster response plans. These plans should incorporate crisis standards of care to optimize medical surge capacity and guide the process of medical care during a catastrophic event. The medical surge capacity continuum is determined by the balance between health care supply and demand. The standards of care within this continuum are categorized as conventional, contingency, or crisis. Components of the health care supply are space (e.g., rooms or areas in which to care for patients), staff (e.g., health care providers), supplies (e.g., medications and medical supplies such as tongue blades), and equipment (e.g., ventilators and monitors). In the conventional (i.e., standard) care setting, standard clinical care spaces, staff, and supplies are used, resulting in a usual level of patient care. In the contingency care setting, although substitutions of space, staff, or supplies are required as demand increases, the level of patient care is not affected. In the crisis care setting, the demand for space, staff, or supplies exceeds that which is available, affecting the level of patient care that can be provided. For example, in a hospital that is providing a conventional standard of care, managing an increasing number of patients might include adding beds to patient rooms to treat more patients. In contingency standard of care settings, measures might include caring for patients in areas not typically used for inpatient care (e.g., postanesthesia care unit and endoscopy suite), and measures in crisis standard of care settings might include caring for patients in areas that are never used for patient care (e.g., classrooms). In a crisis standard of care setting, the focus transitions from actions that prioritize individual patient outcomes to actions that prioritize population-based outcomes. Implementation of crisis standards of care in a given facility should be as brief as possible, and every effort should be made to either obtain appropriate resources or transfer patients to appropriately resourced facilities so conventional standards of care can be resumed. Disaster response plans should incorporate indicators to measure or predict demand for health care services or resources (e.g., emergency department wait time) and triggers that guide decisions about delivering those health care services or resources. For example, an emergency department wait time of greater than a specified period might result in increased staffing. These indicators can mark the transition from conventional to contingency and from contingency to crisis, and the triggers describe which actions should be taken in response to the indicators. Indicators and triggers during a botulism outbreak likely will vary across hospitals. For example, in some hospitals, a conventional standard of care might be appropriate in the emergency department that has five patients in respiratory distress with possible botulism; however, a contingency or crisis standard of care might be needed for other hospitals. Event-specific criteria that might need to be considered in a botulism outbreak include the number of patients affected, the severity of their illness (e.g., patients requiring intubation and mechanical ventilation), and availability of botulinum antitoxin and mechanical ventilators. Certain aspects of a botulism outbreak response, including diagnosis, monitoring, and treatment, might vary across the medical surge capacity continuum (conventional, contingency, and crisis standards of care). ## Diagnosis of botulism Each of the following sections begins with a summary of evidence. Following the evidence are the CDC recommendations for diagnosing, monitoring, and treating suspected botulism as well as (in certain sections) key points for clinicians. In addition, a summary of the recommendations and key points is provided (Supplementary Box; https://stacks.cdc.gov/view/ cdc/105129). Botulism typically produces a distinctive syndrome of cranial nerve palsies that can be followed by bilateral, symmetric, descending flaccid paralysis, affecting proximal before distal limb musculature, that might progress to respiratory failure and death. The extent and severity of paralysis is proportional to the dose of toxin. Patients with botulism are described as alert and oriented, although ptosis, ocular muscle paralysis, voice changes from vocal cord paralysis, and gait disturbance from skeletal muscle paralysis can be mistaken as manifestations of drug or alcohol intoxication or mental status changes of other origin; patients rarely have sensory deficits and rarely report pain. However, the diagnosis of botulism is frequently delayed or even missed. ## Challenges in the diagnosis of botulism Although the progression of paralysis in patients with botulism is described as unique and recognizable, in practice, when a patient is first seen by the health care provider, the neurologic symptoms and the sequence of progression both are sometimes misdiagnosed. The reasons for initial failure to diagnose botulism in subsequently confirmed cases has been investigated most productively in outbreaks, in which cases initially misdiagnosed were eventually identified by outbreak investigators. Outbreak investigations in which some botulism cases were only identified after the patients had been discharged with alternative diagnoses highlight the potential for delayed or missed diagnoses(CDC, unpublished data, 2016). The critical initial treatment and management decisions for patients with suspected botulism must be made based on clinical findings. Botulinum antitoxin, the only specific therapy for botulism, should be administered as quickly as possible. Laboratory confirmation can take several days, and delaying administration of antitoxin to a patient with a high or medium likelihood of botulism while awaiting laboratory results can worsen the patient's outcome. The diagnostic challenges resulting from the variations in the spectrum of signs and symptoms of botulism were highlighted in the delayed recognition of a large foodborne botulism outbreak, in which some patients initially received diagnoses of myasthenia gravis, stroke, or psychiatric disorders. Most of the affected patients were reported to have had the classic signs and symptoms of botulism. In recent literature reviews and a classical case series, botulism was most commonly misdiagnosed as myasthenia gravis and Guillain-Barré syndrome. A wide variety of common and unusual etiologies have been included in differential diagnoses of individual cases (e.g., cerebrovascular accident, Lambert-Eaton syndrome, meningitis, encephalitis, and tick paralysis). In a review of 332 patients with possible botulism for which CDC consulted during 1980-2016, the treating physician provided alternate diagnostic considerations for 274 cases (83%); for these, treating physicians reported a range of zero to six illnesses other than botulism as possible diagnoses at the time of emergency public health consultation. The most to be transferred to a higher acuity hospital, consider administering antitoxin before transfer and ensure serial monitoring can be performed while in transit. - Conduct full diagnostic testing, including neurologic examination, brain imaging, lumbar puncture, electromyography, and nerve conduction study as applicable. - Perform serial monitoring with a complete neurologic examination, including cranial nerves, extremity strength, and respiratory status, before and after antitoxin administration. - Monitor for adverse events (e.g., anaphylaxis) during and after antitoxin administration. - Critical care surge plans are implemented; use adjunct areas (e.g., procedure rooms). - Physicians and advanced practice providers diagnose botulism based on history, examination, and laboratory tests. - Consult public health officials immediately when botulism is suspected, and request antitoxin. - Triage based on severity of illness and respiratory status. - Admit patients with suspected botulism requiring hospitalization (e.g., patients with respiratory symptoms or difficulty swallowing). - If antitoxin is available and a patient needs to be transferred to a higher acuity hospital, consider administering antitoxin before transfer, and ensure serial monitoring can be performed while in transit. - Conduct more limited testing and evaluation using the clinical criteria tool for early diagnosis of botulism. - Perform serial monitoring using the clinical criteria tool for early diagnosis of botulism to identify illness progression - Monitor for adverse events (e.g., anaphylaxis) during and after antitoxin administration. - The maximal critical care surge plan is implemented; use all available areas (e.g., procedure rooms). - All medical staff (e.g., physicians and nurses) diagnose botulism using the clinical criteria tool for early diagnosis of botulism. - Consult public health officials immediately when botulism is suspected, and request antitoxin. - Triage based on severity of illness and respiratory status. - Admit patients with suspected botulism requiring hospitalization based on current capacity (e.g., patients with respiratory symptoms or difficulty swallowing). - If antitoxin is available and a patient needs to be transferred to a higher acuity hospital, consider administering antitoxin before transfer and ensure serial monitoring can be performed while in transit. - For patients not requiring hospitalization, refer stable, moderately ill patients to alternate care sites and send stable, mildly ill patients home (ensure connection with public health resources for telephone check-ins, and provide list of symptoms to self-monitor). - Further limit testing and evaluation subject to resource availability (e.g., limit lumbar punctures, electrodiagnostic testing, and neuroimaging). - Perform serial monitoring focused on illness progression, ability to swallow, and respiratory status for patients who do not require intubation. - Monitor for adverse events (e.g., anaphylaxis) during and after antitoxin administration. Medical facilities that are not hospitals - Refer patients with suspected botulism to the hospital. - Refer patients with suspected botulism to the hospital. - For exposed persons without signs or symptoms of botulism, consider observing on site or asking them to self-monitor at home for signs or symptoms consistent with botulism and go to the hospital if symptomatic. - Discharge asymptomatic persons with unknown exposure home to self-monitor. - Refer severely ill patients with suspected botulism to the hospital. - Send mildly ill patients who do not require hospitalization home to self-monitor for signs and symptoms with telephone follow-up. - Consider locally established alternate care sites (e.g., federal medical stations) to provide for overflow and convalescent care to augment hospitals. - Discharge concerned, asymptomatic persons with unknown exposure home to self-monitor. ## Treatment with antitoxin - Consider treatment with antitoxin of any patient with suspected botulism. - Patients with mild symptoms, reliably observed to have no progression of paralysis over time, might not require treatment. - Prioritize treatment of patients with features most suggestive of botulism. - Use antitoxin with the goal of preventing respiratory collapse requiring mechanical ventilation; prioritize patients with progressing paralysis who are not likely to require intubation before antitoxin can be administered. - Prioritize treatment of patients with features most suggestive of botulism. - Use antitoxin with the goal of preventing respiratory collapse requiring mechanical ventilation; prioritize patients with progressing paralysis who are not likely to require intubation before antitoxin can be administered. common differential diagnoses were Guillain-Barré syndrome (99 cases) and myasthenia gravis (76 cases). For 160 botulism cases that occurred during 2009-2015, treating physicians who consulted with the CDC botulism clinical consultation service listed botulism first for 90% (144) of cases, second for 6% (10), third for 3% (five), and fourth for <1% (one). In children and adolescents, a differential diagnosis was reported in 79 (22%) cases; the most commonly listed alternate diagnoses were myasthenia gravis (22 cases; 28%), poisonings and intoxications (20 cases; 25%), Guillain-Barré syndrome (11 cases; 14%), and poliomyelitis (nine cases; 11%). Misdiagnosis of botulism, including in outbreak settings, might occur because botulism is much less common than other diseases with similar signs and symptoms, such as myasthenia gravis and Guillain-Barré syndrome. In addition, failure to perform a thorough neurologic examination and identify the typical neurologic findings might decrease the likelihood of considering botulism. Although rarely reported, atypical findings or progression, such as reported asymmetry of deficits, might explain diagnostic difficulties. ## Signs and symptoms In reviews and analyses conducted while gathering evidence for these guidelines, the most commonly reported symptoms among patients with botulism were dysphagia; blurred vision; slurred speech, difficulty speaking, and hoarse voice; gastrointestinal symptoms; dry mouth; shortness of breath; and diplopia. The most common signs were descending paralysis, ptosis, and ophthalmoplegia. Signs and symptoms of botulism evolve over a period of hours to a few days. Initially, subjective symptoms of minor visual changes or (in patients with foodborne botulism) abdominal discomfort might occur, followed by progressive cranial palsies, which might then be followed by descending flaccid bilateral paralysis. In different patients, the maximum extent of neurologic signs might range from only ptosis or mild cranial nerve findings to descending bilateral flaccid paralysis, encompassing cranial nerve-innervated respiratory, extremity, and axial muscles. Early gastrointestinal symptoms (e.g., nausea and vomiting) are more common among persons with foodborne botulism than with other types of botulism. For example, vomiting was reported by 172 (50%) patients with foodborne botulism compared with three (5%) with wound botulism. Whether gastrointestinal signs and symptoms are caused by botulinum neurotoxin, other clostridial products, or nonclostridial substances related to food spoilage is unknown. Whether foodborne botulism from intentional contamination of food with purified botulinum toxin would cause gastrointestinal signs and symptoms is unknown. Constipation is often reported as an early symptom among children. Infants and young children might not be able to describe symptoms such as double vision; signs were more commonly reported than symptoms among children. The terminology used to describe the neurologic manifestations of botulism in infants differs from that used for children and adolescents; for example, in one analysis, hypotonia, weak cry, and poor feeding were reported among the three infants with foodborne botulism but not in other children. Botulism is typically described as producing symmetric neurologic deficits, and the pathophysiological mechanism of the disease (i.e., circulatory distribution of the toxin to neuromuscular junctions) (12) is consistent with this description. Certain detailed case studies describe individual patients with asymmetric neurologic deficits. Larger case series have reported asymmetry or unilateral neurologic deficits in the range of 6%-15% of patients. These data are difficult to interpret because many case series present the findings from clinical chart abstractions; data in charts might be missing or incomplete and are typically reported by multiple providers with varying levels of expertise and charting habits. Unreactive pupils are expected in patients with botulism but were reported in only 25% in a large series of confirmed cases (i.e., cases with a positive specimen or epidemiologic association of a clinically compatible case with a case with a positive specimen). Although rare, symptoms such as fever, nondescending paralysis, and altered mental status have been reported. Botulism typically affects proximal before distal muscles; however, equal muscle strengths or even distal muscles weaker than proximal have been reported. The reasons for these rarely reported findings might include an inadequately performed or recorded neurologic examination, a preexisting focal deficit, coincident processes such as infection, or a rare variance from the classical syndrome. Respiratory failure without preceding neurologic deficits has rarely been reported as the presenting symptom. Such a presentation is highly improbable and likely represents an inability to perform a timely, thorough neurologic examination, which would have revealed the cranial nerve palsies that precede pharyngeal compromise and respiratory muscle paralysis. In a series of 72 patients with sporadic (i.e., single) cases of botulism, most had a chief complaint that included symptoms reflecting the classical neurologic deficits of botulism (i.e., slurred speech, weakness, and difficulty swallowing). However, some of the primary signs and symptoms were less indicative of botulism (e.g., gastrointestinal symptoms only, back pain and difficulty using a walker, altered consciousness, and lip and tongue numbness) (CDC, unpublished data, 2016). Patients whose primary signs and symptoms did not reflect classical neurologic deficits of botulism were more likely to have a delayed diagnosis of botulism (CDC, unpublished data, 2016). ## Key points for clinicians - Be aware of the spectrum of signs and symptoms of botulism, ranging from limited cranial nerve palsies (e.g., ptosis) to respiratory failure and complete extremity paralysis. - Be aware that the respiratory system might be compromised early in the illness, when respiratory muscles (e.g., diaphragm) are unaffected but the upper airway is compromised from paresis of cranial nerve muscles, resulting in pharyngeal collapse or pooling of secretions. ## Recommendations - Consider botulism when myasthenia gravis or Guillain-Barré syndrome are suspected and in a patient with unexplained symmetric cranial nerve palsies, with or without paresis of other muscles. - Conduct thorough, serial neurologic examinations to detect the neurologic deficits of botulism and their progression. - If botulism is suspected, immediately contact the local or state health department's emergency on-call staff to arrange an emergency expert clinical consultation and, when indicated, request botulinum antitoxin from CDC. # Ancillary testing background Results from routine laboratory tests, including complete blood counts, examination of cerebrospinal fluid (CSF), and radiologic studies, are typically normal in patients with botulism. In Guillain-Barré syndrome, CSF protein concentrations are often elevated, especially by the second week of illness. In patients with botulism, mild increases in CSF protein concentrations are not reported frequently. Brain imaging might help exclude brainstem strokes that can produce nonlateralizing symptoms. The Tensilon (edrophonium) test, historically used to help diagnose myasthenia gravis, is usually negative in patients with botulism, although minimal responses have been reported. Electrodiagnostic studies such as repetitive nerve stimulation (RNS), electromyography (EMG), and nerve conduction studies (NCSs) can help elucidate the etiology of muscle weakness. RNS involves electrically stimulating a motor nerve at either low (2-3 Hz or possibly 5 Hz) or high frequency and recording the response in the distal muscle. EMG involves inserting a needle electrode into a muscle and recording the electrical activity at rest and with effort, showing motor unit potentials or motor unit action potentials. An NCS involves providing an electrical stimulus to a nerve and recording the electrical response from a sensory nerve (sensory nerve conduction study) or muscle (motor nerve conduction study). Distinctive classical findings of botulism are an increment in the compound motor nerve action potential amplitude, with RNS rates of 30-50 Hz (50); fibrillation; decreased recruitment of muscle units; decreased duration of muscle unit potentials with EMG; and decreased motor-evoked amplitude on an NCS with otherwise normal findings. However, early in the disease course, electrodiagnostic studies might be normal or almost normal and therefore not helpful. EMG, RNS, and NCSs have several limitations. They are operator-dependent and technically challenging, require specialized training and equipment, are not available at all hospitals, and can take 2 hours to complete; in addition, the results require expert interpretation. Early in the course of botulism, electrodiagnostic testing results are likely to be normal (except for testing by singlefiber EMG); late in the course, abnormalities are detected by these tests. EMG requires cooperation from the patient. The entire examination can be painful, especially RNS and particularly at 30-50 Hz. Clinicians must remember that patients with botulism who are paralyzed and intubated are still conscious (unless they are sedated); therefore, they should explain to patients who are not sedated why electrodiagnostic testing is being conducted and what they should expect. The sensitivity and specificity of EMG, RNS, and NCSs for diagnosing botulism are unknown. Electrodiagnostic findings in patients with other neuromuscular diseases (e.g., the Miller Fisher variant of Guillain-Barré syndrome) can be similar to those of botulism. More focused EMG studies, such as single-fiber EMG with measurement jitter, might be more sensitive (although it is nonspecific) than the general EMG but require even more specialized training, more expensive equipment, and more cooperation from the patient (52). The findings of electrodiagnostic studies should always be considered in the context of clinical, epidemiologic, and laboratory data. Results from electrodiagnostic studies might help with the diagnosis of suspected botulism in settings of conventional, contingency, and crisis standards of care, depending on the situation. During an outbreak, electrodiagnostic studies are rarely needed for a cluster of patients with a clear history of bilateral, symmetric cranial nerve palsies followed by descending paralysis. However, for patients for whom the diagnosis is not clear, electrodiagnostic studies might help distinguish botulism from other neuromuscular diseases (e.g., myasthenia gravis or Guillain-Barré syndrome). This is especially true for sporadic (single) cases, in which increasing the diagnostic certainty of botulism as early as possible in the course of illness helps guide clinicians in making the critical decision to treat with antitoxin for suspected botulism rather than plasmapheresis or immunoglobulin therapy for suspected Guillain-Barré syndrome. Because findings from electrodiagnostic studies might remain abnormal for weeks after illness onset, these studies might be useful in the later stages of illness, when botulinum toxin is unlikely to be detectable in the serum. Whereas the identification of multiple patients with cranial nerve palsies and descending flaccid paralysis is highly suggestive of an outbreak of botulism, the additional evidence from electrodiagnostic studies can provide support for clinical and public health management decisions. Electrodiagnostic studies were helpful in establishing the diagnosis of botulism in an outbreak with patients who demonstrated atypical features . For public health events that require contingency or crisis standards of care, the likelihood of being able to conduct electrodiagnostic studies decreases. ## Recommendation - When feasible, consider using electrodiagnostic testing to assist in diagnosis of a suspected botulism case. When conducted and interpreted by experts, EMG, RNS, and NCSs can provide useful diagnostic data. ## Exposure risk factors and botulism diagnosis background A known risk factor for botulism in a patient's clinical history can help focus the clinician's attention on the diagnosis. Risk factors for wound botulism include injection drug use (especially of black tar heroin) and for foodborne botulism include consumption of home-canned food (3). However, because atypical and novel exposures also result in botulism, the absence of typical exposure risk factors does not rule out the disease. The occurrence of more than one case of illness that is suspected to be botulism, especially among persons with some connection to one another, suggests a common-source outbreak and substantially increases the likelihood of the diagnosis (3). However, the occurrence of geographically dispersed cases among persons with no obvious connection does not rule out the possibility of a botulism outbreak that could be caused by a widely distributed, seemingly innocuous product. Public health authorities should immediately investigate all cases of suspected botulism and, when exposures are suspected, inform clinicians about them promptly so that other patients with compatible signs and symptoms can be interviewed and possibly linked to the outbreak. ## Recommendation - Clinicians should ask patients about possible exposures to well-described sources of botulinum toxin, while keeping in mind that absence of such exposures does not exclude the possibility of botulism. ## Clinical criteria tool for early diagnosis of botulism in crisis and contingency settings Because diagnosing botulism can be challenging, a tool with evidence-based clinical criteria has been developed to aid clinicians in early identification of botulism in settings of crisis or contingency standards of care, when the probability of botulism increases above the level of extremely rare; the tool may be used in conventional settings as well (Box 1). Cases of botulism from several sources were used to identify signs and symptoms of acute botulism onset, which were compared and ranked by frequency to botulism, intact mental status is expected. If a patient has altered mental status, this might be from other causes (e.g., respiratory failure, drug or alcohol use, preexisting condition, or concurrent infection). † Although this tool can also be used in a conventional standard of care setting, a more detailed evaluation is expected. In a setting of crisis standard of care, meeting these criteria alone might be sufficient to treat for presumed botulism. § Fever concurrent with the acute onset of botulism in an adult is exceedingly rare; fever also is rare in infants and young children but might be more common than in adults. identify criteria that are optimally sensitive for a case of botulism. The tool was modified to account for reasons illnesses were not captured, and expert input from clinicians and other experts was applied to the criteria that comprise the tool. Ancillary results, including those from electrodiagnostic, neuroimaging, and Tensilon (edrophonium) tests and lumbar puncture, were not included in the tool. The tool was designed for maximum objectivity and reproducibility when used among health care workers; therefore, signs that frequently occurred but were difficult to quantify (e.g., sluggishly reactive pupils) were not included. Also omitted were epidemiologic risk factors that are often not confirmed early in the course of an investigation when most severely ill patients seek care for symptoms. The tool can be used for children and adults, including pregnant women, and by various health care workers without supervision after brief, focused training during contingency and crisis situations such as large outbreaks. The tool is not intended to replace a thorough physical examination and ancillary testing or to diagnose botulism; rather, the purpose is to help clinicians determine when to consider a diagnosis of botulism, without the distractions that can result from atypical or incidental findings. In a setting of conventional standard of care, the tool can be used to stimulate consideration of botulism, followed by a more detailed evaluation. In a setting of crisis standard of care, meeting these criteria alone might be sufficient to treat for presumed botulism. If only some of the criteria are met, physicians might categorize patients as having a medium likelihood of botulism and monitor them. Fulfillment of these criteria should not be considered diagnostic of botulism; patients with illnesses commonly confused with botulism, including myasthenia gravis and Guillain-Barré syndrome, might meet the criteria. During outbreaks, "worried well" persons (i.e., persons who have anxiety about becoming ill during an outbreak) who do not have objective signs or symptoms of botulism often seek care at hospitals for subjective symptoms. Because triaging these patients can be time consuming and delay treatment of other patients, a response to a large botulism outbreak requires managing numerous persons who seek hospital care but do not need treatment and educating the public about which signs and symptoms do not require a hospital visit. ## Laboratory testing The critical initial treatment and management decisions for patients with suspected botulism must be made based on clinical findings. Botulinum antitoxin, the only specific therapy for botulism, should be administered as quickly as possible. Because laboratory confirmation can take several days, delaying administration of antitoxin to a patient with a high or medium likelihood of botulism while awaiting laboratory results can worsen the patient's outcome. Laboratory testing is performed to confirm clinically suspected cases, confirm that administered botulinum antitoxin contains neutralizing antibodies against the serotype of botulinum neurotoxin causing illness, and demonstrate (or confirm epidemiologic data) that botulinum neurotoxin is in the suspected food so the source can be safely removed and additional illnesses prevented. Botulism is confirmed in symptomatic persons by detecting one of the following: 1) botulinum neurotoxin in serum, stool, or gastric fluid; 2) botulinum neurotoxin-producing species of Clostridium (i.e., C. botulinum, C. baratii, or C. butyricum) in a stool or wound culture; or 3) botulinum neurotoxin in food consumed by a ## Types of botulism tests The gold standard method for identifying botulinum neurotoxin, used in specialized public health laboratories, is the mouse bioassay. This method requires maintenance of mouse colonies and expertise in recognizing botulism signs in mice. Specimens are injected intraperitoneally into the mice with and without antitoxin; the mice are then observed for up to 96 hours by expert technicians for signs of botulism. Results might be available within 24 hours of receipt of the specimen by the laboratory if the botulinum neurotoxin level in the specimen is high; however, low levels of toxin that are sufficient to produce human illness might not produce signs in mice. The mouse bioassay is the only FDA-approved method for laboratory confirmation of botulism; however, other methods to detect and identify botulinum neurotoxin and botulinum neurotoxin-producing species of Clostridium can support a clinical diagnosis of botulism. A real-time polymerase chain reaction (PCR) test, which is only available in reference laboratories, detects bont genes A-G and identifies botulinum neurotoxin-producing species of Clostridium in cultures. Because the PCR detects DNA and not the actual proteinaceous toxin, confirming that a strain produces toxin depends on using another method such as a mouse bioassay. The mass spectrometry method for detecting botulinum neurotoxin (Endopep-MS) is highly sensitive and specific and can differentiate among botulinum neurotoxin Monitor for onset of botulism signs or symptoms. Monitor for progression of botulism signs or symptoms. Administer antitoxin, assess for adverse events from antitoxin, monitor for complications (e.g., respiratory failure or swallowing dysfunction), and provide supportive care. Onset or progression of botulism signs or symptoms? serotypes A, B, E, and F within several hours. This method is only available at CDC and a limited number of other public health laboratories. Laboratory confirmation of botulism is usually not possible in nonreference laboratories (e.g., hospital and clinical laboratories) because biochemical tests and mass spectrometry performed in most of these laboratories cannot detect botulinum neurotoxin or distinguish between botulinum neurotoxin-producing Clostridia and nontoxigenic organisms. Occasionally, CDC is notified that a nonreference laboratory has identified C. sporogenes or C. botulinum in a clinical specimen; subsequent testing at a reference laboratory usually identifies the organism as C. sporogenes, which does not produce botulinum neurotoxin (CDC, unpublished data, 2018). ## Collection and transportation of specimens Serum specimens must be collected before treatment with BAT because the treatment neutralizes botulinum toxin, and subsequent testing can misleadingly indicate the absence of toxin. Laboratory confirmation of botulism depends on Administer antitoxin, provide supportive care, and monitor for progression of illness (e.g., respiratory failure) and adverse events from antitoxin. Onset or progression of botulism signs or symptoms? astute clinicians recognizing botulism signs and symptoms in patients, contacting state or local public health departments for an emergency expert clinical consultation (including discussion of laboratory testing), and ordering collection and rapid transport of appropriate specimens; Box 2) (2,3,28). For laboratory confirmation of botulism, collecting clinical specimens as soon as botulism is suspected is essential to ensure that botulinum toxin, if present, is detected before it irreversibly binds within neurons and drops below the level that can be detected by the assay in serum, stool, or gastric fluid. For adults, enough whole blood should be collected without anticoagulant to yield 10-15 mL of serum (20-30 mL whole blood); a smaller volume for children is acceptable, although 4 mL of serum is the minimum volume required for the mouse bioassay. Although 10-20 g of stool should be collected, smaller amounts are sometimes sufficient; rectal swabs from infants or young children are acceptable. In constipated patients, stool specimens can be collected by performing an enema with (preferably) sterile nonbacteriostatic water and non-glycerin-containing suppositories; tap water can interfere with laboratory testing and is not recommended. Stool may be collected after treatment with BAT because Clostridium organisms might still be present in stool even if toxin has been neutralized in the serum (17); BAT treatment should not be delayed to collect stool specimens. Suspect foods should be sent for laboratory testing in their original containers so laboratory experts can determine which parts of the food specimen should be tested. Even containers with dried or sparse amounts of food have yielded positive test results (CDC, unpublished data, 2016). If necessary, food can be sent in sterile, unbreakable containers. All clinical and food specimens should be immediately refrigerated (36°F-46°F [2°C-8°C]) and kept at this temperature while transported; specimens should not be frozen. Specimens from exposed but asymptomatic persons are not routinely tested because the toxin in their specimens is likely to be below the limit of detection of the mouse bioassay; rare exceptions include known exposures to high toxin levels in a research laboratory setting, in which clinical specimens can be obtained and BAT can be administered before illness onset. Confirmation of botulism in a sporadic (single) patient is valuable because it eliminates alternative diagnoses and their treatments and provides a prognosis. In a substantial proportion of cases, test results are negative despite near certainty of the clinical diagnosis. This typically occurs because a delay in recognizing possible botulism leads to collection of clinical specimens later in illness, when levels of toxin in serum have fallen below the limit of detection of laboratory tests. In patients with wound botulism, botulinum neurotoxinproducing species of Clostridium are not always detected in wound specimens, especially after administration of antibiotics. ## Recommendations ## Monitoring illness progression in patients with botulism Botulism causes progressive flaccid, descending paralysis that might result in respiratory compromise from upper airway collapse or respiratory muscle impairment (3). Patients with botulism should be monitored closely for neurologic, respiratory, and autonomic manifestations. Because of the potential for rapid clinical deterioration, frequent examination and other monitoring measures should be performed to allow prompt life-saving interventions. ## Neurologic monitoring Botulism signs and symptoms occur in a typical order. Some patients initially have nausea and vomiting, then nearly all patients develop cranial nerve palsies (which might include respiratory compromise from upper airway compromise); some develop respiratory failure and paralysis of the extremities. A systematic review of 375 patients in the literature documented a range in the number of cranial nerve palsies recorded at hospital admission: 126 (34%) patients had one or two cranial nerve palsies, 119 (32%) patients had three or four, and 130 (35%) patients had five or more; 27 (7%) had no cranial nerve palsies noted. Paralysis can progress rapidly. ## Respiratory monitoring Neuromuscular paralysis in patients with botulism can result in respiratory failure by affecting the muscles that prevent aspiration and maintain a patent upper airway, as well as those involved in respiration (e.g., the diaphragm). In a systematic review of 402 adults with botulism, 169 (42%) patients had respiratory compromise when admitted to the hospital, with either shortness of breath or dyspnea (50 [12%]) or respiratory distress or failure (119 [30%]). Almost half (184 [46%]) later required intubation and mechanical ventilation. Approximately two thirds of patients who had respiratory involvement when admitted to the hospital had been ill for <48 hours. Among patients who required intubation (with data on hospital day of intubation), 87% required intubation in the first 2 hospital days. In a review of medical charts from 99 patients with confirmed botulism, shortness of breath was reported in 67 (68%) patients on the first or second day of hospitalization (CDC, unpublished data, 2016). In a systematic review of 17 pregnant patients with botulism, 11 (69%) patients experienced respiratory failure requiring intubation and mechanical ventilation. Pregnant patients might be at increased risk for respiratory failure because of decreased functional residual lung capacity, diaphragmatic rise, increased oxygen consumption, and increased intra-abdominal pressure. In a systematic review of 360 children with botulism, 91 (25%) required mechanical ventilation. Adult, nonpregnant patients with botulism might require mechanical ventilation more frequently than children with botulism because of comorbid conditions such as chronic obstructive pulmonary disease and obesity. No data are available to indicate whether certain clinical features among patients with botulism are associated with eventual intubation and mechanical ventilation. An analysis of 20 patients with wound botulism found no statistically significant differences in the initial signs and symptoms of patients who developed respiratory failure and patients who did not. Nausea, vomiting, and any cranial nerve palsy with urinary retention or dysphagia were the signs and symptoms most predictive of respiratory failure in an analysis of 137 patients from a foodborne botulism outbreak in Thailand. Because of the paucity of data regarding respiratory monitoring and clinical predictors of respiratory failure in patients with botulism, clinical practices from other neuromuscular disorders that can cause respiratory failure (e.g., myasthenia gravis and Guillain-Barré syndrome) might be used for respiratory monitoring of patients with botulism. Spirometry is an objective measure of respiratory muscle function that, along with physical examination, can help clinicians determine whether a patient needs intubation. For example, forced vital capacity (FVC) <20 mL/kg, maximum inspiratory pressure (i.e., negative inspiratory force) <30 cm H 2 O, and maximum expiratory pressure <40 cm H 2 O were each associated with the need for mechanical ventilation in Guillain-Barré syndrome patients. Respiratory function also might be monitored using sniff nasal inspiratory pressure and the single breath count test. Sniff nasal inspiratory pressure testing, which evaluates diaphragm strength and inspiratory muscle function, involves occluding one nostril with a pressure-measuring device and inhaling sharply through the other nostril.Values greater than −70 cm H 2 O (males) or −60 cm H 2 O (females) might reflect the absence of clinically significant inspiratory muscle weakness; severe nasal congestion might cause falsely low values.The single breath count test involves taking a deep breath and then counting at a rate of two numbers per second for as long as possible while exhaling. A study of 31 patients with myasthenia gravis documented that the single breath count correlated with FVC, with each counted number equal to 116 mL of FVC; counting to ≥25 was proposed to correlate with normal respiratory muscle function. End-tidal carbon dioxide (EtCO 2 ) monitoring, which is noninvasive and available in many hospitals, is an optional modality for monitoring early respiratory failure. Rising partial pressure of CO 2 (pCO 2 ) or EtCO 2 strongly predicts the need for mechanical ventilation. Bulbar dysfunction is often a prominent feature of botulism and has been associated with the need for intubation and mechanical ventilation in patients with Guillain-Barré syndrome. Monitoring pulse oximetry and arterial blood gases might not be reliable early indicators of emerging respiratory failure in patients with botulism because hypoxia and hypercapnia might not develop until the later stages of respiratory failure, as documented in patients with other neuromuscular disorders in which gas diffusion is unimpaired, such as Guillain-Barré syndrome. ## Autonomic function monitoring Botulinum neurotoxins can impair the postganglionic release of acetylcholine in the parasympathetic nervous system, causing unopposed stimulation of the sympathetic system. Case reports and series have noted features of dysautonomia (e.g., dry mouth, urinary retention, constipation, and orthostatic hypotension) in patients with botulism, usually in cases caused by toxin type B. Similarly, autonomic dysfunction is commonly reported in Guillain-Barré syndrome patients, with cardiac manifestations of dysautonomia, including sinus tachycardia or bradycardia, cardiac dysrhythmias, blood pressure lability, abnormal hemodynamic responses to medications, and nonspecific electrocardiogram changes. These manifestations have prompted some experts to recommend close monitoring of pulse and blood pressure in patients with Guillain-Barré syndrome. Similar monitoring would therefore be reasonable for patients with botulism. ## Recommendations - Conduct frequent, serial neurologic examinations, with an emphasis on cranial nerve palsies, swallowing ability, respiratory status, and extremity strength. - In settings of contingency and crisis standards of care, in which time is limited, focus examinations on signs and symptoms of early onset (Box 1). Consider brief, focused training in the emergency setting on the neurologic examination. - When possible, have the same health care provider conduct the serial neurologic and other examinations. - Adjust the frequency of neurologic and other examinations on the basis of signs and symptoms, with very frequent examinations for patients with rapid progression and for patients who have respiratory or bulbar symptoms but have not required intubation. - Institute frequent, serial monitoring of respiratory and bulbar function. Serial measurements might be more helpful than a single measurement. ű Focus the respiratory examination on respiratory rate, lung field auscultation, and work of breathing, including use of accessory muscles of respiration, nasal flaring, and paradoxical breathing (78). 1. Obtain serial objective data through spirometry, EtCO 2 monitoring, blood gas analysis, or other tests. Patients with facial weakness might not achieve an adequate seal around the spirometer mouthpiece and so might require a mask device. If spirometry is not available, consider using the sniff nasal inspiratory pressure or the single breath count test. 2. Consider respiratory status in the context of neurologic status because paralysis can alter signs typically associated with respiratory distress. For example, facial paralysis can produce a placid expression that can obscure distress from respiratory insufficiency and also prevent nasal flaring, and diaphragmatic paralysis can result in paradoxical abdominal movement in which the abdomen moves inward during inspiration. ű Focus bulbar dysfunction examination on dysphagia, dysarthria, nasal voice, drooling, and impaired gag reflex. When feasible, consider assessing the patient's swallowing ability to help determine whether the patient can safely consume liquids or solids. - Continuously monitor cardiac rhythm and frequently measure blood pressure. - Frequently monitor for urinary retention, constipation or ileus, dry mouth, and dry eyes. ## Treatment considerations Treatment involves supportive care, intubation and mechanical ventilation when necessary, and administration of equine-derived botulinum antitoxin. Botulism produces a protracted flaccid paralysis that lasts for weeks to months. Death in the acute state is typically the result of early respiratory failure; later in the course of illness, death is usually caused by complications from protracted intensive care, such as ventilator-associated pneumonia and deep vein thrombosis (DVT). Timely administration of botulinum antitoxin mitigates the extent and severity of paralysis, including, in certain instances, prevention of progression to respiratory compromise, and in other instances, reduction of the duration of mechanical ventilation and intensive care. Almost all patients with botulism can survive, even without antitoxin, if they receive supportive care, including mechanical ventilation, when required. This is reflected in the mortality trend for botulism. The case-fatality ratio approached 70% in the first half of the twentieth century, despite the availability of botulinum antitoxin then. Mortality rates decreased beginning in the 1940s and 1950s to their current rate of <5%, with improvement corresponding to the development of modern intensive care techniques, particularly mechanical ventilation. However, survival and recovery require prolonged use of intensive care resources, which might be limited in events with many patients with botulism. ## Botulinum antitoxin treatment background The only specific therapy for botulism is botulinum antitoxin. When administered early in the course of illness (within 48 hours of symptom onset and ideally within 24 hours), botulinum antitoxin can stop the progression of paralysis and prevent respiratory compromise in certain patients. The antitoxin cannot reverse existing paralysis. The antitoxin is an equine-derived preparation of antibodies that bind and neutralize botulinum toxin in the bloodstream that has not yet irreversibly bound to synaptic receptors; the resulting antitoxin-toxin complex is cleared from circulation. Botulinum antitoxin is toxin type-specific (e.g., antitoxin to toxin type A neutralizes only toxin type A). BAT, the only botulinum antitoxin preparation available for treatment of noninfant botulism in the United States, is a mixture of antibodies to botulinum toxin types A, B, C, D, E, F, and G, licensed for the treatment of symptomatic botulism in adults and children. Antitoxin is stocked by CDC, and health care providers who identify an illness they suspect is botulism can contact the 24-hour CDC botulism consult service and request antitoxin if indicated (https://www.cdc. gov/botulism/health-professional.html). ## Recommendation - Health care providers who suspect botulism on the basis of clinical symptoms should immediately call the emergency contact number of their local or state health department to arrange for an emergency clinical consultation and, when indicated, shipment of antitoxin (https://www.cdc.gov/botulism/health-professional.html). ## Dose The standard adult dose* is one vial, administered by intravenous infusion. The pediatric dose is based on weight. The standard adult dose of BAT contains approximately 10 7 IU of antitoxins A, B, C, and F; 10 6 IU of antitoxins D and E; and 600 units of antitoxin G. These amounts exceed by one to two orders of magnitude (i.e., tenfold * The strength of botulinum antitoxin is quantified in terms of neutralization capacity, which reflects the amount of toxin that a dose of antitoxin can render inactive. The potency of botulinum toxin is quantified in units called the mouse intraperitoneal lethal dose 50 (MIPLD 50 ), the amount of toxin, specific for each serotype, required to kill one half of a group of mice injected intraperitoneally. The antitoxin's neutralization capacity for each toxin type is the number of MIPLD 50 that an amount of antitoxin (of that toxin type) can neutralize and is expressed in international units (IUs). One IU of antitoxin type A, B, C, D, or F neutralizes 10,000 MIPLD 50 of the corresponding toxin; one IU of antitoxin type E neutralizes 1,000 MIPLD 50 of toxin type E. The neutralizing IU for toxin type G has not been standardized. to 100-fold greater) the amount of toxin types A, B, or E documented in the serum of virtually every botulism patient in whom the toxin level has been quantified. A theoretical possibility exists that the neutralizing capacity of BAT could be exceeded by circulating toxin levels in a patient exposed to an extremely high toxin load in naturally occurring disease; the circulating toxin level that might be attained in an intentional contamination event is not known. ## Allergic reactions and other side effects of botulinum antitoxin Background BAT contains purified antibodies from the serum of horses immunized with botulinum toxoids and toxins. As concentrated preparations of foreign proteins, they can elicit immune reactions, including anaphylaxis, in human recipients. Despeciation and other processes used in producing modern equine antitoxin might reduce but do not eliminate the risk for allergic reactions. Data on BAT indicate an anaphylaxis rate of <2%; a similar frequency was calculated for previously used formulations. Among 249 patients treated with BAT in one analysis, the only serious adverse event occurred in a child who experienced hemodynamic instability, including asystole, and recovered; other allergic reactions, typically rash, were noted in six patients and were without sequelae. Skin testing before antitoxin administration, once universally recommended, is no longer recommended. Skin testing requires specialized training, is cumbersome and time consuming, and is likely to have a low positive predictive value. Serum sickness has been reported among antitoxin recipients; the frequency is not well established (37). ## Recommendations - Do not routinely perform skin testing for sensitivity before BAT administration. - Ensure that epinephrine and antihistamine treatments are available for all patients receiving BAT. Caregivers capable of identifying and responding to anaphylaxis should observe patients during antitoxin administration. ## Guiding principles of antitoxin treatment Administration of botulinum antitoxin early in the course of illness decreases mortality, duration of treatment in the intensive care unit, and duration of hospitalization. A systematic review and meta-analysis of data during 1923-2016 indicated that overall, antitoxin reduced mortality (odds ratio [OR] = 0.22; 95% confidence interval [CI] = 0.17-0.29), with the greatest reduction associated with treatment of botulism type E (OR = 0.13; 95% CI = 0.06-0.30), followed by botulism type A (OR = 0.57; 95% CI = 0.39-0.84). Reduction in mortality was not statistically significant for type B botulism (OR = 0.74; 95% CI = 0.27-1.97), possibly because this toxin type causes milder disease. These findings are driven by data from patients treated with anti-ABE trivalent antitoxin, which, when administered for botulism types A, B or E, significantly reduced overall mortality (OR = 0.13; 95% CI = 0.04-0.38). A systematic review of botulism in children found that antitoxin administration (multiple formulations over many decades) significantly reduced mortality (relative risk [RR] = 0.65; 95% CI = 0.53-0.80; p<0.001). When evaluated by age group, patients aged 1 to <5 years (RR = 0.43; 95% CI = 0.20-0.93; p = 0.007) and aged 5 to <9 years (RR = 0.52; 95% CI = 0.33-0.82; p<0.001) who received antitoxin had significantly decreased relative risk for death. The relative risk of the remaining age groups followed a similar trend. Although a systematic review of 17 cases of botulism in pregnant women did not find a significant association between antitoxin administration or early antitoxin administration and improved outcome, the trend observed suggested such a relation. ## Timing of botulinum antitoxin administration ## Administration of antitoxin early in the course of illness Among 104 patients with confirmed botulism treated with BAT, those treated within 2 days after illness onset spent fewer days in the hospital (median: 15 versus 25 days; p<0.01) and in the intensive care unit (10 versus 17 days; p = 0.04) than those treated later. A systematic review and meta-analysis reported similar findings from reports published over nearly a century and entailing the use of various antitoxin formulations. One study from 1984 reported that among 132 patients with type A botulism, those who had received trivalent anti-ABE equine antitoxin had a lower fatality rate and a shorter course of illness than those who did not receive antitoxin, controlling for age and incubation period. Patients who received antitoxin within 24 hours after symptom onset had a shorter course but similar fatality rate as those who received antitoxin later. Another study from 2006 reported on a subset of 18 severely ill patients from a large botulism type A outbreak in Thailand. In this subset, patients who received antitoxin on day 4 of illness onset had significantly shorter duration of ventilator dependence than those receiving it on day 6 (86). ## Recommendation - Administer botulinum antitoxin to patients with suspected botulism as early as possible in the course of illness. The greatest benefit accrues to those who receive it within the first 2 days of illness onset. ## Administration of antitoxin later in the course of illness Neutralizing any circulating toxin should be beneficial. Available evidence does not indicate a point in the course of illness beyond which antitoxin administration provides no benefit. One study found that for 309 foodborne botulism cases, toxin was detected in approximately 20% of serum specimens collected beyond the sixth day of illness. However, toxin was detected in the circulation of one foodborne botulism patient 12 days after and in another 25 days after symptom onset. Because paralysis that continues to progress indicates that toxin is still circulating, such patients should receive antitoxin to protect unaffected muscles, regardless of the number of days after illness onset. Because current tests to identify toxin in patient serum take several days, treatment decisions should not be delayed in anticipation of test results. Antitoxin does not reverse paralysis. Recovery from paralysis takes weeks to months, even after antitoxin administration. ## Recommendations - Patients with suspected botulism whose symptoms or signs (e.g., paralysis) are progressing should be treated with BAT regardless of the time that has elapsed since symptom onset. - Patients with suspected botulism whose symptoms and signs are not progressing and who have no remaining voluntary muscle function are less likely to benefit from antitoxin treatment, especially if >7 days have passed since symptom onset, because toxin is infrequently detected beyond this point of illness. ## Characteristics of patients and success of antitoxin administration background No available evidence indicates that any particular patient characteristic (e.g., age, sex, or preexisting health conditions) predicts better outcome from antitoxin administration. One report found that among 132 patients with botulism type A, the reduction in fatality rate and duration of illness associated with antitoxin administration persisted after controlling for age. General principles of respiratory care suggest that patients with preexisting respiratory conditions (e.g., obstructive or restrictive lung disease) or physiologic or anatomic conditions (e.g., pregnancy, obesity, and chest wall malformation) might have a higher risk for respiratory compromise than the general population. Earlier administration of antitoxin to such patients theoretically might have more impact in preventing respiratory failure. ## Recommendation - Patients with suspected botulism should be treated with BAT regardless of underlying medical conditions or age, sex, or other demographic characteristics. ## Retreatment of adults background Retreatment for a single exposure to botulinum toxin, which would imply circulating toxin levels exceeding the antitoxin's neutralizing capacity, is not described in the modern published literature. Toxin circulation has been reported in untreated patients 12 days and 25 days after exposure. Such persistent presence of toxin from a single exposure suggests an extremely high exposure dose and initial circulating level, very slow absorption of ingested toxin, or development of a botulinum toxin-producing colony of C. botulinum in the patient's intestine after ingestion of a food contaminated both with spores and toxin. Cases such as this are exceedingly rare. Antitoxin prevents progression of paralysis; antitoxin administration is not followed immediately by reversal of paralysis already present at the time of administration. In an outbreak or another situation in which the clinical diagnosis of botulism is certain, progressive neurologic illness >24 hours after treatment suggests a circulating toxin level exceeding the neutralization capacity of administered antitoxin. In a person with a suspected sporadic (single) case, especially with atypical features or other circumstances associated with less diagnostic confidence, progression of paralysis despite antitoxin treatment should increase consideration of alternative diagnoses. Under unusual circumstances, such as documented exposure to high levels of toxin (e.g., unusually high toxin content in food or atypically high toxin levels in patients' circulation), public health officials could recommend increasing or repeating the antitoxin treatment. However, because toxin quantification is not routinely performed, such information is unlikely to be available. The half-life (t 1/2 ) in patients' circulation of the seven antitoxin types in one vial ranges from 7.5 to 34 hours (84). Theoretically, a shorter half-life might result in reduced neutralization of toxin that is being absorbed from the gut into the circulation over time. In the highly rare instance in which it is clinically indicated, a second dose of BAT given within 2 weeks is unlikely to result in a hypersensitivity reaction related to sensitization caused by the first dose because it usually takes longer for the immune system to respond to a new antigen. Older formulations of botulinum antitoxins had longer halflives than BAT. ## Recommendations - Do not give patients with suspected botulism a second dose of BAT unless progression of paralysis clearly continues after the initial dose should have taken effect and suspicion for botulism is high. - If neurologic signs progress for >1 day after administration of one vial of BAT, consider diagnoses other than botulism. ## Infants and children infant botulism syndrome The syndrome known as infant botulism is an exceedingly rare and sporadic disease caused by colonization of the intestine by Clostridia and in situ toxin production. A single case of suspected botulism in an infant is usually presumed to be infant botulism. These guidelines do not address the syndrome of infant botulism, for which the indicated treatment is humanorigin anti-A, anti-B botulinum antitoxin (BabyBIG), available after consultation from the California Department of Public Health Infant Botulism Treatment and Prevention Program. Infant botulism syndrome caused by other toxin types may be treated with BAT. However, infants can be affected by toxin that they ingest. If an infant is affected as part of a group of botulism cases, the infant has likely been exposed to a toxin from food or the environment, and the illness is likely to be botulism in an infant rather than the syndrome of infant botulism. In such circumstances, the infant should receive BAT and be treated using these guidelines. ## Dose The FDA-approved BAT dose for infants (persons aged <1 year) is 10% of the adult dose, regardless of weight. The BAT dose for children (persons aged 1-16 years) is 20%-100% of the adult dose, according to 10 weight-based categories. These doses were derived using the Salisbury rule, which is a method of calculating weight-based brackets for dosing in children: for children who weigh <66 lb (30 kg), double the body weight to determine the percentage of the adult dose to use; for children who weigh >66 lb (30 kg), add 66 lb (30 kg) to the body weight to determine the percentage of the adult dose to use. However, weight-based dosing might not provide a dose of sufficient neutralizing capacity in a child. Botulinum antitoxin acts by neutralizing toxin in the circulation not yet bound to synaptic nerve endings. Therefore, the amount of toxin in circulation is not proportional to the patient's weight and instead reflects the dose of toxin ingested. The dose ingested might not be proportional to the volume of food consumed because the distribution of toxin in a food can vary widely. The absolute amount of botulinum toxin in a child might be no different from, but could also be greater than, the amount in an adult who ate the same contaminated food. Therefore, the amount of neutralizing antitoxin required needs to be proportional to the amount of toxin present and could result in the same (or greater) dose than for an adult. Treatment of pediatric botulism without regard to body weight has been reported in one publication, which documented that 12 patients aged 4-61 years in Sichuan Province, China, all received 100,000 units of antitoxin, with no adjustment of dose for age or weight. Although no data were reported on severity of morbidity or outcome by age, the length of stay in the hospital ranged from 5 to 19 days (median: 8 days), with no deaths. Several other case reports involving children have been published but without specific data on dosing regimen. As noted in the sections pertaining to botulinum antitoxin treatment of adults, if a child needs a second dose of BAT (a situation that is highly unusual and is clinically indicated by progression of paralysis >24 hours after administration of a first dose of antitoxin, with high confidence in the diagnosis of botulism), the dose is unlikely to result in a hypersensitivity reaction because of sensitization caused by the first dose. The immune system takes weeks to complete the humoral immune response after introduction of antigen; therefore, an allergic reaction to a second dose within a period of up to 2 weeks would be unlikely. ## Key point for clinicians - Although weight-based dosing of BAT is advised in the package insert, evidence is lacking to suggest this method is more effective than dosing based on toxin load or that adverse reactions are dose related. Children who have ingested a large amount of toxin might require more antitoxin than is indicated by the weight-based dose described in the BAT package insert. ## Recommendation - Children suspected of having foodborne botulism and treated with BAT according to the weight-based dose described in the package insert should be monitored closely for worsening paralysis. When confidence in the diagnosis of botulism is substantial, a lack of response to the treatment might indicate that the dose was insufficient, and retreatment should be considered. # Pregnant women background A systematic review assessed 17 cases of botulism among pregnant women treated with antitoxin. No antitoxin-related complications were reported in the patients or their fetuses. Although statistical testing of the therapeutic effects of antitoxin administration was not performed because of the small number of cases, descriptive findings suggested that, as in nonpregnant patients, antitoxin improved outcomes when administered early. General principles of respiratory care suggest that preexisting respiratory diseases (e.g., obstructive or restrictive lung disease) or physiologic or anatomic conditions (e.g., pregnancy, obesity, and chest wall malformation) might increase the risk for respiratory compromise in patients with botulism compared with those in the general population. Earlier antitoxin administration might help prevent respiratory failure in these patients. ## Recommendation - Pregnant women with suspected foodborne botulism should be treated with BAT in the same manner as nonpregnant patients. # Antitoxin shortages background The U.S. government has a large stock of BAT. Vials are stored in facilities of the Strategic National Stockpile in readiness for immediate shipment. A temporary shortage might occur at a clinical facility treating patients because of the time required for shipment and distribution. Theoretically, a shortage could occur during a very large outbreak in which cases exceed the doses in the national stockpile. Depending on the severity of shortage, contingency or crisis standards of care might apply to the antitoxin supply. Under conditions without resource restrictions, BAT is typically administered to patients with progressing signs of botulism; the risks from BAT administration in a carefully monitored setting with readily available intensive care are quite low, and the benefits of preventing progression of paralysis are substantial. Antitoxin should not be administered to asymptomatic patients. In settings requiring contingency or crisis standards of care because of a BAT shortage, increasingly restrictive criteria are applied to identify the patients more likely to benefit from antitoxin administration. Available data do not provide unequivocal clinical characteristics or features that identify patients more likely to benefit from antitoxin treatment. However, certain considerations might assist physicians in making antitoxin administration decisions during an antitoxin shortage. The overarching objective of antitoxin treatment is to prevent respiratory failure, the principal cause of death in the early stages of botulism. Treating respiratory failure requires intubation and mechanical ventilation, with its attendant risks and complications, as well as resources for protracted intensive care and hospitalization. These steps might in turn create or exacerbate shortages of ventilators and other resources. Thus, when there is a shortage of ventilators, antitoxin should be used in a way that minimizes the occurrence of respiratory failure (i.e., administration of antitoxin to patients who do not yet require intubation but whose illness might still be progressing). Early administration of botulinum antitoxin (≤2 days from symptom onset) reduces overall death and duration of hospitalization. Among patients who have not experienced respiratory failure, data are insufficient to indicate with certainty those who will benefit most from antitoxin treatment. Some patients with mild symptoms will not progress to experiencing respiratory compromise even without treatment, and some patients with rapidly progressing botulism, even when treated with antitoxin on the first day of symptoms, nevertheless require intubation and mechanical ventilation. Staff should conduct frequent, focused neurologic examinations of patients who do not need intubation to identify those whose signs and symptoms are progressing and who are at greater risk for respiratory failure (see Monitoring Illness Progression in Patients with Botulism). Patients whose signs and symptoms progress rapidly (over hours) are likely at highest risk. However, factors associated with respiratory failure among patients who received prompt treatment with antitoxin are not known, nor is which patients would have required intubation had they not received antitoxin. Also unknown is whether antitoxin administered to patients whose neurologic findings are progressing decreases the duration of mechanical ventilation. The standard adult dose of BAT (one vial) contains sufficient amounts of antitoxin types A, B, C, E, and F to neutralize approximately 100-fold the measured serum toxin level for virtually all patients with botulism type A, B, or E in whom circulating botulinum toxin levels have been quantified and sufficient antitoxin of types D and G to neutralize approximately tenfold the measured serum toxin level. These figures suggest that the standard adult dose of BAT could reasonably be divided among two or more patients during a shortage while maintaining an acceptable excess of neutralization capacity. However, there is no known limit to the dose of botulinum toxin that can be ingested, nor is there a known maximum serum level that can be attained in persons who have botulism from unintentional exposure or from a deliberate contamination event. Ethical decision-making on the allocation of scarce resources during a shortage is not limited to using resources in the manner that is most clinically appropriate. This type of decision-making requires incorporating principles of fairness and equity, meaning that all persons equally likely to benefit from therapy have a similar chance of receiving treatment. Allocation schemes should take into account community preferences. For example, in some communities or cultures, children are considered a privileged, or priority, group. During a shortage emergency, new procedures that incorporate clinical criteria, standards of fairness, equity, and community preferences for allocation of antitoxin cannot be satisfactorily established. Allocation approaches and criteria should be developed as part of emergency planning, using a deliberate, transparent process that incorporates the full range of stakeholders, including those who can articulate the preferences of the community. ## Key points for clinicians - Carefully assessing history of illness and monitoring patients to identify those at greatest risk for progress to respiratory arrest might help in decision-making. - Patients who do not require intubation but have progressing signs and symptoms are at highest risk for developing respiratory compromise. - Patients who do not require intubation, do not have respiratory compromise, and are reliably observed to have stable (nonprogressing) signs or symptoms might be considered to be at less risk for developing respiratory compromise. - Patients who do not require intubation but have progressing signs or symptoms are likely to receive some benefit from antitoxin administration. - Limited data indicate that patients who seek care >7 days after illness onset are less likely to have botulinum toxin in circulation. - No demographic criteria can be used to definitely identify patients with botulism who are more likely to benefit from antitoxin treatment. ## Recommendation - Proactively develop an approach to handle BAT shortages as part of an emergency planning process that incorporates the full range of stakeholders, including local communities. ## Treatments other than botulinum antitoxin A meta-analysis found no evidence for effectiveness of any specific treatment other than botulinum antitoxin to date. Research is ongoing for certain modalities addressed in this section. ## Activated charcoal, polyethylene glycol, cholinergic agonists, and plasmapheresis No data exist on the effectiveness of activated charcoal in the treatment of humans with botulism. A study in mice showed that adding activated charcoal to botulinum toxin injected intraperitoneally provided full protection from signs and death. However, oral administration of activated charcoal in humans might be associated with complications. For example, aspiration and resultant pneumonitis could occur among patients with decreased gag or swallow reflexes, and activated charcoal in the gut might complicate the management of ileus. Although polyethylene glycol preparations have been proposed to speed efflux of toxin from the gut, no evidence of benefit exists. Cholinergic agonists such as guanidine and 3,4-diaminopuridine have been used in attempts to stimulate acetylcholine release because they have been used in the treatment of other neuromuscular illnesses, with apparently transient effects. Patients have also been treated with plasmapheresis, with no clear benefit. ## Antimicrobials Antimicrobials do not provide any benefit in treatment of botulism. Theoretical concerns have been raised concerning increased botulinum toxin release from lysed Clostridia organisms after antimicrobial treatment. Wound botulism is caused by clostridial colonization of an anaerobic wound, treatment of which is generally centered on debridement (3); treatment should address each patient's clinical situation. Aminoglycosides act in vitro as neuromuscular blocking agents (NMBAs) and aggravate botulism anecdotally in several animal species and in humans with infant botulism. In addition, aminoglycosides have been reported as an aid for diagnosing botulism in mouse models. The neuromuscular blocking potency is highest with neomycin and decreases sequentially with gentamicin, streptomycin, kanamycin, amikacin, and tobramycin. The effect is more likely to occur with serosal administration (e.g., intraperitoneal) but has been reported by all routes and with a higher incidence in patients also receiving anesthetics, NMBAs, or both, and with massive transfusions of citrated blood. The suggested mechanism of action is a reduction in presynaptic calcium uptake and acetylcholine release similar to that caused by magnesium, as well as postsynaptic binding. This has been postulated to be reversible with calcium salts, although possible calcium toxicity from such treatment is a concern (108). ## Medications that should be used with caution Most of the following agents are thought to pose theoretical risks to patients with botulism. (Substantive evidence exists for the risk associated with aminoglycosides.) ## Antimicrobials Concerns exist about the ability of clindamycin to block acetylcholine release, and its action might work together with that of aminoglycosides. Theoretical concerns exist regarding penicillins increasing toxin load through cell lysis and with tetracycline through chelation of calcium. However, avoiding the use of these agents in a patient with a comorbid infection must be weighed against the benefits of treating the comorbid condition. Patients with botulism who are being treated with antimicrobial agents should be observed for clinical deterioration that could be related to receiving the antibiotic. ## Magnesium, calcium, and monoamine oxidase inhibitors Magnesium, a competitive inhibitor of presynaptic calciumdependent acetylcholine release, produces dose-dependent skeletal muscle paralysis and prolongs paralysis from NMBAs and diseases such as myasthenia gravis. In a cattle study, calcium infusions were reported to increase paralysis and dissemination of botulinum toxin. Calcium-channel blockers (e.g., verapamil, nifedipine, and diltiazem) can interact with aminoglycosides to produce complete neuromuscular blockade among patients who do not have botulism and theoretically should be avoided on the basis of this interaction. A single report has been published of pretreatment of mice with the monoamine oxidase inhibitor pargyline resulting in rapid botulism-induced death. ## Neuromuscular blocking agents Any agent that can cause paralysis, including NMBAs, should either be avoided or be used after careful consideration and with appropriate monitoring. The NMBA succinylcholine induces sustained depolarization of motor endplate at the myoneuronal junction. The nondepolarizing NMBAs, such as rocuronium, vecuronium, and pancuronium, block acetylcholine from binding to motor endplate receptors. ## Key points for clinicians - Patients with suspected, symptomatic botulism should be treated with BAT and receive supportive care (e.g., intensive care including intubation and mechanical ventilation when necessary). - Evidence does not indicate benefit from any treatment modalities other than antitoxin, although data are limited. ## Recommendation - Aminoglycosides, magnesium, clindamycin, tetracycline, or calcium should only be administered to patients with botulism after careful consideration and with appropriate monitoring. ## Botulism, antitoxin, and breast milk background Three botulism cases have been reported in breastfeeding women, prompting questions about whether such breast milk can be safely fed to infants. Whether botulinum toxin enters breast milk is not known; this issue has not been systematically researched. Many factors influence whether a compound is transferred from serum to breast milk (e.g., molecular weight and lipid solubility). Medications with a molecular weight >800 daltons are less likely to achieve clinically relevant levels in breast milk than smaller compounds. The molecular weight of botulinum toxin (150,000 daltons) might prevent its passage into breast milk. The three breastfeeding women who breastfed their children while ill with botulism are briefly described in the literature. One mother with severe type A foodborne botulism breastfed her infant aged 8 months while acutely ill with cranial nerve palsies, weakness, and shortness of breath that required intubation and respiratory support for 2 weeks. Neither C. botulinum nor botulinum toxin were identified in her breastmilk, which was obtained for testing on the third day of her illness, 4 hours after she received trivalent ABE botulinum antitoxin. The infant was reportedly breastfed throughout the mother's illness, including before the mother received antitoxin, and did not develop any signs or symptoms of botulism. The infant did not receive antitoxin, C. botulinum was not identified in the infant's stool, and botulinum toxin was not identified in the infant's stool or serum collected on the third day of the mother's illness. Another study involved an infant aged 2 months who breastfed while the mother was acutely ill with botulism (119). The mother was reported to have died from type A botulism; however, the signs and symptoms she experienced were not specified. The infant did not develop any signs or symptoms of botulism. The study did not specify whether the infant received testing. Another infant aged 2 months breastfed without becoming symptomatic while the mother was acutely ill with type B botulism (120). The mother had cranial nerve palsies and generalized weakness and required a tracheostomy. The infant received antitoxin (timing of antitoxin not specified) and remained asymptomatic. The study did not specify whether the infant received testing. The BAT package insert states that no data are available to assess the presence or absence of BAT in human milk, the effects on breastfed children, or the effects on milk production or excretion. BAT's molecular weight (150,000 daltons) might prevent BAT from entering breast milk. Few infants have received BAT. One study found that an infant aged 10 days was treated with BAT without any known adverse events, and another study found that a neonate developed a low-grade fever within 1 hour of receiving BAT that continued intermittently for 72 hours. ## Recommendations - Treat breastfeeding women in accordance with recommendations in the treatment section of these guidelines (see Treatment Considerations). - If the mother continues to breastfeed, monitor the infant closely for signs and symptoms of botulism and for adverse events from BAT. - Although the risk for acquiring botulism from the breast milk of mothers who have botulism and do not receive antitoxin treatment is unknown, clinicians and family members should be aware that botulism is a life-threatening illness and that the delay between a request for antitoxin to administration of the antitoxin is typically 1-2 days. Interruption of breastfeeding for this period would have minor to no consequences for the child but could affect maternal milk supply and lead to a serious breast infection. If the decision is made to temporarily stop breastfeeding, the mother should express her milk and throw it away until administration of the antitoxin. This should be done with support from a lactation specialist. ## Critical care: considerations during shortages With adequate critical care, especially intubation and mechanical ventilation when needed, almost all patients with botulism survive and eventually fully recover, even without receiving antitoxin. Clinicians should proactively manage and prioritize critical care to avoid shortages. Thorough planning can be used to anticipate several measures that, when implemented promptly during an outbreak, can help prevent or reduce critical care shortages. When a botulism outbreak is recognized, the extent of the outbreak should guide the mobilization of local, regional, and federal assets as quickly as possible on an appropriate scale. This might include early transfer of supplies and equipment (e.g., intubation supplies, bag-mask combinations, ventilators, sedatives, anesthesia machines, and transport ventilators) from regional or federal sources to the treating medical facilities. Because botulism is not contagious and patients are usually hemodynamically stable, moving patients to facilities with adequate resources might be critical during a large outbreak; proactive mobilization of transportation resources in such circumstances is important. ## Supportive care Because generalized paralysis can require prolonged intubation and mechanical ventilation, many patients are hospitalized for weeks to months and might be at risk for adverse events that complicate their care. Various recommendations and guidelines are available to help prevent serious complications such as catheter-associated urinary tract infections, pressure ulcers, DVT, and ventilator-associated pneumonias. Because of the similarities between Guillain-Barré syndrome and botulism, experience with caring for patients who have this more common disease might be helpful. Several reports highlight major issues that can complicate Guillain-Barré syndrome and multidisciplinary approaches to prevent them. Because the complications of prolonged paralysis are well known to clinicians and general guidelines are available to help prevent complications, these guidelines focus on issues that might be unique to patients with botulism or that require additional attention. Because botulinum toxin is unlikely to cross the bloodbrain barrier in humans, the toxin does not exert any direct effect on the central nervous system. Patients with botulism are typically alert and have no cognitive deficits unless they are hypoxic, are intoxicated from alcohol or illicit drugs (e.g., black tar heroin), are receiving sedatives, or have a secondary process resulting in decreased cognition. Facial paralysis, ophthalmoplegia, slurred speech, and inability to respond to requests because of muscle weakness might lead persons to think the patient has altered mental status or is comatose, although they actually are alert, aware, and listening and comprehending. The importance of understanding that patients with botulism are typically awake and alert despite their appearance is highlighted by one patient's description of being unable to communicate with her health care providers initially and undergoing painful procedures (e.g., EMG and NCS) with no explanation from clinicians. One study systematically reviewed communication methods among conscious, critically ill patients who were receiving mechanical ventilation and provided an algorithm that might be used to optimize communication. Patients with botulism and their families experience emotional distress because of the life-threatening nature of botulism, the unpredictable prognosis of the condition, the need for multiple medical procedures, and communication difficulties. Psychosocial support services have been associated with a reduction in feelings of helplessness and anxiety among patients and family members by the second week of hospitalization. Clinicians who have cared for patients with botulism have reported that music, massage therapy, and reading aloud were often beneficial to their patients (CDC, unpublished data, 2016). Patients with botulism often have autonomic dysfunction because of impairments in the parasympathetic nervous system, resulting in dry eyes, dry mouth, urinary retention, and ileus. However, anecdotal reports from a 2015 Ohio botulism outbreak linked to potato salad indicated that patients reported copious oral secretions, perhaps because of dysphagia and the decreased ability to swallow oral secretions (CDC, unpublished data, 2016). ## Recommendations - Inform staff members that patients with botulism are typically cognitively intact. - Establish a system to enable communication between the patient and health care providers. Explain procedures before performing them. - Provide meticulous attention to bladder and bowel care and the prevention of complications, such as urinary tract infections, DVT, and pressure ulcers. - Assess patients for anxiety and depression and provide psychological support as needed. - Institute speech, physical, and occupational therapy as soon as possible. - Consider music and massage therapy and asking family members or staff members to read aloud to the patient. - Evaluate for and treat dry eyes and dry mouth; anticipate the possibility of copious oral secretions. - Educate family members about botulism, and provide information about supportive care, treatment, and prognosis. Discuss psychosocial support resources that might be available to family members, and consider instituting support groups if multiple patients are hospitalized in the same facility or in nearby facilities. # Conclusion The systematic reviews and discussions during the forums and workshop identified evidence gaps in the diagnosis, monitoring, and treatment of patients with botulism. For clinical diagnosis, identification of clinical features that increase the sensitivity and specificity of clinical diagnosis could facilitate treatment decisions and clinical management. For laboratory diagnosis, the number of days that botulinum neurotoxin persists in the serum of the average patient with botulism is not well established. Better data on the persistence of toxin in serum would help ensure laboratory testing is conducted when warranted. Regarding monitoring neurologic and respiratory status, the optimal methods and frequency of assessment also are unclear. Identifying the optimal methods and frequency would ensure resources are used appropriately, which is especially important in contingency or crisis standards of care. From the treatment standpoint, the point in the course of illness at which botulinum antitoxin offers no further benefit has not yet been identified. Identifying this point might help determine a process for administering antitoxin during an antitoxin shortage. These evidence gaps remain because of the rarity of botulism and a lack of evidence that is more robust than case reports and case series. Prospective studies of patients with botulism might help address these gaps, providing clinicians and public health professionals with additional data on how to treat patients and prepare for and respond to botulism outbreaks.	None	https://www.cdc.gov/mmwr/volumes/70/rr/pdfs/rr7002a1-H.pdf	Summary Botulism is a rare, neurotoxin-mediated, life-threatening disease characterized by flaccid descending paralysis that begins with cranial nerve palsies and might progress to extremity weakness and respiratory failure. Botulinum neurotoxin, which inhibits acetylcholine release at the neuromuscular junction, is produced by the anaerobic, gram-positive bacterium Clostridium botulinum and, rarely, by related species (C. baratii and C. butyricum). Exposure to the neurotoxin occurs through ingestion of toxin (foodborne botulism), bacterial colonization of a wound (wound botulism) or the intestines (infant botulism and adult intestinal colonization botulism), and high-concentration cosmetic or therapeutic injections of toxin (iatrogenic botulism). In addition, concerns have been raised about the possibility of a bioterrorism event involving toxin exposure through intentional contamination of food or drink or through aerosolization. Neurologic symptoms are similar regardless of exposure route. Treatment involves supportive care, intubation and mechanical ventilation when necessary, and administration of botulinum antitoxin. Certain neurological diseases (e.g., myasthenia gravis and Guillain-Barré syndrome) have signs and symptoms that overlap with botulism. Before the publication of these guidelines, no comprehensive clinical care guidelines existed for treating botulism. These evidence-based guidelines provide health care providers with recommended best practices for diagnosing, monitoring, and treating single cases or outbreaks of foodborne, wound, and inhalational botulism and were developed after a multiyear process involving several systematic reviews and expert input.
13bcc6bc4c78dfb24c3cd7d4d643b794bf161fd4	pubmed	Radiologic Evaluation and Structured Reporting Form for Extrahepatic Bile Duct Cancer: 2019 Consensus Recommendations from the Korean Society of Abdominal Radiology	Radiologic Evaluation and Structured Reporting Form for Extrahepatic Bile Duct Cancer: 2019 Consensus Recommendations from the Korean Society of Abdominal Radiology ## Drafting key questions and statements and initial presentation In each section, key questions essential to the imaging evaluation of EHD cancer were developed, and the assigned members brainstormed for all possible recommendations for each key question. Initially, 64 recommendation statements were developed, and they were presented at the annual KSAR meeting on April 26, 2019, with approximately 120 participating KSAR members. The reasons for developing consensus recommendations for EHD cancer and the first draft of statements to be included in the KSAR recommendations were presented at this meeting. An open discussion followed, and all KSAR members commented on each statement and the approach used to develop the consensus recommendations. ## Amendment of key questions Statements were refined after the annual KSAR member meeting, followed by offline and online group meetings. Duplicated or redundant items were deleted or merged, and items deemed essential for the imaging evaluation of EHD cancer were maintained. Finally, 13 key questions with 24 statements were chosen. ## Development of a structured reporting form Imaging studies are essential for initial decisions on patients with EHD cancer by radiologists. Although most radiologists currently do freestyle dictation to report imaging findings, it is limited by inter-reader variability, non-standardized descriptive terms, and possible omission of key findings, among others. Therefore, there is an increasing clinical need for structured reporting forms. Several societies have suggested structured reporting forms for pancreas cancer and rectal cancer. However, no structured reporting forms have been published for EHD cancer, from the perspective of radiologists, with special emphasis on consistent terminology and image interpretation. Therefore, the KSAR study group for EHD cancer was determined to develop a structured reporting form for EHD cancer based on key questions and corresponding recommendation statements. ## Agreement voting After the key questions and statements were finalized, a consensus voting for all statements was held at the KSAR annual organ-based meeting on July 20, 2019. Before voting, participants were asked about their experience in biliary imaging, and only the results of those who had more than two years of experience were used for the analysis. The six-point modified Delphi method was used to collect the opinions of the participants. The participants replied to each statement using one of six choices: "strongly agree," "agree with minor reservations," "agree with major reservations," "disagree with minor reservations," "disagree with major reservations," and "strongly disagree". If more than 80% of the participants with more than 2 years of experience in biliary imaging chose "strongly agree" or "agree with minor reservations" for a given statement, it was considered to have reached consensus. Additionally, two issues on the structured reporting form were heavily debated within the KSAR study group before the annual meeting, and participants voted on their inclusion in the consensus recommendations. ## Determination of evidence level After a consensus was reached on all statements, relevant literature was reviewed again by the KSAR study group for EHD cancer, and the evidence level of each statement was graded based on the criteria of the Oxford Centre for Evidence-Based Medicine from I (highest) to V (lowest). # Results # Voting results Among the KSAR members who voted on each statement (mean: n = 79; range:, approximately 90% (n = 71; range: 67-79) had more than two years of experience in biliary imaging. After voting, 23 of 24 statements reached consensus. For the structured reporting form, the two heavily debated issues did not reach consensus, and they were not included in the final structured reporting form. The first issue, "Length of main portal vein (MPV) invasion should be included in the structured form," got an agreement of 51.4%; thus, it was excluded from the structured reporting form. The length of MPV invasion is https://doi.org/10.3348/kjr.2019.0803 kjronline.org is more important than the length. This may account for the exclusion of this item after it did not reach a consensus. Subsequently, the final assessment of resectability was excluded from the structured reporting form. The statement, "Final assessment (resectability) should be included in the structured reporting form," was agreed to by only 45.5%. To determine the resectability of EHD cancer, factors such as tumor extent, major vascular invasion, vascular or biliary anatomy, ability to reconstruct vessels, and future remnant liver volume need to be considered. Furthermore, decisions regarding tumor resectability may vary between surgeons and institutions without established criteria. Therefore, we concluded that it would be better not to include a standardized resectability assessment in the structured reporting form for EHD cancer. ## Section 1. nomenclature and definition ## Kq 1. what are the criteria for classifying perihilar bile duct cancer and distal bile duct cancer? Statement 1: EHD cancer can be classified as perihilar or distal based on the insertion site of the cystic duct (agreement level, 89.9%; evidence level, not applicable [n/a]). The EHD is composed of the right extrahepatic duct, left extrahepatic duct, common hepatic duct, and common bile duct. Based on the cystic duct insertion site, the EHD can be subdivided into the perihilar area, which includes the right/left extrahepatic duct and the common hepatic duct, and the distal bile duct, which extends from the confluence of the cystic and common hepatic ducts to the ampulla of Vater (excluding the ampulla itself). The KSAR study group for EHD cancer discussed and agreed to use the terms 'perihilar bile duct cancer' and 'distal bile duct cancer' throughout the consensus recommendations, as these terms were intuitive and consistent for distinguishing the two parts of the EHD. EHD cancer is classified into these two categories because surgical techniques and surgical fields differ significantly between them. Furthermore, the T staging of tumors is also different, probably because the distribution of smooth muscles differs with location. The KSAR study group for EHD cancer also discussed how to establish a reference point for classifying the perihilar area and distal bile duct. According to previous studies, only 51-75% of cystic duct insertion sites are located in the middle third of the EHD. Therefore, the KSAR members debated on whether dividing the perihilar area and the distal bile duct by the cystic duct insertion site was appropriate even when the cystic duct insertion site was not located in the middle of the EHD. Although new criteria were suggested, the KSAR study group for EHD cancer finally agreed to follow traditional standards, because the location of the cystic duct insertion site is not of clinical importance for treatment plans, and creating a new reference point can also create controversy. Perihilar bile duct cancer can extend into the intrahepatic bile duct or even the liver parenchyma, and EHD cancer may involve both the perihilar area and distal bile duct. In this case, the location of the tumor epicenter can be a reference point for categorization. However, describing the area of tumor involvement is more important because treatment plans are mainly determined based on tumor extent. ## Kq 2. how is the gross morphology of extrahepatic bile duct cancer categorized? Statement 2: EHD cancer can be classified into the massforming, periductal-infiltrating, or intraductal-growing type based on growth patterns (agreement level, 92.5%; evidence level, n/a). Because the gross morphology of EHD cancer can present with different imaging findings and tumor biology, descriptions of the gross tumor morphology can help in determining treatment plans and prognosis. Various terminologies have been suggested for the gross morphology of EHD cancer, such as mass-forming/nodular/ small fibrous nodules, periductal infiltrating/flat/sclerosing/ segmental stenosis, and intraductal growing/papillary or papillary growth. The KSAR study group for EHD cancer aimed at determining appropriate terms that were intuitive, representative, and familiar to radiologists, and it recommended the mass-forming, periductal-infiltrating, and intraductal-growing type to classify the gross morphology of EHD cancer. EHD cancer usually presents as the periductal-infiltrating type or intraductal-growing type. The periductal-infiltrating type spreads longitudinally through the periductal or perineural connective tissue and lymphatics even with intact mucosa, whereas the intraductal-growing type spreads superficially along the mucosa. Lymph node (LN) metastasis is more common and the periductal-infiltrating type shows a worse prognosis than the intraductal-growing type. Sometimes, EHD cancer can also present as a mixed type with two or more gross morphologies. ## Section 2. imaging technique ## Kq 3. which imaging modality is recommended for patients suspected with extrahepatic bile duct cancer, and when do we perform an imaging study if biliary intervention is needed? Statement 3: Contrast-enhanced CT and/or contrastenhanced MRI with MR cholangiopancreatography (MRCP) are recommended to evaluate EHD cancer (agreement level, 100%; evidence level, IV). Statement 4: Imaging studies are recommended before any biliary interventional procedure whenever possible (agreement level, 98.6%; evidence level, IV). With recent advances in multidetector CT (MDCT) technology, CT provides rapid temporal resolution as well as high spatial resolution. Therefore, contrast-enhanced abdominopelvic CT is recommended when staging malignant diseases. In regards to EHD cancer, CT could facilitate the assessment of the extent of the primary EHD cancer and the relationship between the tumor and adjacent vascular structures, including the hepatic artery and PV, which is very important for tumor resectability. CT also provides information on distant metastases such as liver or distant LN metastasis and/or peritoneal seeding. Thus, contrastenhanced abdominopelvic CT has been regarded as the initial and standard imaging modality for patients suspected of EHD cancer. Contrast-enhanced MR has been https://doi.org/10.3348/kjr.2019.0803 kjronline.org regarded as an alternative imaging modality to contrastenhanced CT for malignant diseases; however, it may be the initial imaging modality for patients who are hypersensitive to iodinated contrast media. In addition, MRCP can provide detailed information about the bile duct anatomy as well as the extent of EHD cancer. Several studies have kjronline.org reported that contrast-enhanced MR with MRCP can provide diagnostic accuracy that is comparable to that of contrastenhanced abdominopelvic CT with direct cholangiography when assessing the longitudinal tumor extent, vascular involvement, and tumor resectability of EHD cancer. It is also important to distinguish distal bile duct cancer from pancreatic cancer because chemotherapy regimens and prognoses differ, especially in unresectable cases. MRI with MRCP may help in ascertaining the origin of periampullary cancer. Hence, we recommend contrastenhanced CT and/or contrast-enhanced MR with MRCP to evaluate EHD cancer. Patients with EHD cancer usually present with jaundice due to bile duct obstruction, and a substantial portion of EHD cancer patients suffer from cholangitis and biliary sepsis as bile flow is blocked off. When biliary infections result from EHD cancer, an endoscopic or percutaneous biliary drainage procedure has to be urgently performed. However, biliary interventions such as the insertion of drain catheters can cause inflammatory changes in the bile duct. This can mimic tumor involvement and negatively affect the diagnostic performance of imaging studies that assess the extent of EHD cancer. Taking this into consideration, we recommend imaging studies before any biliary interventional procedures whenever possible. However, no studies have accurately evaluated how biliary drainage procedures affect the diagnostic performance of imaging studies for assessing the tumor extent of EHD cancer. Additionally, no data has conclusively demonstrated the extent of reduction in diagnostic accuracy after biliary drainage procedures. The effect of biliary drainage procedures on the diagnostic performance of imaging studies for EHD cancer should be evaluated in a future study. ## Kq 4. what is the optimal ct protocol for evaluating extrahepatic bile duct cancer? Statement 5: Multiphase imaging, which includes the precontrast, arterial, and portal venous phase, is recommended (agreement level, 97.1%; evidence level, IV). Statement 6: A slice thickness of 3 mm or less is recommended (agreement level, 95.7%; evidence level, V). Statement 7: Multiplanar reconstruction can aid the evaluation of relationships between EHD cancer and adjacent structures (agreement level, 98.6%; evidence level, IV). Statement 8: Including the pelvis in at least one phase is recommended (agreement level, 85.9%; evidence level, V). Multiphase images with contrast enhancement are usually obtained to evaluate EHD cancer (34). By acquiring multiphase images before and after the administration of contrast media, it is possible to adequately evaluate radio-opaque stones, vascular structures, and abdominal organs (35). Precontrast images help clinicians to detect intraductal stones and differentiate them from tumors. Although some studies showed that routine acquisition of the arterial phase is not necessary for the detection and evaluation of EHD cancer and its extent (36, 37), the AJCC guidelines recommend that dynamic imaging be performed during the arterial and portal venous phases. The arterial phase is useful for enhancing the conspicuity of the distal bile duct cancer against the background. The portal venous phase is useful for judging the extrapancreatic extent of the distal bile duct cancer and detecting liver metastases (1). The delayed phase, which is usually observed 3-5 minutes after the injection of contrast agent, is not commonly acquired for EHD cancer. Detailed imaging findings of EHD cancer are described in Key Question 6 and its statements. Thin-section imaging is recommended for EHD cancer . No studies have conducted a head-to-head comparison between thin-and thick-section CT imaging to evaluate EHD cancer. Several studies use CT images with a slice thickness between 1.5 and 3 mm to distinguish benign papillary strictures from malignant ampullary tumors or determine the resectability of EHD cancers (40-43). The AJCC guidelines suggest 2-to 3-mm thicknesses for thinsection CT imaging (1). Thus, we recommend a CT slice thickness of 3 mm or less. Although axial CT is useful for evaluating biliary trees, cross-sectional images have limited value in demonstrating complex anatomical relationships. In this regard, multiplanar reformation (MPR) images are better at demonstrating the relationships between tumors and adjacent structures . Longitudinal and vertical extensions of tumors can be identified with MPR images (49-52). MPR images can also help radiologists to assess vascular invasion of the primary tumor (49, 53, 54). Curved planar reformation along the course of specific anatomic structures such as bile ducts and vessels is also useful when evaluating the longitudinal extent of the bile duct tumor (55-57). MDCT should facilitate the assessment of distant metastases in addition to the primary EHD tumor . Peritoneum and LNs are among the most common https://doi.org/10.3348/kjr.2019.0803 kjronline.org metastatic sites in both perihilar and distal bile duct cancers . Hence, MDCT that involves the abdomen and pelvis at initial staging is recommended to detect distant metastases such as peritoneal seeding, as this knowledge is critical for appropriate treatment plans and prognostic predictions. To evaluate EHD cancer, precontrast images should always include cross-sectional T2-weighted and T1-weighted sequences as well as heavily two-dimensional (2D) and/or three-dimensional (3D) T2-weighted MRCP, which has been accepted as an effective imaging modality for demonstrating the presence and level of biliary obstruction (58). 3D MRCP has superior image quality and ductal conspicuity than 2D MRCP, although no significant difference was observed when evaluating tumor extent (59). When gadolinium-based contrast agents are used, multiphasic dynamic fat-saturated 3D gradient-echo T1-weighted imaging (T1WI), involving the arterial and portal venous phases, is recommended. For hepatobiliary agent (HBA)-enhanced MRI, T2-weighted sequences and DWI can be performed after contrastenhanced dynamic phases to shorten examination times (60-63). However, heavily T2-weighted MRCP should be performed before the contrast agent is excreted into the biliary tree (60, 64). With higher concentrations of contrast agent in the biliary ductal system, the signal intensity of the bile appears darker on T2-weighted images (T2WIs) owing to the T2-shortening effect. DWI, typically using 0 to 100 sec/mm 2 and 800 to 1000 sec/mm 2 for low and high b values, respectively, can provide additional information for patients with EHD cancer. The application of a 3T MRI system and parallel imaging techniques to DWI can enhance the signal-tonoise ratio and lesion-to-liver contrast by improving image quality. Some studies have reported that adding DWI to conventional MRI shows a high sensitivity for bile duct cancer, and it helps differentiate benign from malignant bile duct strictures. DWI may also facilitate the evaluation of tumor extent and liver invasion as well as help differentiate liver metastases from biliary abscesses. ## Section 3. cancer evaluation ## Kq 6. which imaging features indicate the presence of extrahepatic bile duct cancer? Statement 11: On contrast-enhanced CT or MRI, EHD cancer is indicated by irregular ductal wall thickening with upstream ductal dilatation, hyper-enhancement of the ductal wall relative to the liver, and/or obliteration of the lumen by an intraductal soft-tissue mass or thickened ductal wall (agreement level, 100%; evidence level, III). Statement 12: On cholangiography, EHD cancer is indicated by the abrupt and/or irregular narrowing of the bile duct and irregularly shaped filling defects within the lumen (agreement level, 94.5%; evidence level, III). On cross-sectional imaging and cholangiography, scarlike fibrosis and/or intraductal tumors can result in irregular ductal wall thickening, luminal narrowing, and luminal obliteration, causing upstream bile duct dilatation. EHD tumors show increased enhancement to the liver on the arterial and/or portal venous phase; fibrosis and scirrhous tissue are better visualized on later phases. EHD cancer also more commonly presents with thicker bile duct wall, longer involved segment, luminal irregularity, asymmetric narrowing, and high signal intensity on DWI, compared to benign strictures. However, these features are also found in benign biliary diseases, including but not restricted to primary sclerosing cholangitis, AIDSrelated cholangiopathy, immunoglobulin G4-related sclerosing cholangitis, recurrent pyogenic cholangitis, and ischemic cholangitis. Thus, further histologic evidence is often required to confirm the diagnosis of bile duct abnormalities. ## Kq 7. how is the biliary tree classified when evaluating the longitudinal extent of extrahepatic bile duct cancer? Statement 13: Longitudinal involvement of EHD cancer can be assessed by classifying the presence/absence of tumor involvement in the right secondary confluence, right hepatic duct, primary confluence, left hepatic duct, left secondary confluence, common hepatic duct, suprapancreatic common https://doi.org/10.3348/kjr.2019.0803 kjronline.org bile duct, and intrapancreatic common bile duct (agreement level, 89.0%; evidence level, V). Statement 14: The Bismuth-Corlette classification is recommended for the imaging assessment of bile duct involvement in perihilar bile duct cancer (agreement level, 97.3%; evidence level, V). Statement 15: Proximal and distal extensions of perihilar bile duct cancers and proximal extensions of distal bile duct cancers are included in the imaging assessment for bile duct involvement (agreement level, 95.8%; evidence level, V). Various terminologies have been proposed to describe the longitudinal extent of bile duct cancers. The modified Bismuth-Corlette classification is one of the most widely accepted systems, which uses primary confluence and right or left secondary confluence to describe tumor extent. The Bismuth-Corlette system defines the longitudinal extent of the tumor relative to the biliary confluences, which may roughly yield the estimated extent of surgery. However, the applicability of the system is limited by biliary variation, and the potential resectability or scope of surgery may vary even among patients with the same Bismuth-Corlette type. Therefore, when reporting Bismuth-Corlette classifications, the anatomic variation of the bile duct should be described in detail as well, if present. The longitudinal extent of the tumor dictates the type of curative surgery, such as pancreaticoduodenectomy, hepatopancreaticoduodenectomy, hepatobiliary resection, or segmental bile duct resection, to be performed. Hepatobiliary resection, with or without pancreaticoduodenectomy, is regarded as the standard curative surgery for perihilar bile duct cancer. Hepatopancreaticoduodenectomy is a challenging procedure with high morbidity and mortality rates, but it gives patients a chance for long-term survival when curative resection is feasible. Thus, an accurate description of the proximal and distal extent of the perihilar bile duct cancer as well as the proximal extent of the distal bile duct cancer may help in determining appropriate treatment. In retrospective studies, the accuracy of enhanced CT for the longitudinal tumor extent ranged from 75-96%. In a meta-analysis, the pooled accuracy for CT was 86%. MR cholangiography showed a similar accuracy of 71-80%, and adding enhanced MRI increased accuracy to 87-93.3%. However, imaging studies may underestimate the longitudinal extent of the tumor; microscopic tumors that spread through the mucosa or submucosa are unnoticeable on imaging, although this results in positive resection margins. ## Kq 8. how do we evaluate tumor vascular invasion on mdct and mri for extrahepatic bile duct cancer? Statement 16: The hepatic artery and PV, as well as their branches, and the variant hepatic vessels should be evaluated for tumor invasion, depending on the anatomic location of the EHD cancer (agreement level, 97.2%; evidence level, V). Statement 17: Tumor vascular invasion is indicated by the tumor encasement of vessels, vessel deformity, occlusion, or tumor thrombus (agreement level, 92.6%; evidence level, III). Statement 18: The degree of tumor-vessel contact is classified as no contact (preserved tumor-vessel fat plane), abutment (tumor involvement up to 50% of the vessel circumference), or encasement (tumor involvement more than 50% of the vessel circumference) (agreement level, 95.7%; evidence level, V). The evaluation of tumor vascular invasion is crucial when determining the resectability of EHD cancer, especially for perihilar bile duct cancer. In a previous meta-analysis, the pooled sensitivity and specificity of MDCT for assessing the vascular invasion of perihilar bile duct cancer was 89% (95% confidence interval [CI], 80-94%) and 92% (95% CI, 85-96%), respectively, for PV invasion, and 84% (95% CI, 63-94%) and 93% (95% CI, 69-99%), respectively, for hepatic artery invasion. Tumor vascular invasion on MDCT and MRI is determined by the degree of tumor contact with vessels, vessel deformity, and vessel occlusion or tumor thrombus. We recommend classifying the degree of tumor-vessel contact as no contact (preserved tumor-vessel fat plane), abutment (tumor involvement up to 50% of the vessel circumference), or encasement (tumor involvement more than 50% of the vessel circumference), following the NCCN guidelines for pancreatic cancer (95). Although previous studies evaluated imaging criteria for the vascular invasion of EHD cancer , all of them were retrospective with small to moderate study populations. Another point of consideration is that perivascular infiltration may not always be a tumor; it may be an inflammatory infiltration. In most of these cases, surgery was not performed and, hence, perivascular infiltration was not pathologically confirmed.. Thus, radiologists cannot arrive at a confident diagnosis of vessel invasion using only tumor abutment. However, this finding should be reported in radiologic reports for doctors to consider when planning surgery or considering surgical resectability through multidisciplinary discussions. ## Kq 9. how do we evaluate lymph node metastasis in extrahepatic bile duct cancer? Statement 19: LNs are considered suspicious for metastatic involvement if they are greater than 1 cm Only a few reports on the diagnostic accuracy of LN metastasis in EHD cancer are available. Previous studies have used various combinations of characteristics such as a short diameter of 1 cm, abnormal round morphology, heterogeneous enhancement, or central necrosis to diagnose LN metastasis. A meta-analysis for hilar bile duct cancer yielded a sensitivity of 61% and a specificity of 88% for detecting LN metastases. In terms of LN size, a cutoff of 1 cm for the short diameter is the diagnostic criterion for LN metastasis for other malignancies; metastatic LNs are significantly larger than their non-metastatic counterparts. However, a previous study reported that only 23% of LNs larger than 1 cm were associated with metastatic cells, and 10% of LNs smaller than 1 cm harbored metastatic cells. Furthermore, enlarged reactive regional LNs are more frequent in EHD cancer than in other malignancies because of the accompanying obstructive cholangitis. Therefore, the size criterion should be used with other imaging criteria to provide a reliable diagnosis of LN metastasis on imaging studies. Combinations of the size criterion and round morphology or internal heterogeneity demonstrated an increased positive predictive value for LN metastasis, compared with the size criterion alone. However, the low prevalence of such characteristic LNs is a limitation of this approach. For the preoperative assessment of LN metastasis, similar limitations have been reported for other malignancies as well. Although imaging studies do not show enough accuracy to assess LN metastasis, LNs greater than 1 cm along the short axis with abnormal round morphology, heterogeneous enhancement, or central necrosis are more likely to be metastatic. According to findings from recent studies, 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-CT may help radiologists in differentiating LN metastasis from its differentials. ## Kq 10. how do we evaluate distant metastasis in extrahepatic bile duct cancer? Statement 20: MRI or 18F-FDG PET-CT is recommended for evaluating indeterminate or suspicious findings of distant metastasis on CT (agreement level, 92.6%; evidence level, V). The liver is the most common (11.9-23.2%) site of metastasis, followed by the lung (2.7-5.8%) and distant LNs (3.0-4.4%). The peritoneum is also a common site of metastasis; however, the exact prevalence of metastasis is unknown. Diagnosing liver metastasis is a challenge in EHD cancer patients because small biliary abscesses frequently coexist due to biliary obstruction. The findings from previous studies suggest that patchy parenchymal enhancement, arterial rim enhancement persistent through portal venous phase and perilesional hyperemia on CT and MR, and size discrepancy between T1WI and T2WI as well as T1WI and the hepatobiliary phase on MR are indicative of biliary abscess rather than liver metastasis (108, 109). Short-term follow-up with imaging can also help radiologists to assess lesional size changes. An ultrasound-guided biopsy may also aid differential diagnosis if technically feasible. The extent and location of regional LNs are defined differently for perihilar bile duct cancer and distal bile duct cancer. Hilar, cystic duct, choledochal, portal, hepatic arterial, and posterior pancreaticoduodenal LNs are classified as regional LNs in perihilar bile duct cancer, whereas the common bile duct, hepatic artery, the posterior and anterior pancreaticoduodenal, and the right lateral wall of the superior mesenteric artery LNs are classified as regional LNs in distal bile duct cancer. The differential diagnoses of reactive and metastatic LNs are described in detail in Peritoneal metastases are frequently underestimated on CT. In a meta-analysis of peritoneal metastases in all cancers, 18F-FDG PET-CT demonstrated good sensitivity (87%) and specificity (92%) for the detection of peritoneal metastasis. ## Kq 11. how do we assess the resectability of extrahepatic bile duct cancer beyond the tumor staging/extent? Statement 21: The future remnant liver volume as well as biliary and vascular anatomic variations has to be evaluated to determine the resectability of perihilar bile duct cancer (agreement level, 98.5%; evidence level, VI). Statement 22: A multidisciplinary team consultation is recommended when deciding or assessing resectability (agreement level, 91.7%; evidence level, n/a). kjronline.org depends on hilar biliary and vascular anatomy. For example, the anterior and posterior sectional branches of the right hepatic duct drain directly into the main hepatic duct at a 20% frequency; hence, this case may be misdiagnosed as the Bismuth classification type IV, which is an unresectable case, when the hilar tumor involves the right anterior and posterior hepatic ducts with a segmental involvement of the left side. However, if diagnosed properly, radical resection with an extended left hepatectomy may be preferred as a curative treatment. Various anatomic variations may exist, but the important consideration is whether blood flow to the remaining liver can be preserved. The availability of surgical techniques, such as vascular reconstruction, should also be considered. Because extended hepatic resections are usually required for curative treatment, it is important to estimate the future remnant liver volume in patients with perihilar bile duct cancer. According to previous studies, a future remnant liver volume of > 25-30% is considered a safe cutoff for patients with healthy liver parenchyma, whereas > 40% is considered in patients with compromised livers such as cholestatic livers. CT and MRI are standard techniques for assessing future remnant liver volume. The diagnosis and management of EHD cancer are challenging, and it requires skilled experts. As diagnosis and management of EHD cancer are complex and the availability of surgical resection or liver transplantation depends on surgical expertise, an optimal assessment and decision on resectability require a multidisciplinary collaboration between hepatobiliary surgeons, endoscopists, radiologists, medical oncologists, and pathologists. ## Section 4. tumor response ## Kq 12. how do we evaluate treatment response through imaging after chemotherapy for patients with extrahepatic bile duct cancer? Statements 23: Contrast-enhanced CT or MRI with MRCP, according to the response evaluation criteria in solid tumors (RECIST), is recommended (agreement level, 90.5%; evidence level, V). According to previous literature, most researchers use their follow-up protocols for patients with EHD cancer placed on chemotherapy . There is currently no "standard" follow-up strategy for assessing patients after chemotherapy for EHD cancer with imaging modalities. However, most studies on clinical trials for new drugs have used the RECIST criteria to assess tumor response. We recommend contrast-enhanced CT and contrastenhanced MRI with MRCP as imaging modalities for assessing tumor response using the RECIST criteria. A universal follow-up schedule has not been discussed in these guidelines; schedules should be determined by clinicians according to chemotherapy regimen, complications such as biliary obstruction or infection, and disease stage. This statement on the optimal contrast media for EHD cancer did not reach a consensus because there was not enough data to support the diagnostic superiority of MRI with ECA (ECA-MRI) over MRI with gadoxetate disodium (HBA-MRI) for EHD cancer. So far, only a few publications have evaluated the clinical applications of HBA-MRI when assessing EHD cancer. ## The key questions and statement which did There are several drawbacks to using HBA-MRI in the preoperative evaluation of bile duct cancer. First, there are concerns about transient motion artifacts that appear during the arterial phaseand less vascular enhancement due to the lower amount of administered gadoxetate disodium (0.025 mmol/kg vs. 0.1 mmol/kg for extracellular gadolinium chelates). Second, the uptake of HBA into hepatocytes and its excretion into the biliary tree can be hindered by high bilirubin related to biliary obstruction. In addition, the increased signal intensity of the liver may hinder the evaluation of bile duct wall enhancement. Third, the cost of performing HBA-MRI is higher than that of ECA-MRI ## Structured reporting form This structured reporting form was developed to provide a common reporting form for EHD that could be readily used in daily clinical practice. If a structured reporting form is complicated, it will be inconvenient to incorporate it into clinical practice, and it will eventually be shunned by the medical community. Therefore, a structured reporting form for EHD should be as simple as possible; however, it should include essential items such as bile duct involvement, vessel invasion, regional LN metastasis, and distant metastasis evaluation, while noting whether the EHD cancer is located on the perihilar bile duct or distal bile duct. The starting questions of the structured reporting form should ## Summary Twelve key questions and 23 statements on the imaging analysis of EHD cancer were confirmed through consensus at several meetings. A structured reporting form was developed based on these key questions and recommendation statements, which included essential items to be evaluated such as bile duct involvement, vessel invasion, and LN and distant metastasis. Although the evidence levels of most recommendations were low due to insufficient research, the consensus recommendations and the structured reporting form were developed to summarize existing findings and clarify future research topics. Furthermore, the proposed structured reporting form can be used to accumulate standardized data progressively; based on newly collected data, guidelines may be revised when answers are found to questions that are currently unresolved. This will increase the evidence levels of the current recommendations.	None	https://europepmc.org/articles/pmc7772383?pdf=render	Radiologic imaging is important for evaluating extrahepatic bile duct (EHD) cancers; it is used for staging tumors and evaluating the suitability of surgical resection, as surgery may be contraindicated in some cases regardless of tumor stage. However, the published general recommendations for EHD cancer and recommendations guided by the perspectives of radiologists are limited. The Korean Society of Abdominal Radiology (KSAR) study group for EHD cancer developed key questions and corresponding recommendations for the radiologic evaluation of EHD cancer and organized them into 4 sections: nomenclature and definition, imaging technique, cancer evaluation, and tumor response. A structured reporting form was also developed to allow the progressive accumulation of standardized data, which will facilitate multicenter studies and contribute more evidence for the development of recommendations.
269a90740b7f66e7fea5f81959f7634973fb6aab	pubmed	Interdisciplinary S2k guidelines on the diagnosis and treatment of endometrial carcinoma	Interdisciplinary S2k guidelines on the diagnosis and treatment of endometrial carcinoma # Introduction The first recommendations for the diagnosis and treatment of endometrial cancer had been published by the Uterus Commission of the Gynecological Oncology Working Group (AGO), affiliated to the German Society for Gynecology and Obstetrics (DGGG) and the German Cancer Society (DKG), in 1999 (S1 guideline). This guideline was updated twice, on the S1-level, most recently in 2006. Between October 2007 and 2008 another update was performed on the S2k level by an interdisciplinary group of experts representative of the users. The methodologic procedure was based on the regulations described in the DKG's working instructions for producing interdisciplinary consensus-based guidelines. The process of developing consensus-based guidelines (S2 konsensus guidelines) does not provide the systematic preparation of the evidence; instead, a discussion and critical evaluation of the published literature are carried out by the members of the guideline group. During a consensus conference, the participants also have an opportunity to make suggestions for ways of expressing the detailed guideline text in more concrete ways and supplementing it. The basic principles and criteria for the grading of the recommendations are discussed at the start of the consensus procedure. Changes and additions to the guideline on the basis of the voting results during the nominal group process are carried out by the guideline coordinators. The revised version is sent in written form to all the members of the guideline group for final comments and adoption. ## Epidemiology and risk factors Endometrial cancer is the fourth most frequent cancer among women in Germany. EC is the ninth most frequent cause of cancer death. Type I EC (typically endometrioid EC) is related to exposition to unopposed estrogens. For the more aggressive type II EC (typically serous EC, clear cell EC) only old age and preceding radiotherapy of the uterus have been identified as risk factors. ## Early detection and screening Statements r General screening cannot be recommended r There is no evidence that the mortality can be reduced as a result of screening in high-risk populations Screening with endovaginal ultrasonography and subsequent endometrial biopsy may be useful in high-risk groups (obesity, diabetes mellitus, known endometrial hyperplasia, hereditary nonpolyposis colorectal cancer syndrome). Even in these women, however, there is a lack of studies to demonstrate the efficacy of screening. In HNPCC syndrome, prophylactic hysterectomy (?bilateral salpingoophorectomy) may be useful for prevention of EC (?ovarian cancer). ## Diagnosis Statements r It is necessary to obtain a histological sample in order to confirm the diagnosis r There are no imaging techniques capable of replacing surgical staging in endometrial carcinoma. In patients who are inoperable due to comorbidities, magnetic resonance imaging may be helpful for treatment planning Postmenopausal bleeding and all abnormal bleeding patterns in premenopausal patients with one of the risk factors mentioned above should be examined as follows: - gynecological examination. - Transvaginal ultrasonography (suspicious, if endometrial thickness of more than 5 mm in postmenopausal women with bleeding). In postmenopausal women on hormone or SERM therapy and in premenopausal patients measurement of the endometrial thickness alone is not diagnostically useful. - Hysteroscopy and fractionated curettage. precursor lesions is carried out in accordance with the WHO requirements r Minimum requirements for reporting histopathological findings in endometrial carcinoma are: tumor type, grading, depth of invasion into the Myometrium, cervical infiltration, lymph-node involvement, R classification, and vascular and lymphatic invasion ## Clinical/histopathological diagnosis The ''term'' adenomatous hyperplasia grades I-III should not longer be used. As both, serous and clear cell EC are associated with a poor prognosis, even at low tumor stages, this diagnosis must be explicitly mentioned, even if there is only focal evidence of it in a type I carcinoma or in an endometrial polyp. It is only when there is certain evidence of infiltration of the EC into the endocervical glands or endocervical stroma that curettage is capable of leading to a diagnosis of stage T2a or T2b. The value of intraoperative macroscopic assessment and/or frozen-section of the hysterectomy specimen is uncertain to define the depth of myometrial invasion. ## Structures for providing care Care for patients with preinvasive lesions or EC should be provided in collaboration between registered gynecologists in private practice and specialized centers for gynecological oncology, that work in accordance with the certification criteria of the AGO, the German Society of Gynecology and Obstetrics (DGGG) and the German Cancer Society (DKG). ## Patient information Statements r Information materials (print or Internet media) that are of high quality and produced with appropriate specialist competence should be provided, in accordance with the quality requirements set out in the Guideline on Gynecological Information. By communicating the risks in a comprehensible way (including details of incidences, rather than relative percentages), these materials should provide patients with support in taking independent decisions for or against medical procedures r Information should be communicated to the patient both comprehensively and accurately, observing the following basic principles of patient-centered communication (1) Expression of empathy and active listening (2) Direct and sensitive ways of touching on difficult subjects (3) If possible, avoidance of specialized medical terms, or with explanations of specialist terms being given if necessary (4) Strategies for improving understanding (repetition, summing up of important information, use of graphics, etc.) (5) Encouraging the patient to ask questions (6) Permission and encouragement to express emotions (7) Offering further assistance (e.g., from self-help groups, psychooncology, psychological cancer counseling) ## Basic principles of treatment for primary ec Decision making regarding the appropriate treatment is carried out in an interdisciplinary tumor board involving gynecological oncology, radiotherapy, anesthesiology, pathology and the patient. Only if there are contraindications for surgical treatment, primary radiotherapy and/or systemic treatment become an option. ## Treatment of precursors of ec Statements r Hyperplasia of the endometrium without atypia can be treated conservatively r Hyperplasia of the Endometrium with atypia is associated with a high risk of malignant change. Conservative treatment should only be attempted if the patient wishes to have a child and a high degree of compliance can be expected In patients with atypical endometrial hyperplasia there is a risk of 30% of progression to invasive EC and a risk of 20-40% of invasive EC in the hysterectomy specimen that has been missed by curettage. This risk has to be carefully balanced against the wish for fertility preservation. ## Conservative treatment for early ec Statement r Conservative therapy can be considered for women with welldifferentiated, progesterone receptor-positive endometrioid endometrial carcinoma in clinical stage 1a who strongly wish to have a child Due to the high risk of recurrence after conservative treatment, surgical therapy appropriate to the stage is required if the patient's wish for children has been fulfilled or abandoned. ## Surgical treatment Statements r Surgical treatment for endometrial carcinoma should include removal of a cytological sample from the abdominal cavity, hysterectomy, bilateral adnexectomy and pelvic and para-aortic lymphadenectomy up to the renal pedicle r In the presence of serous or clear cell carcinoma, multiple peritoneal biopsies should be taken and omentectomy should be carried out r In stages pT1a, pT1b and in the presence of G1 or G2, lymphadenectomy is optional r In stage pT2b, the parametria should also be resected If a lymphadenectomy has not been performed since stage 1a or 1b and G1 or G2 had been suspected but the final histology shows a higher stage or grade or high risk histology, the surgical staging should be completed in a second operation, if possible. Similarly, if a simple hysterectomy has been performed as no EC was suspected, and the pathologist describes an unexpected EC, an adequate surgical staging should be performed in a second operation. Lymph node removal should not be carried out as a sampling procedure, but definitely as systematic lymphadenectomy, including both, the pelvic and para-aortic nodes up to the renal veins. At least 15 pelvic and 10 paraaortic nodes should be removed. If there is relevant comorbidity, lymphadenectomy may be omitted. Lack of experience on part of the surgeon with lymphadenectomy in obese patients, or a lack of infrastructure for caring for patients with multiple morbidities cannot be used to justify failure to carry out lymphadenectomy. In these cases, the patient should be referred to a center for gynecological oncology. Routine frozen-section evaluation of the hysterectomy specimen or pelvic lymph nodes is not recommended generally, as this method is not sufficiently reliable, and complete pelvic and para-aortic lymphadenectomy is optional in patients who are at low risk. Frozen-section evaluation, however, may be useful in relation to specific issues in individual patients. If carried out by a surgeon familiar with the technique, laparoscopic lymphadenectomy in combination with laparoscopy-assisted vaginal hysterectomy/bilateral salpingooophorectomy appears to be as safe as the open abdominal procedures. ## Radiotherapy Statements r Primary radiotherapy for endometrial carcinoma is indicated if the patient is not operable due to comorbidity r In patients with a high risk of local recurrence, adjuvant radiotherapy should be carried out in order to reduce the risk of locoregional recurrence r Adjuvant radiotherapy has no effect on the overall survival in stages I and II r There are no adequate data on this topic for more advanced stages Recent randomized controlled trials and respective metaanalyses have shown that teletherapy of the pelvis significantly reduces the loco-regional recurrence rate in stages I and II EC, but has no beneficial effect on overall survival. The effects of brachytherapy and teletherapy reducing locoregional recurrence in stage I are comparable. In particular, if a systematic lymphonodectomy has demonstrated a pN0 status in type I EC stages I and II, teletherapy is not indicated. ## Systemic therapy Adjuvant systemic therapy Statements r Adjuvant endocrine therapy with gestagens has no therapeutic effect r In optimally operated endometrial carcinoma in stages III and IV, chemotherapy is an alternative to radiotherapy r In endometrial carcinomas in stages IC G3, II G3, and III, adjuvant chemotherapy may represent an alternative to radiotherapy A few randomized controlled trials have demonstrated that adjuvant systemic chemotherapy might be superior to or equivalent with traditional radiotherapy in high risk EC or advanced EC. As the data are not sufficient to recommend a replacement of adjuvant radiotherapy by adjuvant chemotherapy, the latter is classified as possible alternative to radiotherapies in the above mentioned situations. Palliative systemic therapy Statements r If surgery and/or radiotherapy are no longer possible in patients with recurrences or metastases, gestagen treatment is recommended for patients with progesterone receptor-positive carcinomas and asymptomatic metastases r If progression occurs during endocrine therapy, in receptornegative tumors, and when there are symptomatic and lifethreatening tumor signs, palliative chemotherapy may be useful r The indication for systemic combination chemotherapy regimens needs to be established strictly, in view of their lack of effect or only marginal effect on the overall survival ## Recurrences, metastases Statements r Resectable recurrences of endometrial carcinoma should be treated surgically r In inoperable patients, radiotherapy should be carried out r If neither surgery nor radiotherapy is possible, palliative systemic therapy should be carried out ## Supportive therapy Statement r Supportive therapy in accordance with the guidelines is required for prophylaxis against and minimization of treatment-related or tumor-related symptoms Apart from general supportive measures (antiemetic treatment, prevention and treatment of granulocytopenia, anemia, etc.) special consideration must be given in EC patients to local side effects (enteritis, proctitis, cystitis, lymphedema, vaginal dryness, vaginal stenosis and disturbed sexual function). ## Psycho-oncology Statements r Psycho-oncological care for patients with endometrial carcinoma is an integral component of oncological diagnosis, treatment, rehabilitation and follow-up and represents an interdisciplinary task r The patients should be informed at an early stage about the availability of inpatient and outpatient psycho-oncological assistance and should receive skilled psycho-oncological care if needed r The patient's quality of life must be regularly assessed during treatment, rehabilitation, and follow-up, also in order to assess the potential need for psycho-oncological treatment ## Rehabilitation Statement r All patients should be informed and advised in detail by the attending physician regarding the statutory facilities for subsequent treatment, regular therapy, and outpatient rehabilitation ## Follow-up care Statements r Aspects requiring attention during the follow-up include: genital atrophy phenomena (dyspareunia), lymphedema in the lower extremities, radiogenic reactions in the ureter, bladder and bowel, and hormonal deficiencies r Since a curative approach is possible if a local recurrence is recognized at an early stage, a 3-month follow-up interval should be observed in the first 2-3 years after primary therapy, with speculum examination, vaginal and rectal examination, and ultrasonography if appropriate continued Statements r More detailed imaging diagnosis is only required in symptomatic patients r The following points should be addressed in discussion with the patient during the follow-up: (1) Transient and long-term effects of the disease and treatment (2) Assistance available (self-help groups, psychosocial cancer counseling services) (3) Psycho-oncological/psychotherapeutic treatment facilities (4) Sexuality and relationship (5) Quality of life EC is a very common cancer. Nevertheless evidence regarding optimal diagnosis and treatment of this disease is rather poor as compared to other cancers. High quality clinical trials with sufficient numbers of participants are necessary to define the optimal modalities. Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. [fig] r: The histological classification of endometial cacinomas and thei [/fig]	None	https://link.springer.com/content/pdf/10.1007/s00432-009-0581-9.pdf	None
5c834fd1d50bb32b220685e142be2a66a294d5fb	pubmed	Clinical Neuropathology Practice Guide 3-2013: levels of evidence and clinical utility of prognostic and predictive candidate brain tumor biomarkers	Clinical Neuropathology Practice Guide 3-2013: levels of evidence and clinical utility of prognostic and predictive candidate brain tumor biomarkers A large number of potential tissue biomarkers has been proposed for brain tumors. However, hardly any have been adopted for routine clinical use, so far. For most candidate biomarkers substantial controversy exists with regard to their usefulness in clinical practice. The multidisciplinary neurooncology taskforce of the Vienna Comprehensive Cancer Center Central Nervous System Unit (CCC-CNS) addressed this issue and elaborated a four-tiered levels-of-evidence system for assessing analytical performance (reliability of test result) and clinical performance (prognostic or predictive) based on consensually defined criteria. The taskforce also consensually agreed that only biomarker candidates should be considered as ready for clinical use, which meet defined quality standards for both, analytical and clinical performance. Applying this levels-of-evidence system to MGMT, IDH1, 1p19q, Ki67, MYCC, MYCN and β-catenin, only immunohistochemical IDH1 mutation testing in patients with diffuse gliomas is supported by sufficient evidence in order to be unequivocally qualified for clinical use. For the other candidate biomarkers lack of published evidence of sufficiently high analytical test performance and, in some cases, also of clinical performance limits evidence-based confirmation of their clinical utility. For most of the markers, no common standard of laboratory testing exists. We conclude that, at present, there is a strong need for studies that specifically address the analytical performance of candidate brain tumor biomarkers. In addition, standardization of laboratory testing is needed. We aim to regularly challenge and update the present classification in order to systematically clarify the current translational status of candidate brain tumor biomarkers and to identify specific research needs for accelerating the translational pace. # Introduction In clinical medicine biomarkers are defined as objectively measurable/determinable patient-related factors that provide clinically meaningful disease-related information with regard to diagnosis, prognosis, therapy decisions and patient follow-up [bib_ref] The US Food and Drug Administration perspective on cancer biomarker development, Gutman [/bib_ref] [bib_ref] Shaping the future of biomarker research in breast cancer to ensure clinical..., Hinestrosa [/bib_ref]. In neuropathological oncology, diagnostic, prognostic and predictive biomarkers assessed in patient biopsy specimens and/or body fluids are of relevance [bib_ref] Neuropathological biomarker candidates in brain tumors: key issues for translational efficiency, Hainfellner [/bib_ref] [bib_ref] Role of biomarkers in the clinical management of glioblastomas: what are the..., Mcdonald [/bib_ref]. A large number of prognostic and predictive candidate tissue biomarkers have been proposed for brain tumors, but almost none have translated into routine clinical use so far [bib_ref] Neuropathological biomarker candidates in brain tumors: key issues for translational efficiency, Hainfellner [/bib_ref] [bib_ref] Use of personalized molecular biomarkers in the clinical care of adults with..., Holdhoff [/bib_ref]. For most biomarkers, there is substantial controversy regarding their clinical usefulness [bib_ref] Role of biomarkers in the clinical management of glioblastomas: what are the..., Mcdonald [/bib_ref]. In this article, we present a levels-of-evidence system for assessing the current translational status of candidate biomarkers. This levels-of-evidence system is based on criteria, which have been elaborated and consensually defined by the multidisciplinary neurooncology task force of the Vienna Comprehensive Cancer Center -Central Nervous System Unit (CCC-CNS). We apply this system to currently debated prognostic and predictive neuro-oncological candidate biomarkers in order to assess their clinical utility. # Methods and definitions Our multidisciplinary neurooncology task force within the CCC-CNS has defined the Clinical Neuropathology, Vol. criteria for a four-tiered levels-of-evidence system and an adjunct scoring system for assessing the clinical utility of prognostic and predictive candidate brain tumor biomarkers in a continued process of discussion and consensual agreement [fig_ref] Table 1: Criteria for the four-tiered CCC-CNS levels of evidence system [/fig_ref]. The levels-of-evidence system is related to the two crucial dimensions analytical and clinical performance, which are considered the essential elements for clinical biomarker translation [bib_ref] Neuropathological biomarker candidates in brain tumors: key issues for translational efficiency, Hainfellner [/bib_ref]. Having established the levels-of-evidence system, we used it for assessing the evidence levels and clinical utility for the following candidate brain tumor biomarkers: O6-methylguanine methyl-transferase gene (MGMT) promoter methylation status, isocitrate dehydrogenase 1 gene (IDH1) mutation status, chromosome arms 1p19q co-deletion status, Ki67 tumor cell proliferation index, MYCN status, MYCC status and β-catenin expression. We selected these biomarker candidates, because they are considered to be close to routine clinical use, but their translational status is still subject to controversy and discussion. For each candidate biomarker, we separately assessed the analytical performance and the prognostic and predictive clinical performance. Our ratings are based on review of published data and rely on consensual agreement within our multidisciplinary task force. We defined analytical performance as the reliability of the results yielded by a particular assessment or test. To this end, we evaluated published data with regard to repeatability of test results (intra-laboratory agreement, intra-observer agreement) and reproducibility of testing (inter-laboratory agreement, inter-observer agreement). As clinical performance, we defined the prognostic and predictive value of a given candidate biomarker. Prognostic markers were defined by their association with patient outcome, and predictive markers by their association with response to a given therapy. As the definition of prognostic and predictive markers in (neuro)oncology has been subject to continued debate and controversy, we provide -for illustration purpose -a generic example of a biomarker in medicine with prognostic, predictive and diagnostic properties, depending on the issue of interest (see Textbox). We perceive this basic biomarker concept also as valid for the field of neurooncology. Only those factors reaching an A or B level for both analytical and cliniical performance were considered to have adequate justification for recommendation in routine clinical use as prognostic or predictive biomarkers [fig_ref] Table 1: Criteria for the four-tiered CCC-CNS levels of evidence system [/fig_ref]. ## Idh testing -analytical performance A recently published ring trial (round robin test) and several studies including large patient cohorts support the high analytical performance of immunohistochemical detection of the IDH1-R132H mutation [bib_ref] IDH testing in diagnostic neuropathology: review and practical guideline article invited by..., Preusser [/bib_ref] [bib_ref] Value and limitations of immunohistochemistry and gene sequencing for detection of the..., Preusser [/bib_ref] [bib_ref] Application of mutant IDH1 antibody to differentiate diffuse glioma from nonneoplastic central..., Capper [/bib_ref] [bib_ref] Type and frequency of IDH1 and IDH2 mutations are related to astrocytic..., Hartmann [/bib_ref] [bib_ref] Interlaboratory comparison of IDH mutation detection, Van Den Bent [/bib_ref]. In contrast, DNA-based IDH sequencing procedures showed inconsistent results among different laboratories [bib_ref] Interlaboratory comparison of IDH mutation detection, Van Den Bent [/bib_ref]. ## Idh testing -prognostic and predictive clinical performance The high prognostic clinical performance of IDH mutations in diffuse gliomas was confirmed in several large cohorts [bib_ref] IDH testing in diagnostic neuropathology: review and practical guideline article invited by..., Preusser [/bib_ref] [bib_ref] Role of isocitrate dehydrogenase in glioma, Alexander [/bib_ref] [bib_ref] Adjuvant Procarbazine, Lomustine, and Vincristine Chemotherapy in Newly Diagnosed Anaplastic Oligodendroglioma: Long-Term..., Van Den Bent [/bib_ref] [bib_ref] Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated..., Hartmann [/bib_ref]. However, all of these studies had a retrospective design. Data from adequately designed prospective trials have not yet been published. With regard to a potential predictive value of IDH1 mutations, there is currently only little evidence based on few and inconsistent results from small studies [bib_ref] IDH testing in diagnostic neuropathology: review and practical guideline article invited by..., Preusser [/bib_ref] [bib_ref] IDH mutations predict longer survival and response to temozolomide in secondary glioblastoma, Songtao [/bib_ref] [bib_ref] IDH mutations occur frequently in Chinese glioma patients and predict longer survival..., Qi [/bib_ref] [bib_ref] IDH1 or IDH2 mutations predict longer survival and response to temozolomide in..., Houillier [/bib_ref]. ## Interpretation of the clinical utility of idh testing Assessment of IDH1-R132H mutation status by immunohistochemistry has sufficient evidence for clinical use as a prognostic marker in diffuse gliomas. IDH testing by DNA-based methods, which is in principle suitable to detect also other and rarer forms of IDH mutations, has promising clinical utility but is not yet ready for routine clinical use. Standard test protocols with the potential of sufficiently high analytical performance need to be elaborated and validated. Textbox. Illustrative generic example of a biomarker in medicine which can be used as prognostic, predictive or diagnostic biomarker, depending on the issue of interest: ## Prognostic biomarker: Core criterion of a prognostic biomarker: provides information with regard to some outcome over time (e.g., phenotype, survival, etc.). Proband: child, gender is unknown Question: as this child grows up, will it adopt a male or female phenotype? Biomarker: sex chromosomal status from karyogram Result of biomarker analysis: XY sex chromosomal status Outcome: when this child becomes an adult, it will adopt a male phenotype, because it is biologically male This example illustrates that a prognostic marker allows to foresee the result of a natural development over time. ## Predictive biomarker: Core criterion of a predictive biomarker: provides information whether a particular intervention or therapy is likely to be effective in the tested person or not. Proband: young adult person of unknown gender Question: will the administration of oral contraceptives be effective? Biomarker: sex chromosomal status from karyogram Result of biomarker analysis: XX sex chromosomal status Outcome: administration of oral contraceptives will be effective, because the person is biologically female This example illustrates that a predictive biomarker allows foreseeing the effect of a particular intervention depending on the status of the biomarker. ## Diagnostic biomarker: Core criterion of a diagnostic biomarker: identifies / confirms a particular entity. Proband: person, gender is unknown Question: is this person biologically female or male? Biomarker: sex chromosomal status from karyogram Result of biomarker analysis: XY sex chromosomal status Interpretation: This person is biologically male This example illustrates that a diagnostic biomarker identifies/confirms a particular entity. We consider this biomarker concept as generic and the core criteria as valid also for the field of neurooncology. 1p19q co-deletion 1p19q testing -analytical performance Published data indicate promising analytical performance of the following methods for 1p19q co-deletions testing in oligodendroglial tumors: fluorescence in situ hybridization (FISH), PCR-based loss of heterozygosity (LOH) analysis and multiplex ligation-dependent probe amplification (MLPA). FISH seems to be the most robust method allowing also visual control of test results. However, a published ring trial formally documenting the high inter-laboratory reproducibility is missing [bib_ref] Hainfellner JA; Research Committee of the European Confederation of Neuropathological Societies. FISH-based..., Woehrer [/bib_ref]. ## 1p19q testing -clinical performance There is a high level of evidence for the prognostic value of 1p19q co-deletion in oligodendroglial tumors coming from several studies, including two large prospective trials [bib_ref] Adjuvant Procarbazine, Lomustine, and Vincristine Chemotherapy in Newly Diagnosed Anaplastic Oligodendroglioma: Long-Term..., Van Den Bent [/bib_ref] [bib_ref] Phase III Trial of Chemoradiotherapy for Anaplastic Oligodendroglioma: Long-Term Results of RTOG..., Cairncross [/bib_ref]. These studies also indicate a promising predictive value of the 1p19q codeletion with regard to a response to PCV (procarbazine, lomustine, vincristine)-based chemotherapy in anaplastic oligodendroglial tumors. ## 1p19q testing -clinical utility There is strong evidence that 1p19q codeletion has a prognostic and predictive value in anaplastic oligodendroglial tumors. Ring trials remain to be performed in order to objectively validate the high reproducibility of 1p19q testing and thus making it recommendable for routine clinical use. ## Ki67 tumor cell proliferation index ## Ki67 proliferation index analysisanalytical performance Several methods for Ki67 proliferation index analysis exist, such as direct counting, semi quantitative estimation, computerbased image analysis and direct microscopeassisted counting with a graticule. These assessments are associated with relatively high reproducibility among trained observers [bib_ref] Interobserver reproducibility of MIB-1 labeling index in astrocytic tumors using different counting..., Hsu [/bib_ref] [bib_ref] Interobserver variability in determining MIB-1 labeling indices in oligodendrogliomas, Prayson [/bib_ref] [bib_ref] Interobserver variability associated with the MIB-1 labeling index: high levels suggest limited..., Grzybicki [/bib_ref] [bib_ref] Prognostic value of Ki67 index in anaplastic oligodendroglial tumours -a translational study..., Preusser [/bib_ref] [bib_ref] Ki67 index in intracranial ependymoma: a promising histopathological candidate biomarker, Preusser [/bib_ref]. However, Ki67 immunostaining procedures lack standardization of antigen retrieval and staining. Modalities of tissue fixation may also impact on Ki67 staining results. This lack of standardization may limit reproducibility among different laboratories [bib_ref] Inter-laboratory and inter-observer reproducibility of immunohistochemical assessment of the Ki-67 labelling index..., Mengel [/bib_ref]. ## Ki67 tumor cell proliferation index analysis -clinical performance A robust association of high Ki67 tumor cell proliferation index with unfavorable survival times in patients with ependymoma has been shown in several independent retrospective series [bib_ref] Ki67 index in intracranial ependymoma: a promising histopathological candidate biomarker, Preusser [/bib_ref] [bib_ref] Immunohistochemical prognostic markers in intracranial ependymomas: systematic review and meta-analysis, Kuncova [/bib_ref] [bib_ref] Identification of relevant prognostic histopathologic features in 69 intracranial ependymomas, excluding myxopapillary..., Kurt [/bib_ref] [bib_ref] Ki-67 immunolabeling index is an accurate predictor of outcome in patients with..., Wolfsberger [/bib_ref]. For nonfunctioning pituitary adenomas promising data exist to support an inverse correlation of Ki67 tumor cell proliferation index with time to progression [bib_ref] Residual nonfunctioning pituitary adenomas: prognostic value of MIB-1 labeling index for tumor..., Widhalm [/bib_ref] [bib_ref] A clinicopathological and immunohistochemical study of clinically non-functioning pituitary adenomas: a single..., Rishi [/bib_ref] [bib_ref] The clinical significance of MIB-1 labeling index in pituitary adenomas, Chacko [/bib_ref]. With regard to the prognostic value of Ki67 tumor cell proliferation index, only small studies or conflicting results exist for oligodendroglial tumors, diffuse astrocytomas, meningiomas and medulloblastomas [bib_ref] Prognostic value of Ki67 index in anaplastic oligodendroglial tumours -a translational study..., Preusser [/bib_ref] [bib_ref] Prognostic significance of the immunohistochemical index of survivin in glioma: a comparative..., Uematsu [/bib_ref] [bib_ref] Diagnostic and prognostic role of Ki67 immunostaining in human astrocytomas using four..., Torp [/bib_ref] [bib_ref] Value of MIB-1 labelling index (LI) in gliomas and its correlation with..., Rodríguez-Pereira [/bib_ref] [bib_ref] Prognostic significance of endothelial surface score and MIB-1 labeling index in glioblastoma, Vaquero [/bib_ref] [bib_ref] Analysis of proliferation and apoptosis in brain gliomas: prognostic and clinical value, Heesters [/bib_ref] [bib_ref] Ki-67 (clone MIB-1) proliferation index in recurrent glial neoplasms: no prognostic significance, Litofsky [/bib_ref] [bib_ref] Significance of Simpson grading system in modern meningioma surgery: integration of the..., Oya [/bib_ref] [bib_ref] The significance of Ki-67/MIB-1 labeling index in human meningiomas: a literature study, Abry [/bib_ref] [bib_ref] Prognostic significance of Ki-67/ MIB-1 proliferation index in meningiomas, Torp [/bib_ref] [bib_ref] The Ki-67 proliferation antigen in meningiomas. Experience in 600 cases, Roser [/bib_ref] [bib_ref] Medulloblastoma: evaluation of proliferative index by monoclonal antibody Mib-1, its prognostic correlation..., Ferrari [/bib_ref]. Several studies indicate that the Ki67 tumor cell proliferation index has no prognostic value in glioblastomas [bib_ref] Prognostic significance of endothelial surface score and MIB-1 labeling index in glioblastoma, Vaquero [/bib_ref] [bib_ref] Ki-67 (clone MIB-1) proliferation index in recurrent glial neoplasms: no prognostic significance, Litofsky [/bib_ref] [bib_ref] Wesseling PEuropean Organisation for Research and Treatment of Cancer Brain Tumour and..., Hegi [/bib_ref]. For none of the mentioned entities sufficient data exist to support a predictive value of the Ki67 tumor cell proliferation index. ## Ki67 tumor cell proliferation index analysis -clinical utility The Ki67 tumor cell proliferation index is associated with a high prognostic clinical performance in ependymoma. However, inter-laboratory variability of tissue processing and immunohistochemical staining protocols limit its clinical utility. There is a need for better standardization of tissue processing and Ki67 immunostaining procedures. ## Mgmt methylation ## Mgmt methylation testinganalytical performance Various DNA-based methods for testing of MGMT promoter methylation status have been developed, but for none of them intraand interlaboratory reproducibility has been sufficiently analyzed [bib_ref] Clinical neuropathology practice guide 06-2012: MGMT testing in elderly glioblastoma patients -yes,..., Berghoff [/bib_ref] [bib_ref] MGMT promoter methylation in malignant gliomas: ready for personalized medicine?, Weller [/bib_ref] [bib_ref] Anti-O6-methylguanine-methyltransferase (MGMT) immunohistochemistry in glioblastoma multiforme: observer variability and lack of association..., Preusser [/bib_ref] [bib_ref] MGMT analysis at DNA, RNA and protein levels in glioblastoma tissue, Preusser [/bib_ref]. ## Mgmt methylation testing -clinical performance The high prognostic value of MGMT methylation in glioblastoma has been confirmed by many studies including prospective trial data [bib_ref] MGMT gene silencing and benefit from temozolomide in glioblastoma, Hegi [/bib_ref] [bib_ref] RTOG 0525: A randomized phase III trial comparing standard adjuvant temozolomide (TMZ)..., Gilbert [/bib_ref]. A predictive value of MGMT promoter methylation status for response to temozolomide-based chemotherapy in elderly glioblastoma patients is supported by two independent prospective randomized clinical trials [bib_ref] NOA-08 Study Group of Neuro-oncology Working Group (NOA) of German Cancer Society...., Wick [/bib_ref]. ## Mgmt methylation testing -clinical utility In glioblastoma, a high prognostic clinical performance of MGMT promoter methylation status has been robustly confirmed. In the subgroup of elderly patients there is also evidence for a high predictive value. However, there is insufficient evidence for a high analytical test performance. In particular, intra-and interlaboratory reproducibility remains to be confirmed by adequate scientific data. This lack of evidence impedes recommendation of MGMT testing for routine clinical use. ## Mycc amplification ## Mycc amplification testinganalytical performance Promising data in terms of analytical performance exist for FISH-based analysis in medulloblastoma [bib_ref] Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes..., Pfister [/bib_ref] [bib_ref] MYCC and MYCN oncogene amplification in medulloblastoma. A fluorescence in situ hybridization..., Aldosari [/bib_ref] [bib_ref] Combined histopathological and molecular cytogenetic stratification of medulloblastoma patients, Lamont [/bib_ref] [bib_ref] MYC family amplification and clinical risk-factors interact to predict an extremely poor..., Ryan [/bib_ref]. Trials analyzing the inter-observer and inter-laboratory reproducibility have not been performed so far, but currently studies are accomplished to test the analytical performance. ## Mycc amplification testing -clinical performance The investigation of the clinical performance of MYCC amplification is limited by sample size issues, as medulloblastomas are relatively rare and only ~ 5% of the cases harbour MYCC amplification. However, several retrospective studies consistently show an association of poor patient outcome and MYCC amplification status [bib_ref] Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes..., Pfister [/bib_ref] [bib_ref] MYC family amplification and clinical risk-factors interact to predict an extremely poor..., Ryan [/bib_ref] [bib_ref] Definition of disease-risk stratification groups in childhood medulloblastoma using combined clinical, pathologic,..., Ellison [/bib_ref] [bib_ref] Large cell/anaplastic medulloblastoma: outcome according to myc status, histopathological, and clinical risk..., Von Hoff [/bib_ref]. In forthcoming SIOP PNET clinical trials, patients with tumors harboring a MYCC amplification will be excluded from the average risk medulloblastoma group and included into the high-risk patient group. ## Mycc amplification testing -clinical utility Data indicate a significant prognostic value of MYCC gene amplification status in medulloblastoma. Currently, there is still a lack of data confirming a high analytical performance of MYCC amplification testing. ## Mycn amplification ## Mycn amplification testinganalytical performance Like in MYCC gene amplification testing, currently available data suggest that FISH has the highest analytical performance for identification of MYCN amplifications [bib_ref] Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes..., Pfister [/bib_ref] [bib_ref] MYCC and MYCN oncogene amplification in medulloblastoma. A fluorescence in situ hybridization..., Aldosari [/bib_ref] [bib_ref] Combined histopathological and molecular cytogenetic stratification of medulloblastoma patients, Lamont [/bib_ref] [bib_ref] MYC family amplification and clinical risk-factors interact to predict an extremely poor..., Ryan [/bib_ref]. No ring trial systematically investigating the inter-observer and inter-laboratory reproducibility has been reported so far. Currently, studies are performed to test the analytical performance. ## Mycn amplification testing -clinical performance Similar as MYCC only ~ 5% of medulloblastomas harbor MYCN amplification. A prognostic value of MYCN amplification has been reported in several studies [bib_ref] Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes..., Pfister [/bib_ref] [bib_ref] MYC family amplification and clinical risk-factors interact to predict an extremely poor..., Ryan [/bib_ref] [bib_ref] Definition of disease-risk stratification groups in childhood medulloblastoma using combined clinical, pathologic,..., Ellison [/bib_ref] [bib_ref] Large cell/anaplastic medulloblastoma: outcome according to myc status, histopathological, and clinical risk..., Von Hoff [/bib_ref]. Recent data suggest that MYCN amplified medulloblastomas comprise two different molecular subgroups with different clinical characteristics and prognosis [bib_ref] Biological and clinical heterogeneity of MYCN-amplified medulloblastoma, Korshunov [/bib_ref]. Thus, to date available data do not support a predictive value of MYCN gene amplification status in the whole medulloblastoma cohort, and refinement of the definition of MYCN amplified tumors by using additional clinical and molecular parameters is needed. In the forthcoming SIOP PNET5/6 clinical trial for average and low-risk medulloblastomas, patients with tumors harboring a MYCC amplification will be excluded and treated with a high risk protocol which is currently developed. ## Mycn amplification testing -clinical utility Currently, there is insufficient evidence, both for analytical and clinical performance of MYCN gene amplification status testing in medulloblastoma. Therefore, it does not fulfill the criteria for being implemented in the routine clinical setting. There is a need to systematically address both, analytical and clinical performance of MYCN amplification testing in adequately designed studies. ## Β-catenin status β-catenin testing -analytical performance The β-catenin status in medulloblastomas can be tested by immunohistochemistry alone or in combination with gene sequencing [bib_ref] Nuclear localization and mutation of beta-catenin in medulloblastomas, Eberhart [/bib_ref] [bib_ref] Wnt/ Wingless pathway activation and chromosome 6 loss characterize a distinct molecular..., Clifford [/bib_ref] [bib_ref] Beta-catenin status in paediatric medulloblastomas: correlation of immunohistochemical expression with mutational status,..., Fattet [/bib_ref] [bib_ref] Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and..., Kool [/bib_ref]. No ring trials and consensus guidelines for β-catenin immunohistochemistry evaluating the analytical performance of β-catenin testing have been conducted so far. Currently, studies are performed to test the analytical performance of β-catenin immunohistochemistry. ## Β-catenin testing -clinical performance β-catenin protein expression and mutations within the β-catenin encoding gene (CTNNB1) have been associated with improved patient outcome in several retrospective medulloblastoma studies including large patient cohorts [bib_ref] Definition of disease-risk stratification groups in childhood medulloblastoma using combined clinical, pathologic,..., Ellison [/bib_ref] [bib_ref] Beta-catenin status in paediatric medulloblastomas: correlation of immunohistochemical expression with mutational status,..., Fattet [/bib_ref] [bib_ref] beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom..., Ellison [/bib_ref] [bib_ref] Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups, Ellison [/bib_ref] , but this correlations have so far not been confirmed in prospective studies. The predictive value of the β-catenin status in medulloblastoma will be tested in the forthcoming SIOP PNET5 clinical trial. In supratentorial primitive neuroectodermal tumors (CNS PNET), several independent studies have shown that β-catenin mutation is neither a prognostic nor predictive marker [bib_ref] Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors, Koch [/bib_ref]. ## Β-catenin testing -clinical utility There is evidence for a prognostic value of β-catenin testing in medulloblastomas. However, there is a need for ring trials and elaboration of consensus guidelines for standardization of laboratory protocols for β-catenin testing. The prognostic value of the β-catenin status in medulloblastoma needs to be confirmed in adequately designed studies. # Discussion Among the biomarker candidates that were evaluated according to our levels-ofevidence system, only immunohistochemical testing for IDH1-R132H mutations unequivocally meets the criteria that indicate sufficient evidence for routine clinical use. The most common and important reason why the other candidate biomarkers failed to meet the criteria for routine clinical use was lacking evidence of sufficiently high analytical test performance. This result indicates that there is a strong need of studies that specifically address the issue of test reproducibility, e.g., by means of repeatability testing, ring trials and interlaboratory comparison, as has been done recently in the case of IDH mutation testing [bib_ref] Interlaboratory comparison of IDH mutation detection, Van Den Bent [/bib_ref] [bib_ref] Clinical Neuropathology Practice News 2-2013: immunohistochemistry pins IDH in glioma -molecular testing..., Preusser [/bib_ref]. Indeed, this ring trial can be considered as the final building element definitely translating IDH testing of diffuse gliomas into routine clinical use [bib_ref] Clinical Neuropathology Practice News 2-2013: immunohistochemistry pins IDH in glioma -molecular testing..., Preusser [/bib_ref]. Another necessity specific to analytical performance is the standardization of testing procedures which constitutes an important prerequisite for interlaboratory comparability of test results. In the case of the widely used Ki67 immunostaining for example, a consensus-based standardized immunohistochemical staining procedure does not exist so far, which limits interlaboratory comparability of Ki67 tumor cell proliferation index threshold values. In the future, Euro-CNS may serve as a common platform for the definition of test standards as has recently been taken place in the case of the 1p/19q FISH protocol [bib_ref] Hainfellner JA; Research Committee of the European Confederation of Neuropathological Societies. FISH-based..., Woehrer [/bib_ref]. The prognostic clinical performance for most of the candidate biomarkers included in this study has been clarified by means of adequately designed and sufficiently powered clinical trials. However, with regard to certain biomarkers relevant for pediatric brain tumors (e.g., MYCC and MYCN amplification, β-catenin testing), the prognostic value has not yet been sufficiently clarified because of the rarity of these tumors. This limitation underscores the need for sharing of tissue specimens within multicenter research collaborations, in order to increase both the total case numbers and -in further consequence -the statistical power of patient outcome studies. For virtually none of the investigated candidate biomarkers, a sufficiently high evidence level for predictive clinical performance exists that would allow rating them as ready for clinical use. The only candidate biomarkers, for which published literature indicates a high predictive clinical performance is MGMT testing in glioblastomas of the elderly and 1p19q status in anaplastic oligodendroglial tumors [bib_ref] Adjuvant Procarbazine, Lomustine, and Vincristine Chemotherapy in Newly Diagnosed Anaplastic Oligodendroglioma: Long-Term..., Van Den Bent [/bib_ref] [bib_ref] Phase III Trial of Chemoradiotherapy for Anaplastic Oligodendroglioma: Long-Term Results of RTOG..., Cairncross [/bib_ref] [bib_ref] MGMT gene silencing and benefit from temozolomide in glioblastoma, Hegi [/bib_ref] [bib_ref] RTOG 0525: A randomized phase III trial comparing standard adjuvant temozolomide (TMZ)..., Gilbert [/bib_ref]. However, translation of MGMT testing into common clinical use has been impeded by controversial evidence for a sufficiently high analytical test performance. In order to translate MGMT testing into common clinical use, a robust and reproducible method needs to be established and validated. Validation of currently used MGMT test methods seems to be very challenging, mainly because of methodological reasons [bib_ref] Anti-O6-methylguanine-methyltransferase (MGMT) immunohistochemistry in glioblastoma multiforme: observer variability and lack of association..., Preusser [/bib_ref] [bib_ref] MGMT analysis at DNA, RNA and protein levels in glioblastoma tissue, Preusser [/bib_ref]. # Conclusion Our four-tiered levels-of-evidence system allows us to clarify the current translational status and clinical utility of candidate brain tumor biomarkers. Among the currently most debated candidates, only IDH mutation testing in diffuse gliomas is supported by sufficiently high evidence unequivocally qualifying it as prognostic clinical biomarker that is ready for routine clinical use. In the other biomarker candidates, insufficient evidence for high analytical test performance and -in some instances -also low clinical performance (mainly due to low case numbers) seem to be the major obstacles that impede the fast translation of candidate biomarkers into common clinical use. Future studies should be aware of and specifically address these limitations. We intend to regularly update the current translational status of candidate brain tumor biomarkers. Such periodic reassessments assessment may also be helpful to identify and exclude inappropriate biomarker candidates, and should be beneficial to identify specific research needs that may help to accelerate the translational pace. [table] Table 1: Criteria for the four-tiered CCC-CNS levels of evidence system. Robust confirmation of sufficiently high analytical performance by one or more adequately designed and published round robin/ring trials B Sufficient evidence for high analytical performance from adequately designed [/table] [table] Table 2: Candidate biomarkers and their levels of evidence for analytical performance and prognostic/predictive clinical performance. [/table]	None	https://europepmc.org/articles/pmc3663466?pdf=render	A large number of potential tissue biomarkers has been proposed for brain tumors. However, hardly any have been adopted for routine clinical use, so far. For most candidate biomarkers substantial controversy exists with regard to their usefulness in clinical practice. The multidisciplinary neurooncology taskforce of the Vienna Comprehensive Cancer Center Central Nervous System Unit (CCC-CNS) addressed this issue and elaborated a four-tiered levels-of-evidence system for assessing analytical performance (reliability of test result) and clinical performance (prognostic or predictive) based on consensually defined criteria. The taskforce also consensually agreed that only biomarker candidates should be considered as ready for clinical use, which meet defined quality standards for both, analytical and clinical performance. Applying this levels-of-evidence system to MGMT, IDH1, 1p19q, Ki67, MYCC, MYCN and β-catenin, only immunohistochemical IDH1 mutation testing in patients with diffuse gliomas is supported by sufficient evidence in order to be unequivocally qualified for clinical use. For the other candidate biomarkers lack of published evidence of sufficiently high analytical test performance and, in some cases, also of clinical performance limits evidence-based confirmation of their clinical utility. For most of the markers, no common standard of laboratory testing exists. We conclude that, at present, there is a strong need for studies that specifically address the analytical performance of candidate brain tumor biomarkers. In addition, standardization of laboratory testing is needed. We aim to regularly challenge and update the present classification in order to systematically clarify the current translational status of candidate brain tumor biomarkers and to identify specific research needs for accelerating the translational pace.
cc9acc9a04c56a7e10b316ed373480ef2ad75d1d	pubmed	2020 WSES guidelines for the detection and management of bile duct injury during cholecystectomy	2020 WSES guidelines for the detection and management of bile duct injury during cholecystectomy Bile duct injury (BDI) is a dangerous complication of cholecystectomy, with significant postoperative sequelae for the patient in terms of morbidity, mortality, and long-term quality of life. BDIs have an estimated incidence of 0.4-1.5%, but considering the number of cholecystectomies performed worldwide, mostly by laparoscopy, surgeons must be prepared to manage this surgical challenge. Most BDIs are recognized either during the procedure or in the immediate postoperative period. However, some BDIs may be discovered later during the postoperative period, and this may translate to delayed or inappropriate treatments. Providing a specific diagnosis and a precise description of the BDI will expedite the decision-making process and increase the chance of treatment success. Subsequently, the choice and timing of the appropriate reconstructive strategy have a critical role in long-term prognosis. Currently, a wide spectrum of multidisciplinary interventions with different degrees of invasiveness is indicated for BDI management. These World Society of Emergency Surgery (WSES) guidelines have been produced following an exhaustive review of the current literature and an international expert panel discussion with the aim of providing evidence-based recommendations to facilitate and standardize the detection and management of BDIs during cholecystectomy. In particular, the 2020 WSES guidelines cover the following key aspects: (1) strategies to minimize the risk of BDI during cholecystectomy; (2) BDI rates in general surgery units and review of surgical practice; (3) how to classify, stage, and report BDI once detected; (4) how to manage an intraoperatively detected BDI; (5) indications for antibiotic treatment; indications for clinical, biochemical, and imaging investigations for suspected BDI; and (7) how to manage a postoperatively detected BDI. Keywords: Laparoscopic cholecystectomy, Biliary duct injury, Magnetic resonance imaging, Antibiotic therapy, Computed tomography, Guidelines # Background The World Society of Emergency Surgery (WSES) was founded in 2007 with the mission of promoting training and continuing medical education in emergency general surgery and trauma. Since its establishment, the WSES has launched and curated several clinical guidelines for specific topics related to emergency and trauma surgery, which are regularly updated to provide evidence-based guidance to emergency surgeons in their daily practice. From this perspective, the present manuscript describes the international work conducted by WSES members to build consensus guidelines for the detection and management of one of the most severe complications of cholecystectomy, namely, bile duct injury (BDI). Laparoscopic cholecystectomy (LC) is the gold standard operation for patients with gallstone disease and represents one of the most common routine interventions performed worldwide in both elective and emergency settings . Bile duct injuries (BDIs) are dangerous complications of cholecystectomy, occurring more often since the introduction and widespread adoption of laparoscopy (0.4-1.5% of cases) compared to open cholecystectomy (0.2-0.3% of cases) . Since early reports, the frequency of BDIs during LC has been progressively decreasing. However, the injuries seen currently tend to be more severe, with the most severe biliary and hepatic artery or portal vein injuries often occurring after conversion from laparoscopy to open cholecystectomy . BDIs are a surgical challenge associated with significant postoperative sequelae for the patient in terms of morbidity, mortality (up to 3.5%), and long-term quality of life. Injuries of the bile duct system occurring during cholecystectomy are complex and require prompt identification and management. Visualization of BDIs might be hindered by accompanying vascular injuries, particularly in the branches of the right hepatic artery. Failed attempts to repair BDIs can result in longitudinal strictures of the common bile duct . Most BDIs are recognized either during the procedure or in the immediate postoperative period, with the two most frequent scenarios being the occurrence of a bile leak or bile duct obstruction. However, some BDIs may be discovered later in the postoperative period, and this often translates to delayed or inappropriate treatments, especially when BDI patients need to be referred from a secondary hospital to a tertiary care center for definitive management. Providing a specific diagnosis and a precise description of the BDI facilitates the decisionmaking process and increases the chance of treatment success. In delayed cases, the choice and timing of the appropriate reconstructive procedure have a critical role in long-term prognosis. Currently, there is a wide spectrum of interventions used in the management of BDI with different degrees of invasiveness, ranging from computed tomography (CT)-guided drainage to various endoscopic and surgical techniques. With such a variety of interdisciplinary options available and the need to act promptly, close cooperation between gastroenterologists, radiologists, and surgeons is of upmost importance. The present WSES guidelines aim to facilitate efficient interdisciplinary cooperation, providing evidence-based recommendations for the prevention, detection, and management of BDIs during cholecystectomy. The process was initiated in April 2019 and was structured around 7 key questions that were addressed by comprehensive literature reviews conducted by 7 groups of international multidisciplinary experts. The worldwide participation in these WSES guidelines was deemed essential to capture the experience and practice of different realities in multiple countries, beyond the evidence in the literature, and to ultimately propose clinical guidelines that can contribute to standardizing BDI treatments and research objectives in the future. The present guidelines apply for all cholecystectomy-related BDI regardless of the surgical approach. However, being LC the gold standard with the great majority of the literature referring to this procedure, it will be the most frequently considered in the following recommendations. ## Guideline scope and methods In April 2019, the President and the scientific committee of the WSES appointed three experts (Fausto Catena, Nicola de'Angelis, and Daniele Sommacale) to establish the project committee and determine the organization of an international multidisciplinary expert panel to develop the WSES Guidelines for the detection and management of BDIs. Briefly, the development of the WSES guidelines was structured in two steps: a synthesis of the current literature and a consensus conference held during the 7 th WSES World Congress. In the first step, the project committee identified 7 key questions regarding BDIs to be addressed by a thorough analysis of the available literature. Seven groups of experts, including surgeons, anesthesiologists, gastroenterologists, hepatologists, and radiologists, were identified . For each working group, a leader and coleader(s) were designated as responsible for coordinating the work of the group's experts and providing a summary document that aligned the group's recommendations. The literature evaluation was conducted by performing bibliographic searches related to the 7 key questions using a systematic approach and exploring different electronic databases, including PubMed and EMBASE. There was no date or language restriction. Within each The 7 key questions and the working groups of experts who contributed to the WSES guidelines on biliary duct injury (BDI) detection and management group, a scientific discussion ensued via email and/or videoconference and a synthesis document based on literature evidence, clinical experience, and expert discussion were developed. Experts were instructed to formulate statements and recommendations, as they did for previous WSES guidelines, and assess the level of evidence and the strength of the recommendations according to the AGREE II requirements and adopting the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria (https:// www.gradeworkinggroup.org/). The quality of evidence was graded as "High," "Moderate," "Low," or "Very low," whereas the strength of a recommendation was indicated as either "Strong" or "Weak." Statements and recommendations were reviewed by the project committee to create a comprehensive draft version of the guidelines, including all 7 key questions to be available prior to the consensus conference. The consensus conference was planned during the 7 th WSES World Congress that was initially scheduled to take place in Milano in June 2020. Due to the COVID-19 pandemic, the event was rescheduled to occur on the 16 th -19 th of November 2020 using a virtual format. During the conference, a representative of the project committee presented the summary documents of the working groups and detailed the statements and recommendations, the supporting literature, and the level and strength of the supporting evidence. The revised statements, their level of evidence, and their recommendation grades are presented below. Please note that the WSES guidelines must be considered as an adjunctive tool in the decision-making process regarding the management of BDIs; they are not intended to substitute a provider's clinical judgment regarding an individual patient or specific clinical situation, and they may need to be adapted to be consistent with the medical team's experience and the available local resources. BDI key questions Q1. What are the general recommendations to minimize the risk of BDI during laparoscopic cholecystectomy in elective and emergency settings? Statements: ## Bdi key questions (continued) Weak recommendation, moderate quality of evidence (GRADE 2B) 1.4. Intraoperative IOC is useful to recognize bile duct anatomy and choledocholithiasis in cases of intraoperative suspicion of BDI, misunderstanding of biliary anatomy, or inability to see the CVS, but routine use to reduce the BDI rate is not yet recommended. Weak recommendation, high quality of evidence (GRADE 2A) 1.5. Intraoperative ICG-C is a promising noninvasive tool to recognize bile duct anatomy and vascular structures, but routine use to reduce the BDI rate is not yet recommended. Weak recommendation, low quality of evidence (GRADE 2C). 1.6. In patients presenting with AC, the optimal timing for cholecystectomy is within 48 h, and no more than 10 days from symptom appearance. Strong recommendation, good quality of evidence (GRADE 1A) 1.7. In patients with at-risk conditions (e.g., scleroatrophic cholecystitis, Mirizzi syndrome), an exhaustive preoperative work-up prior cholecystectomy is mandatory in order to discuss and balance the risks/benefits ratio of the procedure. Weak recommendation, low quality of evidence (GRADE 2C) ## Literature review Due to the potentially severe consequences of BDIs, all efforts should be made to minimize the risk of occurrence in both elective and emergency cholecystectomies. Optimal strategies for the prevention of BDI include technical and procedural considerations that must be adapted based on anatomical factors, the patient's clinical status, disease factors, and the surgeon's experience . An exhaustive preoperative work-up prior to cholecystectomy is mandatory in order to detect at-risk conditions (e.g., scleroatrophic cholecystitis, Mirizzi syndrome, choose the best surgical approach, and discuss the risks/benefits ratio of the procedure. ## Critical view of safety LC is the preferable approach also for AC and is associated with lower mortality and morbidity rates. The risk of conversion to open surgery appears to be higher with male sex, age > 60 years, obesity, cirrhosis, previous upper abdominal surgery, presence of comorbidity, large bile stones, fever, elevated serum bilirubin levels, gangrenous cholecystitis, severe acute, and chronic cholecystitis, contracted gallbladder on imaging, duration of complaints > 48 h, and emergency LC. Conversion to open surgery may be considered for patient safety if the operating surgeon cannot manage a difficult LC; however, there is no evidence to support that conversion to open per se will avoid or reduce the risk of BDI . The critical view of safety (CVS) technique was introduced in 1995 to guarantee the safest approach to LC by promoting the recognition of gallbladder elements, particularly the hepatocystic triangle (composed of the cystic duct, common bile duct, and liver), a crucial step to reduce the risk of BDI associated with mistakes in visual perception. The literature has demonstrated that when the CVS is identified, the risk of iatrogenic intraoperative complications is minimized. Thus, routine use of CVS is recommended over other techniques, such as the infundibular approach . However, achieving a complete CVS is easily obtained in only 50% of cases. The component most commonly incomplete is clearance of the lower third of the gallbladder from the liver bed, and CVS cannot always be applied if the hepatocystic angle is affected by advanced inflammation or contracting fibrosis due to preceding episodes of inflammation. It has been reported that injuries of the common bile duct are more common during the early learning curve in laparoscopic cholecystectomy. Thus, the use of CVS could be of greater importance for trainees and residents; in this scenario, the trainee or resident must secure the CVS, and the supervising surgeon must confirm the CVS before the cystic duct and cystic artery are ligated. ## Bailout procedures Whenever a CVS cannot be achieved and the biliary anatomy cannot be clearly defined, alternative techniques such as the "fundus-first (top-down)" approach or subtotal cholecystectomy (STC) should be considered . Several studies have shown how the "fundus-first" technique is associated with reduced rates conversion rate and iatrogenic complications (including BDIs) during difficult operations, such as in cases of severe AC, although the risk of vascular and biliary injuries cannot be completely eliminated. It is essential to recognize approaching areas of danger during LC and, in response, stop dissection and change to a bailout procedure (STC or cholecystostomy) to minimize the need for conversion and to reduce the risk of BDI. However, STC is associated with significantly more surgical site infections, a need for re-interventions, and a longer hospital stay than total cholecystectomy. STC showed advantages over a converted cholecystectomy in which conversion will not solve the difficulty of an inflamed hepatocystic triangle. ## Intraoperative biliary imaging Intraoperative cholangiography (IOC) is an imaging technique that may be used during LC to recognize choledocholithiasis and define the biliary anatomy. However, its routine use is not currently advisable since it is not associated with a significant reduction in rates of complications and BDIs during LC. Indeed, BDI may also occur after IOC because of misinterpretation of the IOC findings. IOC may be recommended in cases of intraoperative suspicion of BDI, misunderstanding of the biliary anatomy, or even inability to see the CVS, as well as in patients with AC or a history of AC, for whom intraoperative imaging, although associated with longer operative time, could be of greatest benefit . Importantly, identification of a BDI using IOC can lead to earlier diagnosis and treatment. Alternatively, the use of indocyanine green fluorescence cholangiography (ICG-C)as an intravenous infusion before surgery can be a useful technique to visualize the structures of the biliary tree, particularly the cystic duct, without the need for X-ray imaging. The usefulness of ICG-C to prevent BDIs has been suggested in several studies and has also proven useful for acute and chronic gallbladder diseases and in those situations in which IOCs cannot be used. ## Optimal timing of lc for acute cholecystitis Systematic reviews analyzing data from RCTsand population-based studiesshowed higher BDI rates in acute conditions, supporting the hypothesis of increasing BDI risk with increasing severity of local inflammation, such as in the case of acute cholecystitis (AC). Different time frames for operating on patients presenting with symptomatic AC have been proposed, ranging from no more than 72 h up to 10 days. Further delays are associated with disease progression, and despite medical treatments, unfavorable conditions for safe surgical interventions exist. Indeed, an increase in the complication rate and need of conversion to open cholecystectomy has been reported when the time from symptom appearance to surgery was prolonged, with the latest timepoint to safely operate on AC patients being 10 days from symptoms appearance. Q2. What are the reported BDI rates during LC in emergency and elective settings and when should a surgical team review its current practice to improve the standards of care? # Statement: 2.1. Based on large nationwide databases and systematic review of the literature, major BDIs occur in 0.1% of elective LC and 0.3% of emergency LC. If considering all types of BDIs, rates are 0.4% and 0.8% for elective and emergency settings, respectively. When a surgical team experiences an increased rate of BDIs, a careful review of the current practice is mandatory to critically analyze the possible causes and implement educational, training, and technical solutions to improve the standards of care. Strong recommendation, low quality of evidence (GRADE 1C) ## Literature review Given the number of LCs performed worldwide, thousands of patients per year will experience BDIs with severe and long-term implications for their health. Moreover, BDIs can have a substantial impact on the surgeon's mental status and reputation and can constitute a non-negligible financial burden for healthcare systems. The goal of any general surgery unit should ideally be a 0% BDI rate, but this is rarely observed in real-life practice. A nationwide database and worldwide experience are necessary to describe the overall incidence of BDIs in elective and emergency settings. Whenever increased rates are experienced locally, the surgical team should carefully review the current practice, critically analyze the possible causes, and implement educational, training, and technical solutions to improve the standards of care. Epidemiological data are useful for clinicians, surgeons, and healthcare systems to measure surgical outcomes and performance (for monitoring or audit purposes); for patients to weigh the surgical risks; and for researchers to compare and interpret their findings. However, assessing the true frequency of BDIs remains challenging. The main problem is related to the sample size needed to observe BDIs and eventually detect significant changes over time. A systematic literature search limited to articles published between 2011 and 2020 identified 16 studies analyzing 14 different databases from 5 different countries. The rates of BDIs during LC differed significantly depending on the population investigated, the criteria used in each study, and the definition of BDI. Based on the Swedish National Quality Registry of Gallstone Surgery and Endoscopic Retrograde Cholangiopancreatography (GallRiks) established in 2005, Tornqvist et al .analyzed 51,041 cholecystectomies and reported an overall BDI rate of 1.5% according to the Hannover classification system, which includes bile duct leaks. The BDI rates during LC and open cholecystectomy were 1.3% and 2.8%, respectively. AC and emergency admissions were associated with BDI rates of 1.9% and 1.8%, respectively. A more recent article by Pucher et al. provided an extensive literature review of 151 studies accounting for a total of 505,292 patients undergoing LC. The authors selected only studies including at least 100 patients and excluded those explicitly describing early case experiences or learning curves to ensure representativeness of an established surgical practice. Pooled data analyses (based on 70% of the included studies corresponding to 60% of patients) showed an overall BDI rate ranging from 0.32 to 0.52%. Sixty-five studies differentiated between major and minor injuries and showed a prevalence of 0.28% for major injuries and 0.46% for bile leaks (overall 0.74%). Several studies defined BDI as the need for further reconstructive surgery (i.e., bilioenteric anastomosis), and they reported a reconstructive surgery rate range between 0.04 and 0.3%. When considering only the need for any type of surgical repair of the common bile duct, the rate ranged between 0.06% and 0.31%. The California Cholecystectomy Group analyzed 711,454 cholecystectomies (of which 95% were LCs) from the California Office of Statewide Health Planning and Development (COSHPD) database from 2005 to 2014. They found a bile leak rate of 0.5%, defined by the need for isolated endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC) within 4 weeks after cholecystectomy. Patients who underwent choledocho-enterostomy, common bile duct suture, hepatectomy, liver transplantation, more than 1 ERCP within a year, or 1 or more PTCs between 4 weeks and 1 year were considered to have a BDI. The rate of these major BDIs was 0.22%, and together, they accounted for 0.72% of patients requiring any ERCP, PTC, or surgical procedure after LC. A higher incidence of BDIs can be expected in cases of inflammation (acute or chronic)or emergency cholecystectomy. Based on the GallRiks database, patients with AC at the time of surgery or with a positive history of AC are at higher risk of BDI (odds ratios, ORs: 1.23 and 1.34, respectively), which can be reduced by performing IOC. LCs in the NSQIP database, 67% of which presented with AC. They found a small yet significantly higher incidence rate of BDIs in AC (0.21% vs. 0.18%). In a nationwide study of 572, 223 LCs conducted in England, only a very small difference was reported concerning the need for reconstructive biliary surgery between patients presenting with AC on admission and patients operated on in the elective setting (0.09% vs. 0.11%). Other studies found no differences in biliary adverse events between LC patients with or without ACor between elective and emergency procedures (0.3%). . Which classifications of BDI should be adopted, and what is the minimum required information that the surgeon must report after diagnosing BDI during LC? # Statements: 3.1. We recommend knowing Strasberg's classification, which remains the most commonly used classification for BDIs, and the ATOM classification, which represents the most recent and complete classification; the implementation of the ATOM classification should be promoted in the near future. Strong recommendation, low quality of evidence (GRADE 1C) 3.2. The ideal operative report must maximize the amount of intraoperative detail given to describe the BDI. The following should minimally be included: 1. The clinical context and indication for cholecystectomy 2. Intraoperative findings 3. The anatomical landmarks of the critical view of safety4. Any anatomical variation of the biliary tractLiterature review An integrated description and diagnosis of BDI is essential to choose the most appropriate management, which depends on the time of detection, the extent of bile duct and vascular injuries, and the underlying mechanism. These aspects must be included in the diagnostic assessment using an appropriate and specific BDI classification. Several BDI classifications have been proposed over the years. They described different subtypes of injuries according to their severity and have taken into account the biliary tract anatomy or the level of the biliary injury; alternatively, some integrated the possible associated vascular injuries of the hepatic hilum into the description of BDI. To date, there is still no consensus on a "gold standard" classification for BDIs, but there are some widely adopted classification systems, which are summarized in. Direct comparisons among the available classification systems are also difficult. Each classification has strengths and drawbacks, as they all lack the standardization of a common nomenclature. ## How to classify bdi Classification systems that are essentially based on the biliary injury location include the first classification published by Bismuth in 1982, followed by the Strasberg's one proposed in 1995, and other classification systems published by McMahon, Bergman, Neuhaus, and Csendes. Conversely, classification systems that integrate vascular injuries into the description of BDIs are the Stewart-Way classification published in 2007, the Hannover classification, the one proposed by Lau et al., and more recently the ATOM (Anatomic, Time Of detection, Mechanism) classification published by the European Association for Endoscopic Surgery (EAES) in 2013. The ATOM integrates the Bismuth, Strasberg, Neuhaus, McMahon, Connor, and Lau classifications into a composite, all-inclusive, nominal system, which combines bile tract anatomical damage, vascular injury, timing of detection, and mechanism of damage in an exhaustive classification system covering all possible injuries. The EAES intended the ATOM classification as a specific effort toward standardization and transformation of BDI definitions into a unified language. Moreover, the ATOM system was thought to facilitate the collection of data for epidemiological and comparative studies, ultimately leading to a more precise determination of the true incidence of BDI incurred during LC and consequently favoring the development of preventive measures. The main drawback is that it may be too complex and timeconsuming to be used in routine clinical practice. Clinically, BDIs are often grouped into minor or major injuries. Minor BDIs include injuries caused by electrocautery burns or a partial cut from sharp dissection with shears and are not associated with tissue loss. These injuries can typically be repaired primarily with sutures and placement of abdominal drains in the area. Conversely, major BDIs (i.e., Strasberg E) are associated with tissue loss (e.g., the common bile duct is clipped and transected) and require complex reconstruction with a Roux-en-Y hepaticojejunostomy. ## How to describe bdi Once BDI has occurred and been recognized during LC (approximately 25% of cases, a detailed and precise surgical report will be critically important to guide BDI management. The surgical report must include the indication for the surgery, the patient's comorbidities, the operative time, the amount of blood loss, the type of injury that occurred (in detail), and the use of drainage. The ideal report should follow the CVS schema described by Strasberg in 1995. The CVS is composed of three critical steps: (1) the visualization of the hepatocystic triangle with no exposure of the common bile duct; (2) the exposure of the lower part of the gallbladder and its separation from the liver bed; and (3) the visualization of only 2 structures that enter the gallbladder: the cystic duct and the cystic artery. The surgeon must report during which of the CVS steps difficulties were encountered and BDI occurred. Whether a timeout during LC, prior to transecting any ductal structure, is performed should be reported. Similarly, it is important to report whether another surgeon was consulted at the time of the dissection or during the difficult steps. Any anatomical abnormality or unusual findings should be described, including: -Bile drainage from a location other than the gallbladder -Bile draining from a tubular structure -A second cystic artery or large artery posterior to the cystic duct -A short cystic duct -A bile duct that can be traced to the duodenum -Severe hemorrhage or inflammation. Whenever an intraoperative biliary tract imaging technique (IOC or ICG-Cis performed, these findings must also be reported, and cholangiography images should be included in the report. Particularly, the following should be specified: -Failure to opacify the proximal hepatic duct or the cystic duct -Identification of an extra bile duct, an aberrant bile duct, or duct of Luschka -Ductal abnormalities: wide cystic duct (which may be the common bile duct), accessory bile duct, second cystic duct (which may be the common hepatic duct), and abnormal gallbladder infundibulum that may indicate that the common bile duct was dissected. If possible, a drawing of the BDI with biliary drainage positioning (if used) could be helpful. If a videotape of the surgical procedure is available, it should be added to the report. ## Literature review In the event of intraoperative recognition of BDI, the subsequent management is highly dependent on the injury extent and classification. The first key factor is the timing of the intraoperative recognition of BDI: the earlier the recognition, the better the outcomes. Data from the nationwide GallRiks prospective registry highlighted that patients with BDI have a significantly poorer 1-year overall survival than non-injured patients (1-year mortality: 3.9% vs. 1.1%, respectively). Particularly, Cox regression analysis demonstrated that patients who had injuries with delayed detection have almost a doubled risk of mortality compared with patients who had no injury (hazard ratio, HR: 1.95; 95% confidence interval, CI: 1.12-3.37). Conversely, no difference in 1year survival rates was observed in patients with BDIs detected perioperatively compared to those without a BDI. These data demonstrate that the timing of BDI recognition matters; nevertheless, BDIs diagnosed intraoperatively represent only a limited number of cases, although the ranges reported in the literature are highly variable (25-92%). To help in the intraoperative detection and classification of BDI, several adjuncts can be used, such as intraoperative ultrasonography (IOUS), IOC, and ICG-C. Conversion to open surgery may be also considered in the event of BDI during LC, with conversion rates that vary from 23 to 71%. However, conversion to open surgery is not recommended if the surgeon has sufficient experience in minimally invasive surgery to manage BDI laparoscopically. ## Management of intraoperatively diagnosed bdi The presence of an unexplained source of bile in the operative field must raise the suspicion of a BDI. In these cases, the use of IOC is helpful to detect BDI, although it requires additional training and longer operative times . A meta-analysis on 860 patients showed that the selective versus the routine use of IOC is associated with a comparable chance of detecting BDI (odds ratio, OR: 0.36; 95% CI: 0.01-8.92; z = 0.63; p = 0.53). On the contrary, its use appeared to be helpful in terms of BDI risk reduction in patients with AC (moderate or severe). IOUS could be useful to evaluate vascular injuries associated with BDI and should be preferred to hilar dissection during intraoperative staging to avoid further damage. ICG-C provides real-time imaging of the extrahepatic biliary tract during LC and represents a noninvasive, quick, safe, and easy-to-apply tool. A recent metaanalysis of 19 studies including 772 patients explored the potential of ICG-C to identify biliary structures during LC. Four studies compared the use of ICG-C to IOC in 215 patients and found no significant differences for cystic duct, common bile duct, or common hepatic duct visualization. A recent survey involving 3411 surgeons (with an average of 16.1 years of practice) highlighted how the use of adjuncts such IOC, ICG-C, or intraoperative ultrasound, either routinely or selectively during difficult cholecystectomies, is not significantly associated with a lower risk of BDIs. It is important to emphasize that factors such as geographic distance between facilities, equipment, expertise, and logistics, vary significantly between institutions. Some authors proposed that in cases of suspected BDI, asking the opinion of another surgeon (physically or virtually) may be an easy, effective, and inexpensive alternative to IOC. In the event of BDI detected during LC, surgeons must promptly analyze the injury and choose between an intraoperative repair or "drain now and fix later" strategy. For minor BDIs (i.e., Strasberg A-D and conditionally E2), a direct repair, with or without the placement of a T-tube, and the placement of abdominal drains in the area is considered safe and appropriate. This strategy is reported in 5-58% of BDI cases in the literature. If available on site, endoscopic decompression might be considered in cases of Strasberg A injury. However, the recur to this strategy is blunted by the high rate of repair failure (up to 64%). For major BDIs (i.e., Strasberg E) associated with tissue loss and whenever an ischemic injury is suspected, a Roux-en-Y hepaticojejunostomy is the recommended method of reconstruction, with the placement of a T-tube at a healthy region of the common bile duct, either proximal or distal to the injury, to decrease the incidence of future stricture formation. Any dissection in the hilum may make subsequent reconstruction more difficult or cause further biliary or vascular injury. Thus, in case of insufficient experience in hepato-pancreato-biliary (HPB) surgery, it is recommended to place a drain in the right upper quadrant and transfer the patient to a center with experienced HPB surgeons. Conversion to an open surgery to solely confirm diagnosis or perform injury staging is not recommended. A recent systematic review and meta-analysisconsidering 10 low-quality studies showed that on-table repair (by direct suture or bilioenteric anastomosis) is associated with a higher incidence, although non statistically significant, of failure than postoperative repair (60% vs. 34.1%; OR: 2.06; 95% CI: 0.89-4.73; p = 0.09). Moreover, non-expert immediate repair attempts are associated with worse outcomes than expert repair potentially compromising later revisions of the injury by a specialist. As supported by another single-center cohort study on 200 patients with BDIs, on-table repair by non-HPB specialists appears to be an independent risk factor for recurrent cholangitis, biliary strictures, revision surgery, and overall morbidity. On the contrary, an early referral to an HPB center can significantly decrease the rate of postoperative complications (OR: 0.24; 95% CI: 0.09-0.68; p = 0.007) and biliary strictures (OR: 0.28; 95% CI: 0.17-0.47; p < 0.001) compared to delayed referral. Whenever a sufficient HPB experience is locally available, some data suggest that the earlier the repair, the better the results, whereas other studies support that similar and good outcomes are to be expected for on-table / early (within 72 hrepair vs. postoperative repair (within 1 weekwhen the BDI is managed by HPB surgeons or in HPB referral centers. However, it must be considered that in some countries or regions, a tertiary/specialist care center may be too distant, and the "traveling surgeon" practice may be inappropriate. In these specific cases, it is of utmost importance to assure an optimal local management before referral, especially when, due to logistic and geographical constraints, the time prior to transport may be prolonged. ## Management of concomitant vascular injuries Because the hepatic blood supply is mainly carried by the portal vein, the interruption of the right branch of the hepatic artery alone is usually well tolerated. Whenever an injury is recognized, the immediate repair of the right hepatic artery is not the most frequent option even in tertiary care centers, being good results only occasionally reported (i.e., no occurrence of liver infarction and uneventful follow-up). Indeed, opportunities for immediate arterial repair are limited due to the low rate of injury recognition, the low number of patients affected by symptomatic liver ischemia, and the high level of technical expertise required. Moreover, an extensive imaging workup with a contrast-enhanced CT scan is mandatory prior to attempting the vascular repair. Thus, given the low clinical impact and the technical complexity of the procedure, the efficacy of arterial reconstruction remains questionable. Vasculobiliary injuries, defined by the presence of both biliary (bile duct obstruction or hilar plate division) and vascular injuries (hepatic artery and/or portal vein injury), lead to liver ischemia in 10% of cases. Their management depends on the evidence and extent of the liver injury (e.g., ischemia, necrosis, or atrophy). Their stabilization may require few weeks or months. In general, the surgical management should be delayed to allow for an accurate imaging workup and strategic planning, which involves HPB surgeons. A decision tree for the management of intraoperatively detected BDIs is displayed in. Q5. What is the recommended type and duration of antibiotic regimen in cases of BDI? # Statements: 5.1. In cases of suspected BDI during elective LC without a history of previous biliary drainage, antibiotic therapy may be considered using broad-spectrum antibiotics. Weak recommendation, very low quality of evidence (GRADE 2C) 5.2. In patients with previous biliary infection (i.e., cholecystitis, cholangitis) and patients with preoperative endoscopic stenting, ENBD, or PTBD at risk of developing local and systemic sepsis, broad-spectrum antibiotics (4 th -generation cephalosporins) are recommended, with further adjustments according to antibiograms. Strong recommendation, low quality of evidence (GRADE 1C) 5.3. In patients with biliary fistula, biloma, or bile peritonitis, antibiotics should be started immediately (within 1 h) using piperacillin/ tazobactam, imipenem/cilastatin, meropenem, ertapenem, or aztreonam associated with amikacin in cases of shock and using fluconazole in fragile patients and cases of delayed diagnosis. Strong recommendation, low quality of evidence (GRADE 1C) 5.4. In severe complicated intra-abdominal sepsis, open abdomen can be considered an option for patients with organ failure and gross contamination. Weak recommendation, low and very low quality of evidence (GRADE 2C) ## Literature review To our knowledge, no study has specifically investigated the indications, duration, and type of antibiotic therapy in cases of BDI. In the absence of specific scientific data, the following recommendations are adapted from published literature and guidelines about the management of biliary infections and abdominal sepsis. In general, depending on the timing of discovery and presentation of BDI, consistent literature supports the initiation of antibiotic therapy as a complement to source control strategies in early or late identification of BDIs. However, no consensus exists on the duration of antibiotic treatment before or after gallbladder surgery. ## Antibiotic therapy in case of intraoperatively diagnosed bdi In patients with previous biliary infections (e.g., cholecystitis, cholangitis) and patients with preoperative instrumentation such as endoscopic stenting at ERCP/ sphincterotomy, endoscopic nasobiliary drainage (ENBD), or percutaneous transhepatic biliary drainage/ cholangiography (PTBD/PTC), there may be preexisting bactobilia. Consequently, bile flow into the peritoneal cavity may lead to local or systemic sepsis. Thus, intraoperative antibiotic coverage must be initiated or continued in case an antibiotic prophylaxis has been already administered. Bile culture is mandatory to narrow the coverage spectrum and prevent antibiotic resistance. Treatment should last no more than 24h. The recommended antibiotics include cefazolin, cefamandole, or cefuroxime (to be substituted by gentamicin and clindamycin in case of allergy). In case of infection and ongoing drainage, the following antibiotics can be considered: piperacillin/ tazobactam, ceftriaxone, or other 4 th -generation Antibiotic therapy in case of postcholecystectomy biliary ductal stenosis In the case of biliary obstruction without bile leak or signs of sepsis, antibiotic therapy may not be required. However, the majority of patients with biliary obstruction have infected bile and grow bacteria from cultures even when clinical cholangitis is not yet present. Sepsis may occur after biliary instrumentation and drainage using endoscopic stenting, ENBD, or PTBD. Antibiotic prophylaxis is appropriate and recommended to prevent the occurrence of healthcareassociated acute cholangitis, especially in the setting of predictable incomplete drainage. ## Antibiotic therapy in case of biliary leakage The first priority in case of bile leakage is "source control" and early "goal-directed therapy". Antibiotic therapy should be initiated as soon as evidence of cholangitis or infected fluid collections appears. In patients without shock, radiological and bacteriological sampling can be performed to obtain definitive diagnostic studies before starting parenteral antibiotic therapy. A 6-h delay period might be tolerated. In the presence of severe sepsis or shock, the investigation window should be substantially shortened, and broad-spectrum antibiotics should be started within 1 h of the initiation of signs and symptoms. Treatment should be adapted according to bile culture findings. In the worst cases of severe complicated intra-abdominal sepsis, open abdomen (OA) therapy for optimal source control may be considered, although the biological basis for OA in such cases is currently being subjected to rigorous scientific scrutiny. In the case of external biliary fistula without intraperitoneal collection, antimicrobial therapy might not be necessary if infectious signs are absent. The natural history of an external fistula depends on the anatomical subtype of injuries. In complex BDIs requiring delayed surgical repair, complete healing of the fistula is an absolute prerequisite for surgery. During the waiting period, several patients may experience cholangitis. The Tokyo guidelines published in 2018 for the severity grading and management of cholangitis may be applicable. Biliary drainage, most often using PTBD, should be placed in cases of uncontrolled or recurrent cholangitis. Parenteral broad-spectrum antibiotics should be started and subsequently adapted to bile and blood cultures. Management of biloma and peritonitis requires percutaneous drainage and surgery, respectively. In the case of cholangiolytic abscesses, which are usually small and multiple, parenteral antibiotics and biliary drainage (endoscopic or percutaneous) may be indicated. A large cholangiolytic abscess not responding to parenteral antibiotics within 48-72 h may require imaging and US-or CT-guided percutaneous needle aspiration or catheter drainage. The antibiotics most often used in cases of biliary peritonitis are piperacillin/tazobactam, imipenem/cilastatin, meropenem, ertapenem, or aztreonam associated with amikacin in cases of associated shock and fluconazole in cases of fragility or delayed diagnosis. The optimum duration of antibiotic therapy in the setting of biliary infection is a matter of debate. According to the Tokyo Guidelines, an additional 4 days of antibiotic therapy is required after source control of cholangitis by decompression of the biliary tree. Treatment should be continued for 2 weeks in the presence of Enterococcus or Streptococcus to prevent the risk of infectious endocarditis. Frailty and comorbid factors must also be accounted for in the titration of therapy. However, other studies showed that only 3 additional days are sufficient to reduce the risk of recurrence. For biloma and generalized peritonitis, a treatment of 5-7 days should be considered. Q6. Which are the clinical, biochemical, and imaging investigations required for the postoperative diagnosis of BDI? Statements: 6.1. We recommend a prompt investigation of patients who do not rapidly recover after LC, with alarm symptoms being fever, abdominal pain, distention, jaundice, nausea, and vomiting (depending on the type of BDI). Weak recommendation, low quality of evidence (GRADE 2C) 6.2. The assessment of liver function tests, including serum levels of direct and indirect bilirubin, AST, ALT, ALP, GGT, and albumin, is suggested in patients with clinical signs and symptoms suggestive of BDI after LC. In critically ill patients, the serum levels of CRP, PCT, and lactate may help in the evaluation of the severity of acute inflammation and sepsis and in monitoring the response to treatment. Weak recommendation, low quality of evidence (GRADE 2C) 6.3. Abdominal triphasic CT is suggested as the first-line diagnostic imaging investigation to detect intra-abdominal fluid collections and ductal dilation. It may be complemented with the addition of CE-MRCP to obtain the exact visualization, localization, and classification of BDI, which is essential for planning a tailored treatment. Weak recommendation, moderate quality of evidence (GRADE 2B) ## Literature review BDIs should be suspected and diagnosed as early as possible in patients who do not promptly recover after LC. The postoperative diagnosis of BDI is based on the evaluation of signs and symptoms, laboratory tests, and imaging studies. ## Clinical signs and symptoms of bdi The most frequent complaints of patients with BDI are persistent abdominal pain, abdominal distension, nausea and/or vomiting, fever, and jaundice. The BDI clinical presentations are related to the type of injury. The two most frequent clinical scenarios are bile leakage and bile duct obstruction. In patients with a bile leak, an early visible sign is the presence of bile from the drain or surgical incision. If the subhepatic region is not drained, a perihepatic bile collection (biloma), abscess, or biliary peritonitis may develop with corresponding clinical signs. Generally, jaundice is not observed or is mild in these cases because cholestasis does not occur. In patients with biliary strictures, symptoms are often delayed. Cholestatic jaundice with choluria, fecal acholia, and pruritus are the most common clinical signs and symptoms. If cholangitis develops, fever with chills is typically associated with jaundice. Recurrent cholangitis is the main consequence of bile duct stricture, hepatic injury and dysfunction from complete bile duct occlusion. Sepsis and multiorgan failure may develop in both clinical settings. When BDI is not identified intraoperatively or during the first postoperative week, patients may have an insidious evolution with relapsing abdominal pain, cholangitis, and bile collections. A late diagnosis, which sometimes is made years after surgery following multiple ineffective attempted repairs or inappropriate management, may result in increased complexity of bile duct repair. Moreover, even if successfully managed, the patient's quality of life and survival may be impaired. Indeed, the clinical course of undiagnosed or unrepaired BDI can evolve to secondary biliary cirrhosis with portal hypertension, liver failure, and, ultimately, death. ## Biochemical tests for the diagnosis of bdi After elective LC, laboratory tests are not routinely required because mild to moderate elevations in hepatocellular enzymes are frequently observed during the postoperative period but have no pathological meaning; CO 2 pneumoperitoneum seems to be the main reason for these changes. In clinical practice, surgeons should consider postoperative biochemical investigations whenever difficulties were encountered during the intervention or in the presence of postoperative clinical signs suggestive of complications. These are performed to aid in the diagnosis. Ben-Ishay et al.evaluated the utility of post-LC blood examinations by retrospectively analyzing the chart data of approximately 340 patients undergoing LC and confirmed that they may be useful to make diagnoses and lead to early interventions in complicated cases. Blood tests were most often obtained in elderly patients and those who had prolonged surgery, multiple drains, and longer hospital stays. Serum levels of direct and indirect bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), and albumin, as well as a complete blood count (CBC), are usually measured to diagnose iatrogenic BDI. In BDI patients, liver function tests and cholestatic enzymes may either be elevated, supporting the clinical suspicion, or remain within the normal ranges. In the case of stenosis or complete occlusion of the bile duct, bilirubin values increase, whereas no elevation or only a slight elevation may be observed as a result of peritoneal bile absorption in the presence of bile leakage. In the very early stages, cholestasis markers are increased, but there is no significant hepatic damage; therefore, aminotransferases are not increased. Early in the initial postoperative course, the determination of ALP and total bilirubin is not sensitive. Biomarkers, such as C-reactive protein (CRP), procalcitonin (PCT), and serum lactate, can help to evaluate the severity of the inflammation or sepsis and provide a baseline to follow the therapeutic response. PCT, CRP, and lactate levels can also be used to predict fatal progression in septic patients and are associated with poor outcomes and increased mortality. ## Imaging for postoperative diagnosis of bdi The role of imaging is to establish the BDI diagnosis, delineate the type and extent of the injury, and plan the appropriate intervention. Ultrasonography (US) represents the primary noninvasive and easily available diagnostic tool that allows for the detection of intra-abdominal fluid collections, dilation of the biliary ducts, and possibly associated vascular lesions by using Doppler evaluation. Abdominal triphasic CT scanning is useful to identify the possible presence of focal intra-or perihepatic fluid collections, ascites, biliary obstruction with upstream dilation, and long-term sequelae of a longstanding bile stricture, such as lobar hepatic atrophy or signs of secondary biliary cirrhosis. CT can also identify associated vascular lesions, such as injury to the right hepatic artery. The sensitivity of CT is superior to that of US, especially for the detection of small fluid collections and associated vascular complications. US provides good anatomic and contrast resolution, but CT has higher spatial resolution and better identification of fluid collection morphology and site; CT is also essential to define collections that require percutaneous or surgical drainage. However, neither US nor CT examinations can reliably distinguish bile leaks from other postoperative fluid collections, such as blood, pus, or serous fluid, because of their similar densities. Neither can establish the precise location or the active state of a bile leak because the bile collection site may not be separate from the leak site and occasionally may even be intrahepatic. Hepatobiliary scintigraphy (HS) has two potential advantages over US and CT. It seems to be more sensitive and specific than US or CT in detecting bile leaks, and in addition to confirming the presence of a bile leak, it can identify the relationship between the leak and any fluid collection as well as show the primary route of bile flow. Despite this, it is frequently necessary to complete HS with additional investigations. In fact, HS can provide functional information demonstrating the presence of an active leak, but its spatial resolution is poor, and the identification of the leak site can be challenging. Other pitfalls of HS are that extrabiliary structures are not visualized, so no information about them can be obtained, it has poor sensitivity in patients with hepatic dysfunction and large bile duct defects with preferential bile flow in a path of least resistance, and it may not show activity in the duodenum and thus a bile leak may be misinterpreted as a complete bile duct obstruction. The use of ERCP and PTC can identify a continuing bile leak, provide exact anatomical diagnosis, and allow, at the same time, the treatment of the injury by appropriately decompressing or dilating the biliary tree. ERCP can be applied to treat bile leaks using internal stents. Success using this technique may be more likely if the injury to the duct is < 5 mm, if the injury is extrahepatic, and when there is no associated abscess or biloma. In the case of ERCP failure, PTC is a valuable option to accurately depict the location and nature of BDI and to perform an extraluminal percutaneous endoscopic rendezvous procedure with stent placement to restore continuity of the bile duct. On the other hand, ERCP and PTC are invasive techniques that are associated with a nonnegligible risk of complications, including severe acute pancreatitis (mainly after ERCP), bleeding, and cholangitis (after PTC). Other disadvantages are the lack of detection of extrabiliary abnormalities and the nonvisualization of ducts upstream or downstream from an obstructing lesion (e.g., stricture, stone). Moreover, PTC can be technically difficult because intrahepatic bile ducts are usually not dilated. Magnetic resonance cholangiopancreatography (MRCP) represents the "gold standard" for a complete morphological evaluation of the biliary tree, as it is noninvasive, does not use ionizing radiation, and provides excellent anatomical information regarding the biliary tree anatomy proximal and distal to the level of injury. MRCP combined with dynamic contrast-enhanced magnetic resonance using a hepatocyte-selective contrast agent with biliary excretion allows for the functional assessment of the biliary tree, and thus, the detection and localization of bile leaks with an accuracy close to 100%. In the past, the use of mangafodipir trisodium as a contrast agent primarily excreted via bilenow withdrawn from the EU Market was shown to be useful for both diagnosing a bile leak and identifying the source of the leak by direct visualization of contrast material extravasation into fluid collections. Several authorsconfirmed that the additional use of contrast-enhanced MRCP (CE-MRCP) using 3D and 2D T1-weighted images acquired at the hepatobiliary phase after hepato-specific contrast agent injection improves the accuracy of bile anatomy depiction and bile leak detection. In a series of 99 patientsincluding 24 followed after cholecystectomy, 20 after surgical reconstruction of traumatic BDI, and 16 after hydatid cystectomythe use of CE-MRCP increased the sensitivity, specificity, and accuracy, with respective ranges (depending on the bile leak etiology) of 76-82%, 100%, and 75-91% compared to 53-63%, 51-66%, and 55-63% observed with conventional MRCP. The optimal timing for hepatobiliary phase acquisitions with CE-MRCP appears to range between 60 and 90 min when looking for bile leaks. In the post-liver transplant setting, Boraschi et al.studied 384 MRCP examinations in 232 patients. The reported sensitivity, specificity, positive predictive value, and negative predictive value for the detection of BDI were 99%, 96%, 99%, and 97%, respectively. One considerable MRCP limitation is the poor opacification of bile ducts in the presence of obstruction and unreliable depiction of the more peripheral intrahepatic bile ducts. Q7. What are the surgical management strategies and timing for postoperatively diagnosed BDI? Statements: 7.1. In the case of minor BDIs (e.g., Strasberg A-D), if a drain is placed after surgery and a bile leak is noted, an observation period and nonoperative management during the first hours is an option. If no drain is placed during surgery, percutaneous treatment of the collection with drain placement can be useful. Weak recommendation, low quality of the evidence (GRADE 2C) 7.2. For minor BDIs, if no improvements or worsening of symptoms occurs during the clinical observation period after percutaneous drain placement, endoscopic management (by ERCP with biliary sphincterotomy and stent placement) becomes mandatory. Strong recommendation, low quality of the evidence (GRADE 1C) 7.3. In major BDIs (e.g., Strasberg E1-E2) diagnosed in the immediate postoperative period (within 72 h), we recommend referral to a center with expertise in HPB procedures if that expertise is locally unavailable. An urgent surgical repair with bilioenteric anastomosis Roux-en-Y hepaticojejunostomy could then be performed. Strong recommendation, low quality of the evidence (GRADE 1C) 7.4. In major BDIs diagnosed between 72 h and 3 weeks, we recommend percutaneous drainage of the fluid collections whenever present, targeted antibiotics, and nutritional support. During this period, an ERCP (sphincterotomy with or without stent) can be considered to reduce the pressure gradient in the biliary tree, and a PTBD could be Literature review (Continued) useful for septic patients with a complete obstruction of the common bile duct. After a minimum of 3 weeks, if the patient's general conditions allow and the acute or subacute situation is resolved (e.g., closure of the biliary fistula), Roux-en-Y hepaticojejunostomy should be performed. Weak recommendation, low quality of the evidence (GRADE 2C) 7.5. When major BDIs are recognized late after the index LC and there are clinical manifestations of stricture, Roux-en-Y hepaticojejunostomy should be performed. Weak recommendation, low quality of the evidence (GRADE 2C) 7.6. When major BDIs present as diffuse biliary peritonitis, urgent abdominal cavity lavage and drainage are required as the first step of treatment to achieve infection source control. Strong recommendation, low quality of the evidence (GRADE 1C) ## Literature review With the great majority of BDIs being detected and diagnosed postoperatively, the type of management must be chosen based on multiple criteria, including the complexity of the biliary injury, the severity of clinical presentation, the patient's fitness and comorbidities, and the availability of a skilled surgeon with expertise in HPB surgery. In all cases, a multidisciplinary approach involving interventional radiologists, gastroenterologists, and surgeons is advocated.depicts a decision flowchart for cases of postoperatively detected BDI. ## Management of minor bdis Minor BDIs (e.g., Strasberg A-Drequire a stepup approach once diagnosed. Common symptoms (e.g., abdominal pain or distension, fever, nausea), when noted in the postoperative period, may herald postoperative complications. In the presence of bile leakage from the drain, observation and non-operative management are advisable during the first hours. If no drain was placed after surgery and imaging reveals a bile collection with suspicion of minor BDI (such as a cystic duct leak or duct of Luschka), percutaneous drainage of the collection may be the definitive treatment. Several case series have reported the feasibility of drainage under endoscopic ultrasound guidance, but more data are needed before this approach may be recommended in this specific clinical situation. If no improvements or worsening of symptoms occur, endoscopic management becomes mandatory. The same is true for low output biliary fistulas (i.e., a bile leak from the liver bed such as a Luschka's duct). Various endoscopic treatments (i.e. biliary stenting, endoscopic biliary sphincterotomy, and nasobiliary drainage) are highly effective to treat biliary leaks, except in the case of transection of the common bile duct or common hepatic duct. The time lapse between biliary injury and endoscopic treatment does not seem to significantly impact on the treatment outcomes. ## Role of ercp in bdi management ERCP is the key tool in BDIs management because it allows the identification of the site of bile leak and, most importantly, allows internal biliary drainage if the diagnosis of minor BDI is confirmed. Moreover, incidental diagnoses, such as choledocholithiasis or bile duct stricture, may also be treated in a single procedure. For this reason, ERCP is nowadays widely recommended as first-line therapy for postoperative biliary leaks. The reported success rate of ERCP in this situation ranges between 87.1% and 100%, depending on the grade and the location of the leak. Bile leaks are divided into categories: (1) low grade, where the leak can only be identified after complete opacification of the intrahepatic biliary system; and (2) high grade, where the leak can be observed before intrahepatic opacification. Leaks that respond more favorably to endoscopic treatment are those located at the end of a cystic duct stump or from a duct of Luschka, usually associated with low output. The limits of the endoscopic diagnosis concern the lack of visualization of aberrant or sectioned bile ducts (i.e., an aberrant right hepatic biliary duct) and the difficulty in visualization of intra-hepatic proximal leaks. Endoscopic management should be preferred when there is at least partially documented continuity of the BDI (at the MRCP) or a very close proximity of the two biliary stumps (the proximal and the distal stumps); these are the conditions in which attempting endoscopic repair with the multistenting strategy. The main goal of endoscopic therapy is to reduce the transpapillary pressure gradient to facilitate preferential bile flow through the papilla as opposed to the site of the leak, providing time to the biliary tree injury to heal. This is most commonly achieved by placing a transpapillary stent. Temporary naso-biliary drainage showed a similar efficacy when compared to plastic stents but has a lower patient compliance, so it should not be considered as the first choice. There is little consensus on the role of sphincterotomy alone in the management of these patients. Avoiding sphincterotomy may minimize the risk for immediate (e.g., bleeding or perforation) and long-term complications (e.g., cholangitis or pancreatitis). The most frequent approach is the combination of biliary sphincterotomy with the placement of plastic stents or fully/ partially covered metal stents, which is associated with a high success rate in low-grade biliary leaks , and it is deemed even more effective in cases of high-grade leaks. Although less investigated in the literature, long-term (at 10 years) outcomes of endoscopic treatment with stent placement appeared to be good and effective in patients with postoperative biliary strictures. Plastic stents are recommended to be placed to treat bile duct leaks. For refractory bile leaks, fully covered self-expanding metal stents were demonstrated to be superior to multiple plastic stents in a nonrandomized trial. Stents are left in place for approximately 4 to 8 weeks in many studies and removed if retrograde cholangiography shows the resolution of the leakage. The first-line approach to benign biliary strictures complicating cholecystectomy is endoscopic, as well. When recognized early in the post-operative period, strictures are often due to surgical trauma (e.g., energy device) and associated with bile leak. These strictures respond to endoscopic treatment more favorably than fibrotic strictures, which have a delayed diagnosis. Temporary placement of multiple plastic stents over a long period of time is the preferred treatment, with a success rate ranging from 74 to 90%, but with a recurrence rate as high as 30% within 2 years from stent removal. In case of post-cholecystectomy bile strictures located > 2 cm from the main hepatic confluence, fully covered SEMS can be an alternative to plastic stents. When ERCP is unsuccessful or not feasible, PTBD becomes an alternative. Moreover, PTBD can be useful for septic patients with a complete obstruction of the common bile duct as part of the multidisciplinary approach when ERCP fails or when surgical repair failures need to be treated (i.e., stricture of the hepaticojejunostomy). PTBD in the presence of bile leakage may be more difficult as a result of non-dilated bile ducts but still leads to a technical success of 90% and a short-term clinical success of 70-80% in expertise centers. ## Management of major bdis In the case of major BDIs (e.g., Strasberg E1-E5) in which there is a complete loss of common and/or hepatic bile duct continuity, carefully planned surgical treatment is required. Even when an endoscopic approach has been performed, high-grade bile leaks are difficult to manage successfullyand represent an independent risk factor for morbidity. Early aggressive surgical repair (performed within 48 h from diagnosis) seems to guarantee good results, avoid the onset of sepsis, and provide advantages in terms of reduced costs and rate of hospital readmissions. On the other hand, after 48-72 h, while inflammation tends to decrease, the phase of proliferation and healing begins and further complicates surgical repair. A key point is the technical contribution of the surgeon: several studies have emphasized higher rates of postoperative failure, morbidity, and mortality when a primary surgeon without HPB expertise attempts to repair the injury. Accordingly, in the case of a lack of HPB experience, referral to a tertiary care center immediately after diagnosis is essential to ensure early surgical repair with Roux-en-Y hepaticojejunostomy, which showed superior outcomes at 5 years compared to late repairs. An end-to-end anastomosis may be performed if the loss of continuity makes it technically possible, but this approach is associated with increased failure rates. Regardless of the technique used, tension-free bilioenteric anastomosis with good mucosal apposition and vascularized ducts is the mainstay of treatment. Recently, robotic procedures have been suggested due to enhanced visualization, better tissue handling, and more precise surgery. In the presence of increased tissue fragility, the expertise of the HPB surgeon in the tertiary care center is likely to improve the final results and consequently the long-term outcomes. When BDIs are recognized during the early postoperative period (within 2 weeks), persistent tissue injury from ongoing inflammation and the absence of bile duct dilatation appear to negatively influence the results and often lead to late strictures. When the diagnosis is not immediate or logistic constraints limit referral to a tertiary care center, the "drain now, fix later" algorithmwith percutaneous drainage of the biloma, targeted antibiotic therapy, and nutritional support seems to be the best approach. After clinical stabilization, delayed surgical treatment can be safely performed. When a major leak results in progressive biliary peritonitis, urgent surgical intervention is required with laparoscopic lavage of the abdominal cavity and drain placement. Once the patient has been successfully stabilized, several weeks (2-3 weeks) are usually required for the resolution of the acute inflammatory phase. Accordingly, this time will allow for lowering the risks associated with extensive reconstructive surgery by reducing inflammation and guaranteeing the assessment of the extent of ischemic injury resulting from associated vascular injuries (right hepatic artery lesions have been recognized in 25% of BDIs). Similarly, a 1-week delay in the diagnosis of major BDIs suggests the need for a "timeout" of 2-3 months before intervention. Combined BDI and hepatic artery injuries further increase the morbidity and mortality of BDIs and may necessitate an early referral to a specialized HPB center. Combined repair may avoid ischemic damage to the liver parenchyma and the risk of leakage or stricture of the bilioenteric anastomosis. When an injury is not promptly recognized, hepatic necrosis, atrophy, or even abscess within the ischemic parenchyma may occur, which would ultimately require liver resection with bilioenteric anastomosis. Roux-en-Y bilioenteric anastomosis represents the gold standard treatment for major BDIs and is ideally performed during the immediate postoperative period (within 72 h). However, late repair should be considered after the resolution of acute or subacute situations and the closure of a biliary fistula on dilated bile ducts. Indeed, in these complicated clinical scenarios, mortality and morbidity rates after late repair are significantly lower than rates after immediate and early repair: 0.8% vs. 2.8% vs. 2.2% and 14.3% vs. 39.2% vs. 28.7%, respectively. Furthermore, the need for a second procedure, that is, failure of the first repair, appeared to be higher after immediate and early repair than after late repair: 56.7% vs. 40.7% vs. 6.8%, respectively. However, the E-AHPBA multicenter study showed, after multivariate regression analyses, that the timing of biliary reconstruction with hepaticojejunostomy does not have any impact on severe postoperative complications, the need for reintervention, or liver-related mortality, leaving advisable the choice of an individualized treatment strategy after iatrogenic BDI. ## Outcomes of bdi treatment As described above, BDI diagnosis can be made early or late during the postoperative period. We reviewed the literature concerning the management of BDIs suspected and diagnosed postoperatively, leaving aside the clinical scenarios in which BDIs are diagnosed or suspected years after the index surgery due to the presence of biliary sequelae of unrecognized injuries. These scenarios are beyond the scope of the present WSES recommendations, but it is important to emphasize that the evaluation of BDI management and repair outcomes should be pursued in the long term, since late complications, such as post-cholecystectomy biliary strictures, recurrent cholangitis, and secondary biliary cirrhosis, may occur. Although the literature is mainly based on case series, the treatment of BDIs is generally considered as successful. In a series of 31 patients with BDI (of which 83% were major BDIs) referred to be treated in a tertiary care institution, surgical intervention (i.e., duct-to-duct anastomosis or biliary-enteric reconstruction) represented the most frequent treatment followed by naso-biliary drainage, drainage-observation, and endoscopic sphincterotomy with biliary stenting. The overall success rate was 83.3% in the early period; however, 10 patients (32.3%) had late postoperative complications (stricture and cholangitis), and of these, 3 required endoscopic stent placement, and 7 patients underwent a biliary diversion with Roux-en-Y hepaticojejunostomy. Only one out of 24 patients with long-term follow-up developed biliary cirrhosis, supporting satisfactory long-term outcomes of BDI treatments. Studies specifically investigating the long-term outcomes of Roux-en-Y hepaticojejunostomy with biliaryenteric anastomosis performed for major BDIs also support overall good outcomes. However, relevant postoperative complication rates are reported. Based on a recent review of the literature, the incidences of anastomotic strictures vary between 4.1% and 69%, with most studies reporting an incidence of 10-20%, and a median time to stricture formation of 11-30 months. Associated vascular injury, level of BDI, sepsis or peritonitis, and postoperative bile leakage have been shown to be associated with worse outcomes. The reported incidences of biliary cirrhosis after BDI treatment varies between 2.4% and 10.9 %. Mortality rate after BDI is also considerable: BDI-related mortality varies between 1.8% and 4.6%, with some evidence 1.4. Intraoperative IOC is useful to recognize bile duct anatomy and choledocholithiasis in cases of intraoperative suspicion of BDI, misunderstanding of biliary anatomy, or inability to see the CVS, but routine use to reduce the BDI rate is not yet recommended. 2A 1.5. Intraoperative ICG-C is a promising noninvasive tool to recognize bile duct anatomy and vascular structures, but routine use to reduce the BDI rate is not yet recommended. 2C 1.6. In patients presenting with AC, the optimal timing for LC is within 48 h, and no more than 10 days from symptom appearance. 1A 1.7. In patients with at-risk conditions (e.g., scleroatrophic cholecystitis, Mirizzi syndrome), an exhaustive preoperative work-up prior cholecystectomy is mandatory in order to discuss and balance the risks/benefits ratio of the procedure. ## 2c BDI rates and review of current practice in general surgery unit 2.1. Based on large nationwide databases and systematic reviews of the literature, major BDIs occur in 0.1% of elective LC and 0.3% of emergency LC. If considering all types of BDIs, rates are 0.4% and 0.8% for elective and emergency settings, respectively. When a surgical team experiences an increased rate of BDIs, a careful review of the current practice is mandatory to critically analyze the possible causes and implement educational, training, and technical solutions to improve the standards of care. ## 1c BDI classifications BDI reporting 3.1. We recommend knowing Strasberg's classification, which remains the most commonly used classification for BDIs, and the ATOM classification, which represents the most recent and complete classification; the implementation of the ATOM classification should be promoted in the near future. 3.2. The ideal operative report must maximize the amount of intraoperative detail given to describe the BDI. The following should minimally be included: -The clinical context and indication for cholecystectomy -Intraoperative findings -The anatomical landmarks of the CVS -Any anatomical variation of the biliary tract -Cholangiography findings (if performed) -Operative data (e.g., operative time, blood loss, energy device used, need for conversion) -Drawing of the BDI with biliary drain placement (if used) -Videotape of the procedure (whenever available). ## 1c Intraoperatively detected BDI management 4.1. We recommend the selective use of adjuncts for biliary tract visualization (e.g., IOC, ICG-C) during difficult LC or whenever BDI is suspected to increase the rate of intraoperative diagnosis. The opinion of another surgeon should also be considered. 4.5. The repair of complex injuries (e.g., vasculo-biliary) should be delayed and not attempted intraoperatively even by expert HPB surgeons. ## 2c Antibiotic regimen 5.1. In cases of suspected BDI during elective LC without a history of previous biliary drainage, antibiotic therapy may be considered using broad-spectrum antibiotics. 2C 5.2. In patients with previous biliary infection (i.e., cholecystitis, cholangitis) and patients with preoperative endoscopic stenting, ENBD, or PTBD at risk of developing local and systemic sepsis, broad-spectrum antibiotics (4 th -generation cephalosporins) are recommended, with further adjustments according to antibiograms. 1C 5.3. In patients with biliary fistula, biloma, or bile peritonitis antibiotics should be started immediately (within 1 h) using piperacillin/tazobactam, imipenem/cilastatin, meropenem, supporting an increased mortality of 8.8% in BDI patients compared to the expected age-adjusted death rate after 20 years. Finally, most studies suggest that BDIs have a detrimental impact on health-related quality of life when compared to patients undergoing uneventful cholecystectomy. Impaired quality of life, particularly in terms of work-related limitations, loss of productivity, and increased use of disability benefits, has been reported even years after BDI treatment. Thus, the best management strategy will be identified as the one associated with the more stable and predictable results over the follow-up. ## Medicolegal aspects In Europe, approximately 19-32% of patients with BDIs are involved in a litigation claim, which translates into medical liability of the operating surgeon and/or significant payouts. These may represent a further argument to support the management of most BDIs in tertiary expert centers. Moreover, these data highlight the importance of peroperative informed consent, in which the possibility of severe complications, like BDI, is adequately explained to the patient. Straightforward and honest communication once the BDI has occurred and detected is also crucial. In this perspective, we suggest implementing a "synoptic surgery reporting," which represents a standardized reporting of data fundamental to tracking variations in care, evaluating the quality of care, and finally, improving patient outcomes and cost-effective treatments. # Conclusions LC is one of the most common operations a general surgeon performs in elective and emergency settings ## 2c Clinical, biochemical, and imaging investigations for suspected BDI 6.1. We recommend a prompt investigation of patients who do not rapidly recover after LC, with alarm symptoms being fever, abdominal pain, distention, jaundice, nausea and vomiting (depending on the type of BDI). 2C 6.2. The assessment of liver function tests, including serum levels of direct and indirect bilirubin, AST, ALT, ALP, GGT, and albumin, is suggested in patients with clinical signs and symptoms suggestive of BDI after LC. In critically ill patients, the serum levels of CRP, PCT, and lactate may help in the evaluation of the severity of acute inflammation and sepsis and in monitoring the response to treatment. 2C 6.3. Abdominal triphasic CT is suggested as the first-line diagnostic imaging investigation to detect intra-abdominal fluid collections and ductal dilation. It may be complemented with the addition of CE-MRCP to obtain the exact visualization, localization and classification of BDI, which is essential for planning a tailored treatment. ## 2b Postoperatively detected BDI management 7.1. In the case of minor BDIs (e.g., Strasberg A-D), if a drain is placed after surgery and a bile leak is noted, an observation period and nonoperative management during the first hours is an option. If no drain is placed during surgery, the percutaneous treatment of the collection with drain placement can be useful. 7.3. In major BDIs (e.g., Strasberg E1-E2) diagnosed in the immediate postoperative period (within 72 h), we recommend referral to a center with expertise in HPB procedures, if that expertise is locally unavailable. An urgent surgical repair with bilioenteric anastomosis Rouxen-Y hepaticojejunostomy could then be performed. 1C 7.4. In major BDIs diagnosed between 72 h and 3 weeks, we recommend percutaneous drainage of the fluid collections whenever present, targeted antibiotics, and nutritional support. During this period, an ERCP (sphincterotomy with or without stent) can be considered to reduce the pressure gradient in the biliary tree and a PTBD could be useful for septic patients with a complete obstruction of the common bile duct. After a minimum of 3 weeks, if the patient's general conditions allow and the acute or subacute situation is resolved (e.g., closure of the biliary fistula), the Roux-en-Y hepaticojejunostomy should be performed. worldwide. BDI during LC is a severe complication that requires prompt diagnosis and specific treatment to avoid further morbidity and mortality. Practice guidelines have been proposed to prevent BDIs during LC , whereas BDI detection, classification, and management, once they occur, remain basically unstandardized. It is critical to have a plan if an injury is detected intraoperatively and to follow a standardized protocol in case of delayed diagnosis during the postoperative period. The present guidelines offer a thorough overview of the current literature about the key aspects of BDI detection and treatment strategies in various clinical situations. They are the results of international and multidisciplinary work promoted by the World Society of Emergency Surgery culminating in a consensus conference where all proposed statements and recommendations were approved by the worldwide contributing experts (a summary of all statements and recommendations is provided in. We must acknowledge that, despite the large number of publications on the topic, evidence was often derived from retrospective, moderate-to low-quality studies. However, the broad consensus reached by the expert panel allowed proposing recommendations in most cases. The present WSES guidelines contribute to clarifying the complex decision-making process that the surgeon has to face once a BDI is suspected, detected, and diagnosed. BDI management requires not only clinical knowledge and surgical skills but also a sensible evaluation of the availability of local resources and the experience of the medical team in terms of HPB surgery. Better patient outcomes, with decreased morbidity and long-term complications, are expected when BDIs are addressed at high-volume centers by experienced multidisciplinary teams. However, efforts should be made to guarantee the best treatment options for any patient experiencing BDI, irrespective of the hospital, country, or geographical inequalities; this could be achieved by the progressive implementation of the present guidelines in clinical practice to standardize BDI detection and management among surgeons and clinicians worldwide. ## Supplementary information The online version contains supplementary material available at https://doi. org/10.1186/s13017-021-00369-w. Additional file 1. Additional file 2.	None	https://wjes.biomedcentral.com/counter/pdf/10.1186/s13017-021-00369-w	None
d038b3f548625d064ea975585e053702d5bab116	pubmed	ACR Statement on Safe Resumption of Routine Radiology Care During the Coronavirus Disease 2019 (COVID-19) Pandemic	ACR Statement on Safe Resumption of Routine Radiology Care During the Coronavirus Disease 2019 (COVID-19) Pandemic The ACR recognizes that radiology practices are grappling with when and how to safely resume routine radiology care during the coronavirus disease 2019 (COVID-19) pandemic. Although it is unclear how long the pandemic will last, it may persist for many months. Throughout this time, it will be important to perform safe, comprehensive, and effective care for patients with and patients without COVID-19, recognizing that asymptomatic transmission is common with this disease. Local idiosyncrasies prevent a single prescriptive strategy. However, general considerations can be applied to most practice environments. A comprehensive strategy will include consideration of local COVID-19 statistics; availability of personal protective equipment; local, state, and federal government mandates; institutional regulatory guidance; local safety measures; health care worker availability; patient and health care worker risk factors; factors specific to the indication(s) for radiology care; and examination or procedure acuity. An accurate risk-benefit analysis of postponing versus performing a given routine radiology examination or procedure often is not possible because of many unknown and complex factors. However, this is the overriding principle: If the risk of illness or death to a health care worker or patient from health care-acquired COVID-19 is greater than the risk of illness or death from delaying radiology care, the care should be delayed; however, if the opposite is true, the radiology care should proceed in a timely fashion. # Background The ACR recognizes that radiology practices are grappling with when and how to safely resume necessary nonurgent radiology care during the coronavirus disease 2019 pandemic. Although it is unclear how long the pandemic will last, it may persist for many months. Throughout this time, it will be important to perform safe, comprehensive, and effective care for patients with and without COVID-19, recognizing that asymptomatic transmission is common with this disease. Local idiosyncrasies prevent a single prescriptive strategy. However, general considerations can be applied to most practice environments. A comprehensive strategy will include consideration of local COVID-19 statistics; availability of personal protective equipment (PPE); local, state, and federal government mandates; institutional regulatory guidance; local safety measures; health care worker availability; patient and health care worker risk factors; factors specific to the indication(s) for radiology care; and examination or procedure acuity. ## Overriding guiding principle If the risk of illness or death to a health care worker or patient from health care-acquired COVID-19 is greater than the risk of illness or death from delaying radiology care, the care should be delayed; however, if the opposite is true, the radiology care should proceed in a timely fashion. The risk from health care-acquired COVID-19 can be made very low for most diagnostic radiology examinations and interventional radiology procedures if appropriate safety measures are in place (eg, screening, testing, infection control processes, PPE). However, an accurate risk-benefit analysis of postponing versus performing a given nonurgent radiology examination or procedure often is not possible because of many unknown and complex factors. These include the specific outcome-based risk of COVID-19 (which considers local prevalence and transmissibility in the setting of local preventive measures) and the outcome-based risk of postponing imaging (which considers unknowns related to non-COVID-19 disease aggressiveness, comorbid conditions, and treatability). Therefore, decision making will be guided by imperfect attempts to estimate these risks. Practices should do their best to determine the risk to health care workers and patients of developing illness or death from health care-acquired COVID-19 in their local environment, as well as the patient-specific risk of illness or death from postponing an examination or procedure, and then use that information to guide the re-engagement of nonurgent radiology care. In this determination, the probability of negative outcomes (from COVID-19 and non-COVID-19 disease) should take precedence. Patient-specific risk is best determined through collaboration between referring providers and radiologists. The ACR recognizes that government and institutional mandates may interact with this decision making. ## General guidance for the safe re-engagement of nonurgent clinical work There is no single ideal approach for the safe re-engagement of nonurgent radiology care. Practices are developing local solutions that work best for their needs. The ACR recommends that radiology leaders work closely with hospital systems, referring providers and patients to coordinate safe and effective care. The following recommendations apply to the safe re-engagement of nonurgent diagnostic and interventional radiology care during the COVID-19 pandemic. It is recognized that because of local factors it may not be possible for individual practices to adopt all of these recommendations. Recommendations for the Safe Re-Engagement of Nonurgent Radiology Care During the COVID-19 Pandemic ## Enact safety measures. n Screen all patients for symptoms of COVID-19 during scheduling. n Screen all patients, workers, and visitors for symptoms of COVID-19 on building entry. n Create system awareness and flags identifying patients with recent COVID-19. n Develop a plan for how to manage individuals who screen positive on building entry. n Ensure sufficient PPE for workers and patients, balancing current and future needs. n Coordinate PPE use with health system efforts, emphasizing highest-risk care. n Train staff and providers on safe PPE use and hand hygiene. n Implement universal masking of health care workers. n Implement universal masking of patients and visitors. n Ensure PPE for aerosolizing care (N95, powered airpurifying respirator). n Concentrate activity at specific sites if insufficient PPE for enterprise-wide activation. n Enable social distancing within waiting rooms, hallways, and work areas. n Streamline patient flow to minimize unneeded contacts (eg, one-way corridors). n Implement methods to minimize time in waiting rooms (eg, waiting in cars). n Optimize the efficiency of every patient encounter. n Provide care in designated areas to patients with known or suspected COVID-19. n Clean and decontaminate patient care areas according to Centers for Disease Control and Prevention guidelines. n Restrict the number of visitors accompanying the patient. n Prevent symptomatic visitors from accompanying patients. n Create a policy for the safe ambulatory imaging of patients with recent COVID-19. n Enable remote work (eg, home workstations). n Enable telehealth when feasible (eg, pre-and postprocedure visits). n Develop an effective communication strategy for safe best practices. 2. Respect local pandemic statistics. n Defer time-insensitive care until at least 2 weeks after the local peak of the pandemic. n Ensure PPE needed for low-risk care will not consume PPE needed for high-risk care. n Follow institutional and governmental regulations. n Monitor local data to predict secondary and tertiary peaks of COVID-19. n Prepare for repeat de-engagement of nonurgent care if local data predict another peak. 3. Engage in risk-benefit decision making. n Consider benefits of radiology care against risks from health care-acquired COVID-19. n Consider clinical acuity, risk factors, the underlying disease and risk from COVID-19. n Engage referring providers and other stakeholders to safely triage nonurgent care. n Determine whether lower-risk diagnostic strategies can be pursued. n Coordinate re-engagement strategies with institutional plans for ambulatory care. 4. Develop a tiered plan for re-engagement of nonurgent radiology care (see following example). n Tier 1: Urgent and emergent care n Tier 2: Nonurgent time-sensitive care n Tier 3: Elective care and screening n Tier 4: Research subjects for imaging trials 5. Manage accreditation and regulatory deferrals to avoid unintended lapses. 6. Address the backlog of previously deferred and delayed care. n Consider extending hours of operation to improve access and preserve social distancing. n Determine if previously ordered care is no longer needed and can be canceled. n Implement strategies to safely shorten imaging examinations and procedures. n Consider modifying scheduling grids to promote social distancing. n Enable clear communication of examination acuity by referring providers. n Consider cooperation with regional "competitors" to smooth access challenges. 7. Manage fear. n Provide frequent, calm, fact-based information to patients and staff to alleviate fear. n Message that for most radiology care, COVID-19 risk is low with appropriate safeguards. n Message that COVID-19 risk is highest for aerosolizing procedures or prolonged contact. n Advertise institutional infection control processes. n Acknowledge that stress and anxiety are normal during a pandemic. n Disseminate local and national wellness information. ## Financial considerations relevant to the re-engagement of nonurgent radiology care The COVID-19 pandemic has had a devastating effect on the economy and the US workforce. Health care systems are reporting massive losses due to the discontinuation of nonurgent care and the general reluctance of patients to enter the health care environment. This is relevant for health care workers, who, despite heroic work to treat this disease, are experiencing furloughs, layoffs, and pay cuts. Resuming nonurgent clinical care activities is anticipated to address some of these challenges and may affect the ability of a health care organization to provide care to future patients. There are financial considerations directly relevant to patients. For example, some patients may be unable to get needed health care because of loss of employment and loss of health insurance. This is particularly problematic for patients who had insured care postponed to a future state in which they are no longer insured. Health care institutions should anticipate these needs, take steps to mitigate them, and remotely communicate solutions to patients before arrival. ## Specific considerations for academic practices The safe integration of trainees (ie, fellows, residents, medical students, technologist students) into patient care is beyond the scope of this statement. In some environments, trainees are directly involved in patient care because of redeployment needs. In other environments, radiology trainees have been socially distanced into their home environment and are learning remotely. The ACR recommends that ACGME guidancebe followed for the safe involvement of trainees in patient care during the COVID-19 pandemic. The safe resumption of research is beyond the scope of this statement. In general, research subjects for imaging trials should be considered the most vulnerable of our patients because their personal benefit may be low or nonexistent. Therefore, these subjects should be considered our most protected patients. However, patients requiring imaging while enrolled in investigational therapeutic trials may need to be prioritized based on clinical need similar to a patient not on a research protocol. ## Take-home points -A comprehensive strategy for the safe resumption of routine radiology care during the COVID-19 pandemic will include consideration of local COVID-19 statistics; availability of PPE; local, state, and federal government mandates; institutional regulatory guidance; local safety measures; health care worker availability; patient and health care worker risk factors; factors specific to the indication(s) for radiology care; and examination or procedure acuity. -Overriding guiding principle: If the risk of illness or death to a health care worker or patient from health care-acquired COVID-19 is greater than the risk of illness or death from delaying radiology care, the care should be delayed; however, if the opposite is true, the radiology care should proceed in a timely fashion. -The risk from health care-acquired COVID-19 can be made very low for most diagnostic radiology examinations and interventional radiology procedures if appropriate safety measures are in place (eg, screening, testing, infection control processes, PPE). -An accurate risk-benefit analysis of postponing versus performing a given routine radiology examination or procedure often is not possible because of many unknown and complex factors. Therefore, decision making will be guided by imperfect attempts to estimate these risks. -Practices should do their best to determine the risk to health care workers and patients of developing illness or death from health care-acquired COVID-19 in their local environment, as well as the patientspecific risk of illness or death from postponing an examination or procedure, and then use that information to guide the re-engagement of routine radiology care. ## Appendix a: supplementary checklist of questions As practices consider when and how to re-engage routine clinical care, answers to the following questions can help guide local decision-making regarding competing risks. Answers to these questions will vary by site because of local and sitespecific information. As COVID-19 testing becomes more widely available, the relevance of some questions may change. The questions are organized into two major categories: how to estimate the risk from COVID-19 and how to estimate the risk from postponement. In this determination, the probability of illness or death (from COVID-19 and non-COVID-19 disease) should take precedence. Is there a process to monitor and account for sick or quarantined radiology workers? B Is there a backup plan to compensate for shortages in the radiology workforce? n Local regulatory guidance B Has your local institution created rules or regulations that will affect your practice? B Has your government created rules or regulations that will affect your practice? n Patient factors B What is the patient's risk of serious harm should they develop COVID-19? B How will anxiety and fear be managed? n Radiology workforce considerations B How will radiology workers be protected from known and unknown COVID-19? B How will worker social distancing be maintained as patient volumes increase? B Is there a process for covering gaps in care because of unexpected worker shortages? B How will unneeded contact with patients and other workers be minimized? B Is there capability for remote work or protected work areas? B How will anxiety and fear be managed? B Has an effective communication strategy been developed? ## Factors to consider when weighing Estimating the risk from imaging delay: n Examination or procedure acuity (arranged from most risk to least risk from a delay) B Urgent or emergent imaging and procedures (e.g., severe abdominal pain) B Routine but time sensitive imaging and procedures (e.g., cancer staging CT) B Elective imaging and procedures (e.g., MR arthrography) B Screening (e.g., lung cancer screening) B Research outside clinical care n Patient factors B Does the patient have risk factors that predict a better or worse outcome from delay? B Is there clinical data (e.g., prior imaging, labs) that can inform time-sensitivity of care? B How will anxiety and fear be managed? n Disease considerations B What is the aggressiveness of the suspected disease or symptom being imaged? B Are there interventions that will be more efficacious if the disease is diagnosed earlier? B What does the referring provider consider the risk of postponement to be? ## Appendix b: statement writing group Writing group	None	http://www.jacr.org/article/S154614402030510X/pdf	None
fc6b970717e3b19cba92f68702fa0170bd0bd815	pubmed	Avoiding, diagnosing and treating well leg compartment syndrome after pelvic surgery	Avoiding, diagnosing and treating well leg compartment syndrome after pelvic surgery Background: Patients undergoing prolonged pelvic surgery may develop compartment syndrome of one or both lower limbs in the absence of direct trauma or pre-existing vascular disease (well leg compartment syndrome). This condition may have devastating consequences for postoperative recovery, including loss of life or limb, and irreversible disability. Methods: These guidelines represent the collaboration of a multidisciplinary group of colorectal, vascular and orthopaedic surgeons, acting on behalf of their specialty associations in the UK and Ireland. A systematic analysis of the available peer-reviewed literature was undertaken to provide an evidence base from which these guidelines were developed. Results: These guidelines encompass the risk factors (both patient-and procedure-related), diagnosis and management of the condition. Key recommendations for the adoption of perioperative strategies to facilitate prevention and effective treatment of well leg compartment syndrome are presented. Conclusion: All surgeons who carry out abdominopelvic surgical procedures should be aware of well leg compartment syndrome, and instigate policies within their own institution to reduce the risk of this potentially life-changing complication. Key recommendations 3. Unless mandated by other patient safety considerations, the patient's legs should be kept at a level below the heart for the maximum duration possible during a procedure. 4. Where elevation of the legs is required to facilitate surgery, the maximum unbroken period of elevation should not exceed 4 h. The patient's legs should be kept at a lower level than the heart for a minimum of 15 min after each 4-h interval. The duration of elevation and the time allowed for recovery should [bib_ref] Current thinking about acute compartment syndrome of the lower extremity, Shadgan [/bib_ref]. There should be a low threshold for reassessment in patients whose symptoms persist or deteriorate. 12. If initial assessment is equivocal, for example in a sedated/unconscious patient, in whom adequate clinical assessment cannot be undertaken, and there is a high index of suspicion, measurement of compartment pressures may be used to confirm or exclude compartment syndrome. [bib_ref] Crush injury, Burzstein [/bib_ref]. If compartment pressure measurement is undertaken, and the difference between diastolic pressure and compartment pressure is less than 30 mmHg in any compartment, an immediate (within 1 h), bilateral four-compartment fasciotomy should be undertaken. 14. Reassessment of the compartments in theatre should be carried out betweenand 72 h after decompression. [bib_ref] Compartment syndrome following prolonged pelvic surgery, Peters [/bib_ref]. After fasciotomy, early discussion with, and involvement of, plastic and reconstructive surgeons is recommended for patients with significant tissue loss. # Introduction Acute lower limb compartment syndrome may follow prolonged abdominopelvic surgery in the Lloyd-Davies/ lithotomy position and complicate the postoperative management of patients undergoing major pelvic surgery. It may result in life-changing morbidity or even death. The purpose of this guideline is to clarify the nature of this condition and summarize the available evidence regarding pathogenesis, to ensure that appropriate arrangements can be made for prevention, early diagnosis and effective treatment. ## Search strategy and review of the literature A PubMed search was carried out using the following keywords: laparoscopic surgery, robotic surgery, lower limb, lower extremity, lithotomy, Lloyd Davies, compartment syndrome, well leg compartment syndrome. Other papers were identified using references from the original results, with exclusion of non-English language papers. Owing to the rarity of the condition, there have been no RCTs or prospective case-control studies. The best level of evidence is presented by retrospective cohort studies (level III evidence), with the majority of published work taking the form of case series (level IV) with expert opinion (level V). Although this is a substantial limitation to the creation of this guideline, it must be accepted that more robust studies have not been undertaken. However, it is possible to produce key recommendations from the available evidence that may be adopted easily into clinical practice. ## Definition of compartment syndrome Compartment syndrome is defined as a condition in which fascial compartment pressure exceeds perfusion pressure, causing tissue ischaemia and necrosis 1 . Although commonest in the lower extremity, compartment syndrome has also been described in the hands, forearms, buttocks, thighs and abdomen. Well leg compartment syndrome (WLCS) is defined as an acute lower limb compartment syndrome that develops in the absence of trauma, and may occur without pre-existing vascular disease. It is characteristically associated with prolonged operative positioning with the hips and knees flexed, especially in patients maintained with a head-down tilt (Lloyd-Davies/Trendelenburg position). # Background ## Incidence Although no attempt has been made to collect risk-adjusted data in large populations, clinically evident WLCS appears Gastrocnemius muscle relatively uncommon. The incidence of the condition varies from as high as one in 500 patients undergoing cystectomy 2 , to one in 3500 (0⋅03 per cent) or six of 52 319 (0⋅01 per cent) undergoing abdominopelvic surgery in the lithotomy position [bib_ref] Effect of various lithotomy positions on lower-extremity blood pressure, Halliwill [/bib_ref] [bib_ref] Compartment syndrome in surgical patients, Warner [/bib_ref]. However, the lowest reported figures almost certainly represent an underestimate of the true incidence of the condition as many cases, especially those with less severe clinical features, are probably not reported. It seems likely, with the advent of laparoscopic or robotic surgery, resulting in more prolonged abdominopelvic operations undertaken in extreme Trendelenberg tilt and the decreased venous return associated with a pneumoperitoneum, that more patients will be put at risk of WLCS, although there have been no studies that have addressed this specifically. ## Sequelae of well leg compartment syndrome In a German survey 5 of 21 patients with WLCS following gynaecological surgery (all carried out in the lithotomy position), six were left with permanent neurological disability. Expert review concluded that malpractice had occurred in over half of all of the cases, because preventative measures had not been undertaken clearly, and delays had occurred in diagnosis and/or treatment. A comprehensive review [bib_ref] Well leg compartment syndrome after abdominal surgery, Christoffersen [/bib_ref] of Danish cases of WLCS where claims for compensation had occurred found that 24 of 40 were successful. Only one patient made a full recovery; 13 patients had a sensory defect in the leg, 14 had pain and a sensory defect, and 12 had paresis, pain and sensory defects. ## Pathophysiology The leg is divided into four fascial compartments [fig_ref] Figure 1: Lower limb compartments [/fig_ref] , namely the anterior, lateral, deep posterior and superficial posterior compartments 7 . The anterior compartment is the most commonly affected by compartment syndrome as it is rigidly bound by the tibia, fibula, interosseous septum and deep fascia 8 . However, delayed diagnosis is associated with all four compartments being affected. WLCS results from tissue hypoperfusion, caused by a decrease in the perfusion pressure owing to elevation of the lower limb in patients in the lithotomy position. This is further exaggerated (where relevant) by head-down (Trendelenburg) tilt. This reduces tissue oxygen availability, which causes cells in the affected regions to switch to anaerobic metabolism, generating lactate and other intermediary metabolites of incomplete fuel substrate oxidation. The ischaemia causes hypoxic disruption of capillary endothelium, allowing leakage of fluid and plasma proteins into the interstitial space. This leads to interstitial oedema and a rise in intracompartmental pressure [bib_ref] Lower limb acute compartment syndrome after colorectal surgery in prolonged lithotomy position, Beraldo [/bib_ref]. The injury associated with tissue hypoperfusion itself may be reversible for up to 4-6 h. However, on levelling out the patient and lowering the limbs, thus restoring perfusion, a reperfusion injury may then occur. This results from the release of oxygen-free radicals and other vasoactive mediators as tissues are reoxygenated, damaging the endothelium further. This causes a further increase in permeability to plasma proteins and aggravates interstitial oedema, resulting in a further, often abrupt rise in intracompartmental pressure [bib_ref] Ischaemia-reperfusion injury, Grace [/bib_ref]. Normal compartment pressures in the lower extremity range from 0 to 8 mmHg. The first clinically significant effects of raised intracompartmental pressure probably begin to develop at pressures of 20-30 mmHg. The compliance of the fascial compartments of the leg is exceeded at pressures of 30-33 mmHg [bib_ref] Current thinking about acute compartment syndrome of the lower extremity, Shadgan [/bib_ref]. Pressures rise steeply thereafter, resulting in significant impairment of tissue perfusion, worsening ischaemia and, ultimately, tissue necrosis. If left untreated, cell lysis and release of intracellular proteins lead to myoglobinuria and renal damage, followed by multiple organ dysfunction syndrome [bib_ref] Compartment syndromes: concepts and perspectives for the anesthesiologist, Martin [/bib_ref] [bib_ref] Crush injury, Burzstein [/bib_ref]. ## Risk factors and prevention # Patient-related Age Younger patients may be at greater risk of WLCS. Among those with tibial fractures, a threefold higher rate of acute lower limb compartment syndrome has been noted in patients under 35 years of age, compared with older patients [bib_ref] Acute compartment syndrome. Who is at risk?, Mcqueen [/bib_ref]. This may reflect greater muscle bulk in the compartment and the presence of a stronger, thicker enclosing fascia, but it is unclear whether these alone are sufficient explanations for the apparent difference [bib_ref] Current thinking about acute compartment syndrome of the lower extremity, Shadgan [/bib_ref]. It is also unclear whether the same factors might predispose younger patients to WLCS after pelvic surgery, or whether they are specific to compartment syndrome complicating trauma. Although younger patients may need prolonged pelvic surgery, for example to treat inflammatory bowel disease, it seems likely that most patients undergoing surgery of this nature will tend to be older than the typical population of patients with a tibial fracture. ## Obesity Obesity may increase the risk of developing WLCS. In patients with a BMI above 25 kg/m 2 a linear relationship has been reported between increasing BMI and a decrease in ankle BP in the elevated lithotomy position [bib_ref] Compartment syndrome following prolonged pelvic surgery, Peters [/bib_ref]. There is also a correlation between BMI and intramuscular pressure in the hemilithotomy position, which may explain this association [bib_ref] Well-leg compartment pressures during hemilithotomy position for fracture fixation, Tan [/bib_ref]. There have been no studies analysing the impact of the individual weight of the lower limb on the risk of WLCS but, when positioning, care must be taken that excessive pressure on the popliteal fossa and posterior compartments is avoided in patients with a high BMI. ## Vascular disease As one might expect given the pathophysiology, patients with pre-existing lower limb vascular disease may be at increased risk of further impairment of tissue perfusion when placed in the lithotomy position, especially with a head-down tilt, and therefore be at greater risk of WLCS [bib_ref] Effects of the lithotomy position on arterial blood flow in the lower..., Canterbury [/bib_ref]. This impairment may result from the simple effects of gravity in a circulatory system already compromised by a degree of vascular stenosis, leading to a critical degree of ischaemia that might not otherwise have been apparent in a supine or erect position 12 . ## Intraoperative Type of surgery WLCS can occur in any type of abdominopelvic surgery where the patient is positioned with their hips and knees flexed, especially when a period of head-down tilt is required. This includes colorectal, urological and gynaecological procedures [bib_ref] Survey of compartment syndrome of the lower extremity after gynecological operations, Bauer [/bib_ref] [bib_ref] Well leg compartment syndrome after abdominal surgery, Christoffersen [/bib_ref]. Indeed, WLCS has been reported in all the relevant surgical specialties, and after open, laparoscopic and robotic procedures. Laparoscopic and robotic procedures might expose patients to a greater risk of WLCS than open procedures, as a result of prolonged operating times, a greater degree of head-down tilt, and possibly reduced venous drainage associated with pneumoperitoneum [bib_ref] Lower limb compartment syndrome following laparoscopic colorectal surgery: a review, Rao [/bib_ref]. ## Positioning The position in which a patient is placed, and the duration for which it is maintained, are key factors in the development of WLCS. The most important consideration, even in a patient who would conventionally be regarded as having been positioned optimally for prolonged pelvic surgery, is the position of the lower limbs with reference to the heart. Although operative positioning of patients is often undertaken by other members of the theatre team, ensuring appropriate exposure to facilitate adequate surgery, avoidance of inappropriate or unsafe positioning, and the prevention of adverse consequences of even appropriate positioning, remain the ultimate responsibility of the operating surgeon. Elevation of a patient's legs from the supine position has been said to result in a 2-mmHg drop in mean arterial BP (MAP) in the calf for every vertical 2⋅5-cm rise in height above the heart [bib_ref] Postural ischaemia and blood-pressure, Enderby [/bib_ref]. Therefore, a patient with a MAP of 90 mmHg, but whose lower limbs are raised so that the midpoint of the calf is elevated 50 cm (a common surgical position), would have a MAP of only 50 mmHg at this level. The addition of a head-down Trendelenberg position been shown to result in a significant decrease in deep muscle mixed tissue oxygen saturation, owing to a combination of hydrostatic, blood and intra-abdominal pressures, compounding the relative tissue underperfusion 20 . Some studies have suggested that a head-down tilt of as little as 15 ∘ (as opposed to hip abduction and flexion) may be the dominant factor in impaired limb perfusion during prolonged pelvic dissection [bib_ref] Lloyd-Davies position with Trendelenburg -a disaster waiting to happen?, Horgan [/bib_ref]. Even short periods of head-down tilt, systemic hypotension or co-existing peripheral vascular disease (or a combination of these) may therefore result in significant lower limb tissue ischaemia. Ankle position may also affect leg compartment pressures, with full dorsiflexion increasing it in all four compartments, whereas knee position (full extension of the knee with full dorsiflexion of the ankle) affects only pressures in the superficial posterior and lateral compartments [bib_ref] Lower limb acute compartment syndrome after colorectal surgery in prolonged lithotomy position, Beraldo [/bib_ref] [bib_ref] Ankle and knee position as a factor modifying intracompartmental pressure in the..., Gershuni [/bib_ref]. Great care must be taken at all times to protect the legs in order to avoid compression of the popliteal fossae and calves from support boots, other devices, or even the excessive use of material for lower limb wrapping. The upper part of the patients' calves should be clear of the support boots. Care should be taken to avoid dorsiflexion of the ankles, which should be maintained in a neutral or slightly plantar-flexed position, and this should also be documented contemporaneously in the operative care chart. There is no evidence to suggest that any one form of lower limb support is preferable for avoiding WLCS. There are no clinical outcome data, but anterior compartment pressures have been compared in Allen stirrups (a boot-like device supporting the calf), posterior knee supports and ankle slings [bib_ref] Effects of lithotomy position and external compression on lower leg muscle compartment..., Pfeffer [/bib_ref]. Both stirrups and knee supports resulted in significant increases in compartment pressures when the legs were elevated, although these pressures were reduced by pneumatic calf compression. Ankle slings did not increase compartment pressures significantly when the legs were elevated. Although it is unclear whether this might protect against WLCS, ankle slings are relatively unstable; they are acceptable for brief procedures (less than 30 min), but are usually inappropriate for more prolonged operations. Even though lower limb positioning may be extremely important, it should be noted that there are some case reports of WLCS developing in patients in the supine position For operations that are anticipated to be extremely long (for example complex reconstructive or exenterative pelvic surgery), it may be safer to start the procedure with the patient in the supine position, and to adopt the Lloyd-Davies/lithotomy position only when the pelvic phase of the procedure commences. Alternatively, it may be appropriate to position the lower limbs in supports, but to ensure that they are kept level with the patient's heart for as long as possible, and to document this. Where adequate pelvic exposure is needed for more than 4 h to complete a procedure, the time at which the lower limbs are elevated above the level of the patient's heart should be recorded routinely, and arrangements made to notify the surgeon as the 4-h cut-off approaches, so that preparations can be made to lower the legs at that time. ## Duration of leg elevation and head-down tilt The minimum degree and duration of head-down tilt required for safe and effective exposure of the operative field should be adopted at all times, and the tilt corrected at the earliest opportunity. Given the pathophysiology described above, it seems reasonable to conclude that, in general, the likelihood of WLCS developing is time-critical. The duration of compartment ischaemia is likely to be reflected in the extent of reperfusion injury when the legs are lowered. It is likely that subclinical degrees of muscle ischaemia and raised compartment pressures, which are asymptomatic (or at least minimally symptomatic), may occur more frequently, but go undetected, or at least unreported. The degree of compartment ischaemia in WLCS is probably the result of overall arterial perfusion and local perfusion abnormalities in the calf resulting from the degree of limb elevation and head-down tilt. However, the extent (if any) of fluid overadministration, the presence of pre-existing vascular insufficiency, and the duration for which the lower limbs are exposed to these factors are likely to also be important. Lower limb compartment pressures have been measured in patients undergoing colorectal procedures in the lithotomy position. Compartment pressures increased immediately on putting the legs into the lithotomy position, but remained below 20 mmHg. They increased further with Trendelenburg tilt. Compartment pressures then continued to rise, reaching a mean of 30 mmHg at a mean of 5 h. After returning the patients to the supine position, all compartment pressures had returned to less than 10 mmHg within 15 min [bib_ref] Intraoperative lower extremity compartment pressures in lithotomy-positioned patients, Chase [/bib_ref]. The majority of accounts of WLCS in abdominopelvic surgery report that patients have been maintained for at least 4 h in the Lloyd-Davies/lithotomy position. It should be noted that there are, however, several case reports in which WLCS developed within 4 h 29 . Of 125 case reports identified by Christoffersen and colleagues [bib_ref] Well leg compartment syndrome after abdominal surgery, Christoffersen [/bib_ref] , the median duration of surgery was 7⋅5 (range 2-12) h. These were a mix of colorectal, gynaecological, obstetric, plastic surgical and urological procedures. As the factor common to published case reports (where this is stated) has generally been an operating time exceeding 4 h, it is recommended that care is taken to document the interval during which the legs are elevated above the heart, and to restrict this to a maximum unbroken period of 4 h 5,6,30 . Where technical difficulties or operative challenges prevent safe lowering of the patient's legs (for example, because of the need to control pelvic bleeding), the risk to the patient from lowering the legs may exceed the risk of WLCS. The reasons for exceeding the 4-h period of elevation should, under those circumstances, be documented clearly when the relevant operation note is completed. There are no clinical data to support the minimum time that should be allowed to elapse before the limbs can safely be elevated again, in order to minimize the risk of WLCS. Based on the change in compartment pressures noted above, it is recommended that the legs are returned to the same level as the heart for at least 15 min, before being elevated again. Lowering the legs appears to be safe and, in particular, there is no evidence to suggest that this results in an increase in the incidence of surgical-site infection [bib_ref] Nerve damage due to positioning during surgery, Balen [/bib_ref]. ## Antiembolism stockings and/or intermittent pneumatic compression devices Antiembolism/thromboembolism deterrent (TED) stockings generate a constant pressure of at least 25 mmHg 32,33 , whereas intermittent pneumatic compression devices produce an intermittent pressure of approximately 40 mmHg for 12 s each minute [bib_ref] Anterior tibial compartment pressures during intermittent sequential pneumatic compression therapy, Gilbart [/bib_ref]. As the risk of compartment syndrome increases at pressures above 30 mmHg, the application of antiembolism stockings and intermittent pneumatic compression devices could increase the risk of a patient developing compartment syndrome. It has been suggested that both modalities of thromboprophylaxis should not be used concurrently during extended surgery in the lithotomy or Lloyd-Davies position, because of this risk [bib_ref] Complications associated with intermittent pneumatic compression, Lachmann [/bib_ref]. Current National Institute for Health and Care Excellence guidancerequires only that patients should be offered either modality, and there may be specific contraindications to one or other form of thromboprophylaxis. However, the potential risk of causing (or at least increasing the risk of) WLCS seems unlikely to represent adequate justification for not using one or both forms of prophylaxis, properly undertaken, in high-risk circumstances such as prolonged pelvic surgery. There are no randomized trials or even observational studies that have compared the risks of WLCS in patients with, and without TED stockings or intermittent pneumatic calf compression. The theoretical possibility that measures taken to reduce the risks of thromboembolism (taken alone or together) might increase the risk of WLCS has therefore to be evaluated based on the balance of the relative risks of these two potentially fatal postoperative complications. In the absence of any form of thromboprophylaxis, the risk of an asymptomatic deep vein thrombosis (DVT) is up to 25 per cent and the risk of a fatal pulmonary embolism is 0⋅5 per cent following abdominopelvic surgery. It therefore seems inappropriate to avoid carefully applied TED stockings and/or intermittent pneumatic calf compression devices, purely because of potential concerns about causing WLCS. ## Fluid and bp management Current enhanced recovery after surgery protocols suggest that traditional perioperative intravenous fluid therapy of 3⋅5-7 l of fluid on the day of surgery can lead to delays in return of normal gastrointestinal function, impairment in wound and anastomotic healing, and a decrease in tissue oxygenation [bib_ref] Enhanced Recovery After Surgery (ERAS) Group. Consensus review of optimal perioperative care..., Lassen [/bib_ref]. A recent meta-analysis [bib_ref] Liberal or restrictive fluid management during elective surgery: a systematic review and..., Schol [/bib_ref] showed that fewer patients suffered complications with a restrictive fluid protocol, and the risk of infection was lower. However, perioperative fluid restriction has not been shown to reduce postoperative hospital stay [bib_ref] Randomized clinical trial of the effect of postoperative intravenous fluid restriction on..., Mackay [/bib_ref]. Although perioperative fluid restriction may improve patient outcomes, it may also, at least in theory, lead to impaired tissue perfusion, and excessive hypotension; it should therefore be avoided, especially while the legs are elevated, to minimize the risk of WLCS. No evidence has currently been identified to implicate the perioperative use of inotropes/vasoconstrictors in the aetiology of WLCS. ## Other operative factors Care must be taken to avoid vascular compromise in the lower limbs as a result of intra-abdominal retractor placement. WLCS has been reported to have developed as consequence of compression of the external iliac vein by a disposable intra-abdominal retractor [bib_ref] Two cases of compartment syndrome of the lower extremities during surgery for..., Kikuchi [/bib_ref]. ## Preoperative planning and time out Theatre teams undertaking expected prolonged (more than 2 h) pelvic surgery on patients in the Lloyd-Davies/lithotomy position must recognize that they are potentially exposing their patient to a risk of WLCS. Although, in the authors' view, WLCS is insufficiently common to mandate routine discussion during consent, the needs and likely preferences of the patient should be considered so that, where appropriate (for example in an athlete or other active individual), a discussion satisfying the requirements of Montgomery v Lanarkshire Health Board 2015can be undertaken and documented. The nature of the proposed surgery and the fact that the patient is likely to be placed, at least for a period, in a position that puts them at risk of WLCS should be noted specifically during the team brief at the start of the theatre list and the WHO preoperative time out, to draw attention to the potential risk of this complication. A plan should be agreed before operation, between the surgical, anaesthetic and theatre nursing teams, to minimize this risk (notably with regard to the duration of limb elevation and head-down tilt). This plan and the resulting actions should be documented in the contemporaneous theatre records, notably the operation record. Some centres have already instituted these practices in every at-risk procedure [bib_ref] Lessons learned from a case of calf compartment syndrome after robot-assisted laparoscopic..., Rosevear [/bib_ref]. ## Diagnosis ## Intraoperative Intraoperative monitoring of compartment pressures with needle transducers is technically possible, but unlikely to be helpful as it is not simply the duration of ischaemia, but also the subsequent reperfusion that leads to WLCS 12 . For example, in patients undergoing intra-abdominal colorectal surgery, anterior compartment pressures can reach up to 70 mmHg for intervals while in the lithotomy position, without this resulting in WLCS once the legs are returned to a supine position [bib_ref] Intraoperative lower extremity compartment pressures in lithotomy-positioned patients, Chase [/bib_ref]. Intraoperative compartment pressure monitoring therefore seems unlikely to be a useful basis on which to guide practice, and routine monitoring is therefore not currently recommended. ## Postoperative Leg pain after pelvic surgery is a red flag symptom and mandates immediate assessment. It should lead automatically to clinical suspicion of WLCS [bib_ref] Acute compartment syndrome of the lower limb and the effect of postoperative..., Mar [/bib_ref]. WLCS should be considered the most likely diagnosis in any patient complaining of otherwise unexplained unilateral or bilateral leg pain after pelvic surgery. Immediate assessment requires taking an accurate history, recording the site, onset and character of the pain. Enquiry should be made regarding the presence of paraesthesia, numbness, weakness and paralysis. The sensory/motor effects of epidural analgesia or the potential masking effect of patient-controlled analgesia should be taken into account, but should never be assumed to account for symptoms and signs. Although the use of analgesics has been implicated in the delayed diagnosis of compartment syndrome in patients with limb fracture, the same does not apply to WLCS. Symptoms are typically bilateral, but are frequently asymmetrical, and may even be unilateral. Approximately half of patients complain of pain appearing almost immediately on waking from anaesthesia and over 99 per cent do so within 24 h of return to theatre recovery [bib_ref] Well leg compartment syndrome after abdominal surgery, Christoffersen [/bib_ref]. Notably, the pain is severe and unremitting, and patients may complain that the leg pain greatly exceeds that of the abdominal surgery. Pain that is severe, unremitting and exacerbated by passive dorsiflexion of the toes and ankles is a cardinal symptom, together with the presence of tension and/or tenderness in the leg compartments. Active dorsiflexion of the ankle, or even of the toes, may be impossible owing to pain and also to impairment of peroneal nerve function. In patients with unilateral symptoms, there may be a palpable difference between sides. Limb neurology and perfusion, including capillary refill and distal pulses, should be documented but they do not contribute to early diagnosis of the condition [bib_ref] Acute compartment syndrome of the limb, Köstler [/bib_ref]. It should be emphasized that evidence of vascular insufficiency or numbness is not required for diagnosis; indeed, these are features of a diagnosis made too late, and consequently of irreversible injury. The British Orthopaedic Association Standards for Trauma (BOAST)state that 'in high-risk patients, regional anaesthesia should be avoided as it can mask the symptoms of compartment syndrome. In addition patient-controlled analgesia with intravenous opiates can also mask the symptoms'. However, this is most relevant to the diagnosis of traumatic compartment syndrome (where the analgesia is aimed at treating pain in the injured limb in which the compartment syndrome might be diagnosed). It is not relevant to epidural analgesia (where the aim is to provide effective control of abdominal wound pain, usually without affecting sensation in the legs). Epidural anaesthesia should not be a barrier to the effective diagnosis of WLCS [bib_ref] Acute compartment syndrome of the lower limb and the effect of postoperative..., Mar [/bib_ref] [bib_ref] Epidural opioid analgesia does not obscure diagnosis of compartment syndrome resulting from..., Montgomery [/bib_ref]. If initial clinical assessment is equivocal, a repeat clinical assessment in 30 min is mandatory, as WLCS is usually a rapidly progressive condition. ## Exclusion of deep vein thrombosis Although DVT is a possible explanation for postoperative leg pain when associated with a swollen, tense lower limb, WLCS and DVT may co-exist; therefore, an attempt to diagnose DVT should not delay consideration and treatment of WLCS. The High Court in England found in 2013 that it was not reasonable to delay diagnosis and treatment of WLCS in order to exclude DVT and pulmonary embolism first, in a patient who had recently undergone abdominoperineal excision for rectal cancer. ## Special investigations Diagnosis of WLCS is, in almost all cases, based on clinical assessment. Special investigations are not usually required for the diagnosis of WLCS in a conscious patient. They should not delay treatment, which, in almost all patients, requires consideration of urgent fasciotomy if neuromuscular function and, ultimately, the legs are to be preserved. They may be of value, however, in an obtunded/unconscious patient, in whom it may not be possible to diagnose WLCS without measurement of compartment pressures. The relevant technique and interpretation of results are outlined below. ## Compartment pressure measurement Compartment pressure measurement is not recommended for the routine diagnosis of WLCS. Clinical judgement is usually sufficient for the diagnosis in a conscious patient. However, in patients whose level of consciousness is impaired and the diagnosis of WLCS is difficult to establish, compartment pressure measurement [fig_ref] Figure 2: Compartment pressure measurement [/fig_ref] may be valuable to support clinical judgement. Unless a raised pressure is identified in one compartment, measurement should be undertaken in all four compartments of both legs and done by the surgeon who will be responsible for performing fasciotomy. The measurement of compartment pressures may also be used to support/refute the diagnosis in a patient with equivocal findings complaining of limb pain, without other positive physical signs. Facilities for measurement are available in the standard anaesthetic room. There are differing opinions regarding whether compartment pressure alone, perfusion pressure (mean BP minus compartment pressure) or the difference between diastolic pressure and compartment pressure (so-called delta P, Δp) is the most useful in the diagnosis of compartment syndrome. The Vascular Society of Great Britain and Ireland considers Δp to be the easiest and most reliable measurement for routine use. A Δp below 30 mmHg is indicative of compartment syndrome and mandates immediate bilateral four-compartment fasciotomy. A Δp of less than 30 mmHg in a single compartment is a positive result for that leg. A negative result requires that all four compartments in the leg have a Δp of at least 30 mmHg. ## Laboratory investigations Abnormal laboratory investigations indicate that significant tissue damage has already occurred and should not be relied on to make the timely diagnosis of WLCS. Measurement of the serum concentration of the muscle enzyme creatine phosphokinase (CK) may provide an indication of severe muscle damage. A CK value of over 2000 units/l is uncommon after surgery and, if associated with symptoms, should be interpreted as indicating compartment syndrome [bib_ref] Postoperative bilateral compartment syndrome resulting from prolonged urological surgery in lithotomy position...., Lampert [/bib_ref]. A CK concentration of over 4000 units/l may be diagnostic when associated with a chloride level of greater than 104 mg/dl, and blood urea nitrogen level of less than 10 mg/dl 50 . However, these significant increases are usually a late feature of WLCS [bib_ref] Acute compartment syndrome of the limb, Köstler [/bib_ref]. Similarly, urinary myoglobin may be present if rhabdomyolysis has occurred, but this too is an ominous and late development, frequently associated with a high risk of acute renal failure. Urgent referral to a renal physician is required under such circumstances. ## Mri T2-weighted MRI has been suggested to be useful in demonstrating and localizing muscle oedema 51 . However, the findings are not specific and a scan should not be allowed to delay treatment. MRI should certainly not replace clinical judgement. ## Near-infrared spectrometry Near-infrared spectrometry (NIRS) is a non-invasive technique that can identify muscle deoxygenation and perfusion, and may be of value in the assessment of acute and chronic compartment syndromes. Tissue oxygen saturation was reduced significantly when affected legs were compared with unaffected legs in patients with acute traumatic compartment syndrome 52 and the reduction in tissue oxygen saturation appears to persist, even after fasciotomy [bib_ref] Utility of near-infrared spectroscopy in the diagnosis of lower extremity compartment syndrome, Giannotti [/bib_ref]. However, Bariteau and colleagues 54 aborted a trial of NIRS prematurely after false-negative results were observed in patients with acute compartment syndrome. This might, however, have been because tissue ischaemia had not yet developed at that time point [bib_ref] Systematic review of clinical applications of monitoring muscle tissue oxygenation with near-infrared..., Boezeman [/bib_ref]. All studies of NIRS to date have been undertaken in acute compartment syndrome following trauma, and not WLCS. There is insufficient evidence to recommend NIRS for the diagnosis of WLCS and, in particular, to assume that a satisfactory NIRS result excludes WLCS. ## Management The management of WLCS is no different from the treatment of compartment syndrome secondary to trauma. The greater the level of intracompartmental pressure, the more rapidly ischaemic tissue injury occurs. In addition, a less significantly raised intracompartmental pressure maintained for longer may cause equally severe damage [bib_ref] Well-leg compartment syndrome after gynecological laparoscopic surgery, Boesgaard-Kjer [/bib_ref]. BOAST 45 recommend two-incision, four-compartment decompression. When suspected, WLCS should be considered a surgical emergency and treatment should be commenced within 1 h of diagnosis. Once compartment syndrome is suspected, an immediate referral should be made to colleagues in either orthopaedic or vascular surgery, depending on local protocols. There is usually no place for conservative treatment for suspected WLCS, and arrangements should be made for immediate transfer to theatre and fasciotomy. A delay in fasciotomy of more than 12 h increases the risk of permanent sequelae. Full recovery is more likely if fasciotomy is undertaken within 6 h of diagnosis [bib_ref] Diagnosing acute compartment syndrome, Elliott [/bib_ref]. In patients with a reduced level of consciousness in whom WLCS is suspected and there are therefore no reliable physical signs, bilateral measurement of compartment pressure in all four compartments may be appropriate. Concurrent measurement of diastolic BP is required to calculate Δp. A Δp of less than 30 mmHg measured in any compartment mandates immediate bilateral four-compartment fasciotomy. As WLCS develops rapidly and 99 per cent develops within 24 h of return to recovery, it follows that it is safer to undertake bilateral four-compartment fasciotomies in patients with a reduced level of consciousness. There should be a low threshold for re-evaluation in borderline cases. After fasciotomy, return to theatre for examination of the affected limb(s) under anaesthesia, assessment and, where appropriate, debridement of affected tissues should be arranged routinely 48-72 h later. Subsequent debridement and wound management includes delayed primary closure, skin grafting and healing by secondary intention. The wound management will depend on surgeon experience, preference and local arrangements. Early liaison with plastic and reconstructive surgeons for advice and clinical input is recommended for challenging wounds. The knowledge, skills and procedures required to assess and manage compartment syndrome, and therefore WLCS, are prescribed by the Trauma and Orthopaedic Surgeryand Vascular Surgery 59 curricula. [fig] Figure 1: Lower limb compartments [/fig] [fig] Figure 2: Compartment pressure measurement [/fig]	None	https://bjssjournals.onlinelibrary.wiley.com/doi/pdfdirect/10.1002/bjs.11177	Patients undergoing prolonged pelvic surgery may develop compartment syndrome of one or both lower limbs in the absence of direct trauma or pre‐existing vascular disease (well leg compartment syndrome). This condition may have devastating consequences for postoperative recovery, including loss of life or limb, and irreversible disability.
5a7486d9d48110287816300523db5a66ee1e3a37	pubmed	Practice guidelines for management of cervical cancer in Korea: a Korean Society of Gynecologic Oncology Consensus Statement	Practice guidelines for management of cervical cancer in Korea: a Korean Society of Gynecologic Oncology Consensus Statement 1-1. Generation of key questions based on PICO* [KQ 1] Are PET/ CT scans more sensitive than the CT or MRI in predicting lymph node metastasis for the treatment of cervical cancer? P : Cervical cancer I : PET C : MRI or CT O : nodal metastasis or lymph node metastasis 1-2. Medical literature search and study identification PubMed, EMBASE, and Cochrane were used for the literature search, and the search formula is as follows. Table 1. Procedure used for MEDLINE, EMBASE, and COCHRANE to identify eligible clinical trials for answering KQ1 MEDLINE 1. "Uterine Cervical Neoplasms"[Mesh] 59998 2. Five articles were finally selected using aforementioned method. ## 1-3. quality assessment Two non-randomized studies were finally selected and summarized in the table. # 1-5. meta-analysis There is insufficient evidence that PET/CT is more sensitive than CT or MRI to predict pelvic or para-aortic lymph node metastasis. PET/CT shows discrepant results in terms of sensititivity in selected studies for metaanalysis. As per the study protocol, CT, MRI, and PET/CT have different sensitivity, specificity, negative predictive value and positive predictive value. Overall, when metastases are not identified in the CT or MRI scans or when the results are uncertain, PET/CT could be helpful in predicting pelvic or aortic lymph node metastasis. Range of effect has been suggested by figures. PubMed, EMBASE, and Cochrane were used for the literature search, and the search formula is as follows. Four articles were finally selected using aforementioned method. ## 2-3. quality assessment The result of the evaluation of the the paper is summarized in the table below. The evidence for the key question was supported by the four NRS research results. (Level of evidence: LOW) # 2-5. meta-analysis There is no randomized trial comparing laparoscopic or robotic surgery and open surgery. Based on the meta-analysis, relative risk reduction (RRR)=27%, event rate (ER)=7.4%, optimal information size (OIS)=600, and the number of death=50 is needed to have statistically significant results. This means that larger number of the study population is needed to clarify the differentiation in the death. From several retrospective studies, treatment outcome in terms of progression-free and overall survival is comparable between two groups. Laparoscopic or robotic radical hysterectomy can be performed in cervical cancer stage IB-IIA. ## Level of evidence: d (very low) Strength ## 3-2. medical literature search and study identification PubMed, EMBASE, and Cochrane were used for the literature search, and the search formula is as follows. Two articles were finally selected using aforementioned method. [fig_ref] Figure 1: Flow chart of searching strategy for answering KQ1 [/fig_ref]. Flow chart of searching strategy for answering KQ3 ## 3-3. quality assessment The result of the evaluation of the the paper is summarized in the table below. # 3-5. meta-analysis Meta-analysis has been performed to investigate the survival outcome in early cervical cancer. Survival outcome after nerve sparing radical hysterectomy is similar to that of type III hysterectomy and results in decreased urinary difficulty. Based on the meta-analysis, relative risk reduction (RRR)=39%, event rate (ER)=6.8%, optimal information size (OIS)=200, and the number of death=5 is needed to have statistical analysis. One randomized trial and one non-randomized trial showed no impact of nerve sparing radical hysterectomy on survival outcome. ## Figure 2. result of meta-analysis ## 3-6. summary [kq 3] does the nerve sparing radical hysterectomy have similar survival outcome compared to type iii hysterectomy in early staged cervical cancer? Nerve sparing radical hysterectomy could be performed in early staged cervical cancer. ## Level of evidence: c (low) Strength of recommendation: 2 (weak) ## 3-7. [ One article was finally selected using aforementioned method. ## 4-3. quality assessment The result of the evaluation of the the paper is summarized in the table below. ## 4-4. level of evidence and grade of recommendation Page 17 The evidence for the key question was supported by the one RCT research results. (Level of evidence: VERY LOW) Page 18 # 4-5. meta-analysis Although based on the limited study results including one prospective randomized trial, we do not observe the definitive loss of survival outcome from type I hysterectomy compared to radical hysterectomy in women with cervical cancer ≤2cm and type I hysterectomy shows better outcome for complication. Relative risk reduction (RRR)=62%, event rate (ER)=26%, optimal information size (OIS)=100, and the number of death=22 is needed for the near future prospective study. ## 5-2. medical literature search and study identification PubMed, EMBASE, and Cochrane were used for the literature search, and the search formula is as follows. Three articles were finally selected using aforementioned method. [fig_ref] Figure 1: Flow chart of searching strategy for answering KQ1 [/fig_ref]. Flow chart of searching strategy for answering KQ5 ## 5-3. quality assessment The result of the evaluation of the the paper is summarized in the table below. There is risk of bias related randomization and allocation concealment for the previous results. Relative risk reduction (RRR)=83%, event rate (ER)=50%, optimal information size (OIS)=50, and the number of death=7 is needed for the near future prospective study. ## 5-4. level of evidence and grade of recommendation # 5-5. meta-analysis ## Figure 2. result of meta-analysis ## 5-6. summary [kq 5] does intensity modulated radiotherapy (imrt) result in less complications compared to standard radiotherapy in women with cervical cancer? IMRT could be used as primary treatment for cervical cancer, based on the similar treatment outcome in terms of recurrence and survival with fewer complication rate. ## Level of evidence: c (low) Strength of recommendation: 2 (weak) ## 5-7. [ ## 6-2. medical literature search and study identification PubMed, EMBASE, and Cochrane were used for the literature search, and the search formula is as follows. One randomized trial result and 4 non-randomized studies were finally selected using aforementioned method. [fig_ref] Figure 1: Flow chart of searching strategy for answering KQ1 [/fig_ref]. Flow chart of searching strategy for answering KQ6 ## 6-3. quality assessment The result of the evaluation of the the paper is summarized in the table below. # 6-5. meta-analysis Similar survival outcome has been observed between radical hysterectomy with selective adjuvant treatment and primary concurrent chemoradiotherapy in cervical cancer stage IB2 and IIA2. Althought the result of one randomized trial is not consistent to that of 4 non-randomized study, decrease of survival has not been observed in primary surgical group. ## 7-2. medical literature search and study identification PubMed, EMBASE, and Cochrane were used for the literature search, and the search formula is as follows. ## 7-3. quality assessment Page 32 The result of the evaluation of the the paper is summarized in the table below. The evidence for the key question was supported by the four NRS research results. (Level of evidence: VERY LOW) ## 8-3. quality assessment The result of the evaluation of the the paper is summarized in the table below. ## 9-2. medical literature search and study identification PubMed, EMBASE, and Cochrane were used for the literature search, and the search formula is as follows. ## 9-3. quality assessment The result of the evaluation of the the paper is summarized in the table below. One article was finally selected using aforementioned method. ## 10-3. quality assessment The result of the evaluation of the the paper is summarized in the table below. [fig] Figure 1: Flow chart of searching strategy for answering KQ1 [/fig] [fig] Figure 4: Result of meta-analysis Does laparoscopic or robotic surgery have similar survival outcomes compared to open surgery for radical hysterectomy in cervical cancer stage IB-IIA? Medical literature search and study identification [/fig] [fig] Figure 2: Result Does laparoscopic or robotic surgery have similar survival outcomes compared to open surgery for radical hysterectomy in cervical cancer stage IB-IIA? [/fig] [table] Table 2: Study design characteristics based on the Ottawa Quality Assessment ScaleThe evidence for the key question was supported by the one NRS research result. [/table] [table] Table 1: OR Cervical[tiab] OR "Signet Ring Cell"[tiab] OR Neuroendocrine[tiab] OR "Cervix Uteri"[Mesh] 237378 4. cancer[tiab] OR malignant[tiab] OR carcinoma[tiab] OR neoplasm[tiab] OR cancers[tiab] OR malignancy[tiab] OR carcinomas[tiab] OR neoplasms[tiab] 1749249 5. Adenocarcinoma[tiab] OR Adenocarcinomas[tiab] Adenosquamous[tiab] OR "Squamous Carcinoma"[tiab] OR "Squamous Carcinomas"[tiab] OR "Epidermoid Carcinoma"[tiab] OR adenocarcinoma'/de OR 'adenoid cystic carcinoma'/exp OR 'adenosquamous carcinoma'/exp OR 'clear cell carcinoma'/exp OR 'large cell carcinoma'/exp OR 'small cell carcinoma'/exp OR 'undifferentiated carcinoma'/exp OR 'endometrioid carcinoma'/exp OR 'signet ring carcinoma'/exp OR 'large cell neuroendocrine carcinoma'/exp 107895 3. cervix:ab,ti OR Cervical:ab,ti 235901 4. 'Signet Ring Cell':ab,ti OR Neuroendocrine:ab,ti OR cancer:ab,ti OR malignant:ab,ti OR carcinoma:ab,ti OR neoplasm:ab,ti OR cancers:ab,ti OR malignancy:ab,ti OR carcinomas:ab,ti OR neoplasms:ab,ti OR Adenocarcinoma:ab,ti OR Adenocarcinomas:ab,ti OR Adenosquamous:ab,ti OR 'Squamous Carcinoma':ab,ti OR [/table] [table] Table 3: Evidence table [/table] [table] Table 4: Estimation of GRADE [/table]	None	None	Clinical practice guidelines for gynecologic cancers have been developed by academic society from several countries. Each guideline reflected their own insurance system and unique medical environment, based on the published evidence. The Korean Society of Gynecologic Oncology (KSGO) published the first edition of practice guidelines for gynecologic cancer treatment in late 2006; the second edition was released in July 2010 as an evidence-based recommendation. The Guidelines Revision Committee was established in 2015 and decided to develop the third edition of the guidelines in an advanced format based on evidence-based medicine, embracing up-to-date clinical trials and qualified Korean data. These guidelines cover strategies for diagnosis and treatment of primary and recurrent cervical cancer. The committee members and many gynecologic oncologists derived key questions through discussions, and a number of relevant scientific literature were reviewed in advance. Recommendations for each specific question were developed by the consensus conference, and they are summarized here, along with the details. The objective of these practice guidelines is to establish standard policies on issues in clinical practice related to the management in cervical cancer based on the results in published papers to date and the consensus of experts as a KSGO Consensus Statement.
742b8a5c762647c183d4bb471017a4295277752f	pubmed	ESCMID rapid guidelines for assessment and management of long COVID	ESCMID rapid guidelines for assessment and management of long COVID a b s t r a c tScope: The aim of these guidelines is to provide evidence-based recommendations for the assessment and management of individuals with persistent symptoms after acute COVID-19 infection and to provide a definition for this entity, termed 'long COVID'. Methods: We performed a search of the literature on studies addressing epidemiology, symptoms, assessment, and treatment of long COVID. The recommendations were grouped by these headings and by organ systems for assessment and treatment. An expert opinion definition of long COVID is provided. Symptoms were reviewed by a search of the available literature. For assessment recommendations, we aimed to perform a diagnostic meta-analysis, but no studies provided relevant results. For treatment recommendations we performed a systematic review of the literature in accordance with the PRISMA statement. We aimed to evaluate patient-related outcomes, including quality of life, return to baseline physical activity, and return to work. Quality assessment of studies included in the systematic review is provided according to study design. Recommendations: Evidence was insufficient to provide any recommendation other than conditional guidance. The panel recommends considering routine blood tests, chest imaging, and pulmonary functions tests for patients with persistent respiratory symptoms at 3 months. Other tests should be performed mainly to exclude other conditions according to symptoms. For management, no evidence-based recommendations could be provided. Physical and respiratory rehabilitation should be considered. On the basis of limited evidence, the panel suggests designing high-quality prospective clinical studies/trials, including a control group, to further evaluate the assessment and management of individuals with persistent symptoms of COVID-19. Dana Yelin, Clin Microbiol Infect 2022;28:955 Scope Long COVID is an umbrella term referring to signs and symptoms that persist after acute SARS-CoV-2 infection. The prevalence of long COVID is highly heterogeneous among studies, probably reflecting the variability of definitions of this entity, the populations surveyed, and follow-up durations. According to the literature, 22% to 40% of convalescent patients are expected to experience one or more symptoms of long COVID [bib_ref] Post-COVID-19 symptoms 6 months after acute infection among hospitalized and non-hospitalized patients, Peghin [/bib_ref]. The most common symptoms include fatigue, dyspnoea, cognitive impairment, and various pain symptoms (e.g. chest pain, headache, myalgia). Despite the mounting evidence, there are still significant gaps in our knowledge regarding pathogenesis, actual incidence, The search hierarchy was to first identify systematic reviews and meta-analyses, followed by randomized controlled trials and observational comparative studies. Prospective cohort, retrospective cohort, and case-control studies, as well as case series were included. Case reports and case series including less than 20 participants were excluded, unless they provided an innovative finding. If a methodologically appropriate meta-analysis was identified to answer a specific question, we planned to end the search for additional studies. Key questions were formulated in a PICO format (population/ participant, intervention, comparator/control, outcome) when appropriate. Population/participant was defined as any adult patient (!18 years) after the acute phase of COVID-19 (see definitions given in the following). Intervention was defined as any intervention for the assessment and management (pharmacological or other) of participants, and comparison/control as patients receiving a comparator intervention (studies comparing two interventions) or no intervention. Outcomes for management was defined as any outcome addressing improvement in physical, cognitive, or mental function, including quality-of-life measures. We did not attempt to contact the study authors for primary data. Two independent panel members performed the search and screened for relevant studies. Any discrepancies were resolved through discussion with a third panel member. The process followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement [bib_ref] Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement, Moher [/bib_ref]. # Search results The PubMed search yielded 13 881 titles (13 066 after exclusion of 815 duplicates). After inspection of titles and abstracts, 12 390 articles were excluded due to irrelevant study design, irrelevant population, or irrelevant topic. Subsequently, 676 articles were further inspected in full text, and 529 were excluded for similar reasons. Overall, we present data on 147 studies. Due to the paucity of comparative and/or randomized data, no recommendation could be based on evidence, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was not used. ## Quality of evidence scoring Quality assessment of included studies was performed by two panel members independently, and discrepancies were resolved through discussion with a third member. For systematic reviews and meta-analysis, we used the AMSTAR tool for quality assessment [bib_ref] AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised..., Shea [/bib_ref]. Studies were graded as having high, moderate, low, and critically low quality of evidence according to the AMSTAR critical appraisal tool [bib_ref] AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised..., Shea [/bib_ref]. For randomized controlled trials (RCTs), risk of bias was assessed using the domains recommended by the Cochrane handbook. Studies were graded as having low, high, or unknown risk of bias per the Cochrane handbook criteria [bib_ref] Updated guidance for trusted systematic reviews: a new edition of the Cochrane..., Cumpston [/bib_ref]. For nonrandomized studies, the Newcastle Ottawa tool was used. We planned to classify evidence certainty per question as high, moderate, low, or very low and recommendation strength as strong or conditional according to the GRADE system [bib_ref] The GRADE system for rating clinical guidelines, Kavanagh [/bib_ref]. The panel also provided recommendations for research. ## Definitions of long covid The WHO defines post-COVID-19 condition as persistent symptoms and/or signs, developing during or after an acute COVID-19 illness and lasting for at least 2 months and persisting beyond 12 weeks from the acute disease, that cannot be explained by an alternative diagnosis [bib_ref] WHO clinical case definition working group on post-COVID-19 condition. A clinical case..., Soriano [/bib_ref]. The CDC provides a similar definition, with a different timeframe of beyond 4 weeks after the acute disease. The Royal Society defines the same condition; however, no time frame is provided [bib_ref] WHO clinical case definition working group on post-COVID-19 condition. A clinical case..., Soriano [/bib_ref]. A similar term called post-acute sequelae of SARS-CoV-2 infection has been termed by the National Institutes of Health. A repository of published/available definitions of posteCOVID-19 condition is maintained by the WHO [bib_ref] WHO clinical case definition working group on post-COVID-19 condition. A clinical case..., Soriano [/bib_ref]. Although no consensus regarding a single term for long COVID/ posteCOVID-19 condition has been obtained by a WHO Delphi process [bib_ref] WHO clinical case definition working group on post-COVID-19 condition. A clinical case..., Soriano [/bib_ref] , we used the term long COVID in the current guidelines. [fig_ref] Table 1: Summary of definitions for long COVID/post-acute COVID according to level of certainty... [/fig_ref] provides the definitions used for long COVID for the purposes of this document. Long COVID is defined herein as one or more symptoms and/or signs (detailed in the following) persisting or relapsing/remitting for more than 12 weeks since an acute COVID-19 diagnosis, without an alternative explanation. This condition can affect all individuals who encountered COVID-19, regardless of the severity of the acute disease. The syndrome can be definite, probable, or possible, according to the level of certainty of the original acute COVID-19 infection [fig_ref] Table 1: Summary of definitions for long COVID/post-acute COVID according to level of certainty... [/fig_ref]. We define post-acute COVID as one or more symptoms and/or signs persisting or relapsing/remitting from 4 to 12 weeks since a confirmed acute COVID-19 diagnosis, without an alternative diagnosis. This definition also includes several specific entities (thyroiditis, myocarditis, venous thromboembolism) that may appear during this period. ## Symptoms and risk factors of long covid Across systematic reviews/meta-analyses, the most commonly observed symptoms among patients with long COVID are fatigue (31%e58%), dyspnoea (24%e40%), musculoskeletal pain (9%e19%), anosmia/dysgeusia (10%e22%), cognitive impairment (or brain fog; 12%e35%), sleep disturbances (11%e44%), cough (7%e29%), and chest pain (6%e17%) . provides a summary of reported symptoms and their respective prevalence ranges. [fig_ref] Table 4: Prevalence of long COVID symptoms in studies investigating patients regardless of disease... [/fig_ref] provide symptom prevalence according to time intervals from the acute illness (1e3 months, 3e6 months, >6 months) and hospitalization status, respectively. Persisting symptoms seem to considerably affect patients' quality of life and return to daily activities and work. A systematic review of 39 studies found that decreased quality of life was reported among 57% of patients with symptoms persisting beyond 12 weeks [bib_ref] A systematic review of persistent symptoms and residual abnormal functioning following acute..., Jennings [/bib_ref]. Follow-up studies report persistence of long-COVID symptoms up to 12 months after the acute disease [bib_ref] Sequelae in adults at 12 months after mild-to-moderate coronavirus disease 2019 (COVID-19), Boscolo-Rizzo [/bib_ref] [bib_ref] 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study, Huang [/bib_ref]. The pathophysiologic mechanisms that underlie this disorder remain largely unknown, but available data implicate the multisystemic nature of COVID-19, immune dysregulation, autoimmunity, and the neurotropism of SARS-CoV-2 [bib_ref] Long COVID has exposed medicine's blind-spot, Burke [/bib_ref] [bib_ref] Confronting COVID-19-associated cough and the post-COVID syndrome: role of viral neurotropism, neuroinflammation,..., Song [/bib_ref] [bib_ref] Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments, Yong [/bib_ref]. Posteintensive care syndrome may provide an explanation for prolonged symptoms after critical COVID-19. This syndrome encompasses new or worsening abnormalities in physical, cognitive, and psychiatric domains after critical illness [bib_ref] Post-acute COVID-19 syndrome, Nalbandian [/bib_ref]. For patients who have long-COVID symptoms after critical care, it is difficult to distinguish whether persisting symptoms are caused by SARS-CoV-2 infection or posteintensive care syndrome. Data on potential factors associated with an increased risk of developing specific long-COVID symptoms are accumulating in the literature, although the evidence is inconsistent. The two consistent risk factors for any long-COVID symptom are acute COVID-19 severity and sex [fig_ref] Table 1: Summary of definitions for long COVID/post-acute COVID according to level of certainty... [/fig_ref] [32e34]. Women have been shown to have an estimated two-fold risk of having long-COVID symptoms (OR: 1.3e5). Similarly, severe acute disease has been associated with an increased risk for long-COVID symptoms, with the strongest association with fatigue. Other risk factors, such as age, obesity, and the presence of comorbidities, have shown mixed results [fig_ref] Table 1: Summary of definitions for long COVID/post-acute COVID according to level of certainty... [/fig_ref]. ## Recommendations We aimed to answer the following PICO questions: (a) Who should be assessed; (b) what assessment is needed for individuals with long COVID (subdivided according to systems and further subdivided by specific tests); and (c) how should individuals with long COVID be managed (also subdivided according to systems). Each section reports the main summary of evidence for each topic. Tables 5e8 provide details of the studies included. ## Who should be assessed for long covid? In symptomatic patients, other serious/life-threatening conditions should be ruled out prior to considering long COVID. These include prior overlooked conditions (e.g. malignancy) or complications of acute COVID-19 (e.g. thromboembolic events, myopericarditis, encephalitis). The investigation for other conditions should be guided by symptoms, signs, and other tests, performed according to the physician's discretion. Long COVID is a diagnosis of exclusion. ## Recommendation As a first step, collecting specific clinical history is recommended to rule out previous underlying conditions, as well as iatrogenic causes or complications related to the acute episode. Hence, any patient with persisting or new symptoms that last more than 12 weeks after acute COVID-19 should be referred to medical care. For patients with symptoms 4 to 12 weeks after acute infection, assessment should be considered on a case-by-case basis, according to the severity and course of symptoms. ## General blood tests Few studies have assessed the use of routine blood tests in patients with long COVID. Huang et al., at a follow-up of 12 months after patients with COVID-19 were hospitalized, demonstrated low rates of laboratory abnormalities and no significant difference in rates of lymphocyte count <0.8 Â 10⁹ per L or serum creatinine abnormality between recovering participants and controls. Nevertheless, as suggested, blood tests according to symptoms should be performed as part of an investigation to rule out other conditions. Some blood tests may be considered to identify possible complications after acute infection. These, however, should be interpreted with caution due to possible persistent abnormalities after COVID-19. In one study evaluating 734 patients with severe disease 28 days after recovery, an increase in insulin dependency from 18% to 63% was noted, and 1.4% of new-onset diabetes cases were identified [bib_ref] Clinical characteristics and short term outcomes after recovery from COVID-19 in patients..., Akter [/bib_ref]. Two additional studies found an increase in new-onset diabetes in the months after recovery from COVID-19 [bib_ref] Consortium for Characterization of COVID-19 by EHR (4CE), Patel CJ et al...., Estiri [/bib_ref] [bib_ref] Clinical characteristics and the long-term post-recovery manifestations of the COVID-19 patientseA prospective..., Chowdhury [/bib_ref] This might be a result of surveillance bias in previously unknown diabetics or a real shift from prediabetes to diabetes caused by the acute disease or its treatment, although there is no evidence for the latter. Elevated D-dimer can be observed at a median of >2 months after resolution of acute COVID-19, despite normalization of inflammatory markers and other coagulation parameters [bib_ref] Prolonged elevation of D-dimer levels in convalescent COVID-19 patients is independent of..., Townsend [/bib_ref]. Similarly, detectable levels of high-sensitivity troponin T (>3 pg/ mL) were reported in 71 of 100 patients evaluated at a median of 71 days (interquartile range (IQR), 64e92 days) after diagnosis of COVID-19, with 5 of 100 patients having significantly elevated high-sensitivity troponin T levels (>13.9 pg/mL) [bib_ref] Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus..., Puntmann [/bib_ref]. Increased NT-pro-BNP levels at a median follow-up of 71 days (IQR, 14e124 days) were reported from a systematic review in 10% of individuals tested (57 of 571) [bib_ref] Durante-mangoni E, monaldi hospital cardiovascular infection study group. Cardiac sequelae after coronavirus..., Ramadan [/bib_ref]. A systematic review accumulated data on 27 patients presenting with subacute thyroiditis after COVID-19 infection. Patients presented with typical features, including elevated fT4 and fT3, low thyroid stimulating hormone, and raised inflammatory markers (C-reactive protein and erythrocyte sedimentation rate) [bib_ref] COVID-19-associated subacute thyroiditis: evidence-based data from a systematic review, Trimboli [/bib_ref]. ## Recommendation As recommended by other guidelines [5e7], the following may be considered for symptomatic patients according to symptoms: C-reactive protein, blood count, kidney function, and liver function tests. Consider troponin, CPK-MB, and B-type natriuretic peptide for cardiac symptoms and complete thyroid function tests to rule out thyroiditis, if clinically suspected. For patients with decreased oxygen saturation, blood gases are recommended by some guidelines, although the benefit of this test is limited. Ddimer should not be used in patients without respiratory symptoms. Patients at increased risk for diabetes or impaired fasting glucose should be monitored for fasting glucose and glycated haemoglobin levels. ## What assessment is needed for individuals with long covid? After ruling out other conditions, the following evaluations are suggested for individuals with suspected long COVID. First, the evaluation should include an interview with the patient to identify symptom severity and their impact on quality of life. Physicians should consider whether further assessment is needed for symptoms that are self-limited and without an effective and safe therapy. Options for therapy that can be considered in the context of clinical trials are discussed later in this article. ## Investigating individuals with dyspnoea In previous guidelines/recommendations [5e7], a diagnostic pathway is suggested for patients with dyspnoea persisting more than 4 to 12 weeks after acute COVID-19. Several studies used the modified Medical Research Council dyspnoea scale to assess severity of dyspnoea but did not provide a cut-off, thus necessitating further investigation [bib_ref] Postdischarge critical COVID-19 lung function related to severity of radiologic lung involvement..., Truffaut [/bib_ref] [bib_ref] A follow-up study of lung function and chest computed tomography at 6..., Wu [/bib_ref]. ## Pulmonary function testing Various rates of abnormal pulmonary function testing (PFT) have been reported in recovering patients, depending on definitions of abnormality, duration of follow-up, baseline (pre-COVID) pulmonary function, and mainly acute COVID-19 severity and the need for ventilatory support [bib_ref] Diffusion capacity abnormalities for carbon monoxide in patients with COVID-19 at 3-month..., Qin [/bib_ref]. The most frequently impaired Prevalence of most common long-COVID/post-COVID-19 condition symptoms according to systematic reviews/meta-analyses pulmonary function test is diffusion capacity for carbon monoxide (DLCO), and the most frequent pattern observed is restrictive. DLCO impairment (<80% of predicted) has been found in varying proportions of patients, in correlation to disease severity. After critical disease and intensive care unit (ICU) admission, patients had up to 80% abnormal DLCO at discharge and 50% to 70% impairment at 3month follow-up. After severe disease, patients had 30% to 68% impairment at 3 months [bib_ref] Diffusion capacity abnormalities for carbon monoxide in patients with COVID-19 at 3-month..., Qin [/bib_ref] [bib_ref] Radiological and functional lung sequelae of COVID-19: a systematic review and meta-analysis, So [/bib_ref]. At 3 months, higher computed tomography (CT) severity score and acute respiratory distress syndrome at acute disease were associated with impaired DLCO in one study including hospitalized patients [bib_ref] Diffusion capacity abnormalities for carbon monoxide in patients with COVID-19 at 3-month..., Qin [/bib_ref]. Surprisingly, even among patients after mild-to-moderate disease, abnormal DLCO was demonstrated in approximately 10% [bib_ref] Radiological and functional lung sequelae of COVID-19: a systematic review and meta-analysis, So [/bib_ref]. Future progression to pulmonary fibrosis has been raised as a concern [bib_ref] Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy, George [/bib_ref] When tested at 6 months, patients exhibited somewhat lower rates of abnormalities than at 3 months, although the rates were still high (DLCO reduced in 29% for severe, 58% for critical) [bib_ref] 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study, Huang [/bib_ref]. This correlates with the finding that, on serial testing of patients with a restrictive pattern, tested individuals demonstrated an overall improvement at 6 months compared with 10 weeks, but not complete resolution [bib_ref] Clinical status and lung function 10 weeks after severe SARS-CoV-2 infection, Smet [/bib_ref] [bib_ref] Evolution of lung function and chest CT 6 months after COVID-19 pneumonia:..., Stylemans [/bib_ref]. At a longer follow-up of 1 year, Huang et al. reported DLCO <80% in 23% to 54% of 243 patients with severecritical acute COVID-19. Total lung capacity less than 80% of predicted decreased among critically ill patients from 39% at 6 months, but was still considerable at 29% at 12 months [bib_ref] 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study, Huang [/bib_ref]. There is a paucity of data for patients with mild-to-moderate disease. Several studies included some patients after mild-tomoderate disease, mostly as a control group for the patients with severe disease [bib_ref] 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study, Huang [/bib_ref] [bib_ref] Pulmonary function and radiological features 4 months after COVID-19: first results from..., Guler [/bib_ref] [bib_ref] Comprehensive health assessment three months after recovery from acute COVID-19, Van Den Borst [/bib_ref]. These studies reported normal median PFTs and DLCO, but a considerable percentage of patients (10%e 22%) still had abnormal results. ## Recommendation Evidence is insufficient to provide a recommendation for or against PFT. Considering that the test is simple and noninvasive and that future studies may suggest beneficial treatment for patients with abnormal PFT, the panel recommends considering routine PFT, including diffusion capacity, in all patients with severe and critical COVID-19 at 3 months from diagnosis, regardless of symptoms, as well as considering completing PFT with diffusion for patients Prevalence of symptoms by time from acute diseases Symptom 4e12 wk (%), range [bib_ref] A systematic review of persistent symptoms and residual abnormal functioning following acute..., Jennings [/bib_ref] 3 e6 mo (meta-analysis), % (95% CI) [bib_ref] Characterising long COVID: a living systematic review, Michelen [/bib_ref] 6e12 mo (%), range reporting persistent dyspnoea 3 months after acute disease and those with known prior lung disease. Chest imaging Chest X-ray. Two observational studies investigating follow-up chest x-ray in patients with COVID-19 at 6 to 8 weeks concluded that it is a poor marker for recovery, demonstrating correlation to severity of initial disease but not to ongoing symptoms [bib_ref] Symptomatic, biochemical and radiographic recovery in patients with COVID-19, Mallia [/bib_ref] [bib_ref] Chest radiography is a poor predictor of respiratory symptoms and functional impairment..., D'cruz [/bib_ref]. Three additional small observational studies reported conflicting findings. One study found reticular opacities/peripheral atelectasis in 88% and ground-glass opacities in 61% of x-rays performed at 8 to 12 weeks, and the other two studies found only 12% and 7% abnormalities, respectively (Tables 5e7) [bib_ref] Comprehensive health assessment three months after recovery from acute COVID-19, Van Den Borst [/bib_ref] [bib_ref] Radiological management and follow-up of post-COVID-19 patients, Alarc On-Rodríguez [/bib_ref] [bib_ref] Patient outcomes after hospitalisation with COVID-19 and implications for follow-up: results from..., Arnold [/bib_ref]. Long-term followup data are lacking. Among survivors of SARS and Middle East respiratory syndrome severe illness, chest x-ray was found to have residual abnormalities in approximately a third of patients at 3 and even 6 months [bib_ref] Followup chest radiographic findings in patients with MERS-CoV after recovery, Das [/bib_ref] [bib_ref] Impact of severe acute respiratory syndrome (SARS) on pulmonary function, functional capacity..., Hui [/bib_ref]. No studies had correlated abnormal chest xray with clinical outcomes. Recommendation. Evidence is insufficient to provide a recommendation for or against chest x-ray. Chest x-ray may be considered in patients with long COVID and persistent respiratory symptoms at 3 months to rule out other diagnoses and for a possible early diagnosis of pulmonary fibrosis. Chest computed tomography/magnetic resonance imaging. Chest CT in patients after severe and critical disease frequently shows abnormalities, mainly ground glass opacities (GGOs), consolidations, and fibrotic changes. These changes are reported in approximately 60% to 75% of patients at 3 months . A systematic review summarizing chest CT findings at 3 to 6 months after COVID-19 of any severity, rates of polled CT abnormalities were 59% (IQR, 44%e73%), with GGO being the most prevalent pattern (39%; IQR, 26%e52%), followed by fibrosis and reticulation (each approximately 30%) [bib_ref] Long-term impact of COVID-19: a systematic review of the literature and meta-analysis, Sanchez-Ramirez [/bib_ref]. According to two studies including around 500 patients, approximately 60% still had parenchymal findings at 6 months [bib_ref] Impact of coronavirus disease 2019 on pulmonary function in early convalescence phase, Huang [/bib_ref] [bib_ref] Six-month follow-up chest CT findings after severe COVID-19 pneumonia, Han [/bib_ref]. In one of these studies, fibrotic-like changes were reported in 35% of patients (40 of 114) [bib_ref] Six-month follow-up chest CT findings after severe COVID-19 pneumonia, Han [/bib_ref]. These findings correlated with older age and severity of acute disease and were reported regardless of ongoing symptoms. It is still unknown whether these findings predict future lung impairment. Later chest CT follow-up results were reported by Huang et al. for hospitalized patients 12 months after acute COVID. This study reported abnormal CT findings at 1 year for 55% of patients , with GGOs in 46%, mainly derived from critically ill patients, who had abnormalities in 87% of examinations [bib_ref] 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study, Huang [/bib_ref]. Chest magnetic resonance imaging (MRI) was performed on 53 recovering patients at 2 to 3 months, showing parenchymal abnormalities in 60% (n ¼ 32), without clear clinical correlation [bib_ref] Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition,..., Raman [/bib_ref]. Limited data are available to report the long-term chest CT findings in mild-to-moderate patients, with some data showing similar rates of abnormalities as for severe patients and some showing lower rates. In the Huang et al. cohort, at 6 months, hospitalized patients with mild-to-moderate disease had CT abnormalities in approximately 50% of patients, which was similar to patients with more severe disease; however, at 1 year, rates were significantly lower among patients with mild-to-moderate disease (39%) [bib_ref] 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study, Huang [/bib_ref] [bib_ref] 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study, Huang [/bib_ref] Another study reported similar rates of chest CT abnormalities among 51 patients recovering from moderate COVID-19 compared with those with severe disease. Signs of fibrosis specifically were significantly less common among patients with moderate disease [bib_ref] Comprehensive health assessment three months after recovery from acute COVID-19, Van Den Borst [/bib_ref]. In another study, CT abnormalities at 6 months were significantly less common among patients with moderate (~3%) compared with severe (53%) disease [bib_ref] A follow-up study of lung function and chest computed tomography at 6..., Wu [/bib_ref]. Recommendation. Evidence is insufficient to provide a recommendation for or against chest imaging. Chest CT should be considered at 3 to 6 months in patients with dyspnoea or abnormal PFTs, regardless of symptoms, to rule out other causes and identify fibrotic changes. Investigating patients with dyspnoea, cardiac complaints, and fatigue Cardiac imaging. Reports on severe cardiac complications (pericarditis, myocarditis, heart failure, and cardiac arrhythmias) after COVID-19 have been published, although causality is not always evident. One observational study showed that 27.5% of patients (14 of 51) admitted for evaluation of cardiac symptoms (chest pain, palpitations, effort dyspnoea, oedema) 2 months after acute COVID-19 were diagnosed with severe cardiovascular complications [bib_ref] COVID-19 and cardiovascular complicationsePreliminary results of the LATE-COVID study, Lewek [/bib_ref]. However, this reflects the most severe end of the spectrum, due to selection bias. Another study assessed patients referred to outpatient cardiology evaluation in the first 3 months after mild-tomoderate disease and reported transthoracic echocardiographic (TTE) abnormalities in 25% of patients (38 of 150), mostly reduced ejection fraction (EF), elevated pulmonary artery pressure, diastolic dysfunction, and thickened pericardium [bib_ref] Associations between the severity of the post-acute COVID-19 syndrome and echocardiographic abnormalities..., Tudoran [/bib_ref]. Additional studies demonstrated considerable rates of TTE findings in asymptomatic people 30 to 100 days after COVID-19, including a reduction in the left ventricular global longitudinal strain, diastolic dysfunction, and pulmonary hypertension [bib_ref] Elevated highsensitivity troponin is associated with subclinical cardiac dysfunction in patients recovered..., Hayama [/bib_ref] [bib_ref] Cardiopulmonary recovery after COVID-19: an observational prospective multicentre trial, Sonnweber [/bib_ref]. At a similar follow-up duration, a systematic review reported echocardiographic findings for symptomatic patients with variable severity, including diastolic dysfunction in up to 55% of individuals tested, reduced left ventricular EF in up to 16%, and pulmonary hypertension in up to 10% [bib_ref] Durante-mangoni E, monaldi hospital cardiovascular infection study group. Cardiac sequelae after coronavirus..., Ramadan [/bib_ref]. Cardiac MRI studies have shown common abnormalities ranging from 19% to 71% in recovering patients at 1 to 4 months . These findings usually did not correlate with symptoms and were temporary, as suggested by Joy at el., and demonstrated resolution of findings at 6 months after diagnosis [bib_ref] Prospective case-control study of cardiovascular abnormalities 6 months following mild COVID-19 in..., Joy [/bib_ref]. In data from systematic reviews, including variable severity of an acute COVID-19 population at a follow-up of 14 to 180 days, cardiac MRI abnormalities were reported with wide variability, and in up to 60% of 73% of tested patients. In four studies reporting formal diagnoses using cardiac MRI, myocarditis was reported in 0% to 37%, myopericarditis in 0% to 11%, pericarditis in 0% to 3%, and myocardial infarction in 0% to 2% of patients [bib_ref] Durante-mangoni E, monaldi hospital cardiovascular infection study group. Cardiac sequelae after coronavirus..., Ramadan [/bib_ref] [bib_ref] Cardiac magnetic resonance imaging findings in 2954 COVID-19 adult survivors: a comprehensive..., Hassani [/bib_ref]. Recommendation. Evidence is insufficient to provide recommendations for or against any of the aforementioned cardiac tests. Considering TTE is noninvasive, it may be offered for patients presenting with persistent symptoms suggestive of perimyocardial injury (chest pain, palpitations, signs and symptoms of heart failure). It is reasonable that for patients who had cardiac abnormalities during acute disease (myocarditis, pericarditis, heart failure), a repeat TTE would be performed at 2 to 3 months. Further investigation for cardiac abnormalities should be performed according to symptoms in patients presenting with cardiac symptoms. Cardiac MRI should only be performed on a case-by-case basis with a specific clinical question in mind (e.g. athletes returning to physical activity). Functional testing. There are several functional tests aimed at evaluating physical performance in frail and post-illness patients. The 6-minute-walk test (6MWT) includes measurement of distance walked during 6 minutes and SpO2 before and after. The sit-tostand test measures the number of repeats during a certain time period (15e30 seconds, usually). The Short Physical Performance Battery includes balance assessment in a standing position, walking speed for 4 minutes, and standing up from a chair with five repetitions. Several studies assessed discharged patients with acute or long COVID using these methods and mostly found moderate-to-severe impairment that correlated with acute disease severity . Specifically, for the 6MWT, individuals recovering from COVID-19 exhibited inconsistent results in this test, depending on disease severity. In general, a mild-to-moderate limitation that was evident during the first few months after acute illness abated with time. A small comparative study found pulmonary rehabilitation to be effective in improving the physical capacity of recoverees, as reflected by the 6MWT [bib_ref] Six-month outcomes and effect of pulmonary rehabilitation among patients hospitalized with COVID-19:..., Dun [/bib_ref]. For the 6MWT according to disease severity in individual studies, refer to . Cardiopulmonary stress testing (CPET) can potentially reveal the mechanisms leading to subjective symptoms in individuals with long COVID. This has the potential to guide rehabilitation efforts. Although most studies assessed previously hospitalized individuals and found at least mild impairment months later, data gathered thus far have yielded conflicting results with respect to the pathophysiological mechanism contributing to dyspnoea and effort intolerance (see [fig_ref] Table 5: Studies addressing assessment of long COVIDdPulmonary function tests AMSTAR, A MeaSurement Tool... [/fig_ref]. Further research with appropriate control arms is warranted. Recommendation. Evidence is insufficient to provide recommendations for or against any of the aforementioned functional tests. Consider performing them at the beginning of an interventional/rehabilitation program to assess progress. Investigating patients with neurocognitive complaints Brain imaging. Few small studies have assessed brain imaging in patients with long COVID (Tables 5e7). Guedj et al. [bib_ref] 18F-FDG brain PET hypometabolism in patients with long COVID, Guedj [/bib_ref] conducted positron emission tomography/CT in 35 patients at a mean of 95.5 ± 30 days after acute COVID-19 and compared the findings with age-and sex-matched historical uninfected controls. They found specific areas of hypometabolism that were associated with symptoms of hyposmia/anosmia, memory/cognitive impairment, pain, and insomnia and that were significantly distinguished from the control group [bib_ref] 18F-FDG brain PET hypometabolism in patients with long COVID, Guedj [/bib_ref]. These findings were also demonstrated in smaller studies [bib_ref] 18F-FDG-PET imaging for post-COVID-19 brain and skeletal muscle alterations, Rudroff [/bib_ref]. Raman et al. conducted a prospective study including 58 participants 2 to 3 months after acute moderate-tosevere COVID-19 compared with matched controls. Of the study cohort, 53 underwent brain MRI, with 32 showing abnormalities and higher rates of pathology in the thalamus and sagittal stratum compared with controls. Periventricular white matter hyperintensities in the study group did not correlate with cognitive impairment [bib_ref] Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition,..., Raman [/bib_ref]. Recommendation. Limited evidence does not support the use of brain imaging to investigate long-COVID complaints, other than to rule out other causes or for research purposes. Psychological/psychiatric evaluation. Anxiety, depression, and posttraumatic stress disorder were reported in 16% to 47% of patients hospitalized for COVID-19 within 2 to 3 months of discharge, with no comparison to a control group [bib_ref] Psychological outcomes after hospitalization for COVID-19: data from a multidisciplinary follow-up screening..., Bonazza [/bib_ref] [bib_ref] A living systematic review of the psychological problems in people suffering from..., Dong [/bib_ref]. In a large retrospective cohort of 236 379 patients followed for 6 months after COVID-19, the estimated incidences of mood, anxiety, or psychotic disorders were higher compared with patients after other respiratory infections. Substance use disorders and insomnia were more common as well. Incidences of anxiety and psychotic disorder were 17% and 1.2%, respectively, for the entire cohort, but were higher in hospitalized patients and specifically those admitted to the ICU [bib_ref] 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a..., Taquet [/bib_ref]. Recommendations regarding psychological/psychiatric assessment are beyond the scope of these guidelines. Nevertheless, health care practitioners should be aware of the substantial incidence of psychological sequelae of COVID-19 of any severity, and, whenever relevant, refer patients for assessment and therapy. ## Management of patients with long covid The studies included are summarized in [fig_ref] Table 8: Summary of studies addressing management of long-COVID/postCOVID-19 condition [/fig_ref]. Should post-discharge (extended) thromboprophylaxis be administered to patients with COVID-19? Recommendations from several societies do not support routine use of post-discharge (extended) thromboprophylaxis based on low rates of post discharge venous thromboembolism (VTE) among patients with COVID-19 and studies addressing other hospitalized populations. All recommend individualized risk assessment and decisions. Extended prophylaxis refers to up to 45 days. The types of anticoagulation recommended include low-molecular-weight heparin or direct oral anticoagulants [84e87]. One randomized controlled trial suggested a benefit of rivaroxaban 10 mg daily compared with no anticoagulant after discharge in high-risk individuals [bib_ref] Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE):..., Ramacciotti [/bib_ref]. Other than this study, the recommendations are not based on comparative studies, but on considerations of risk and benefit. ## Recommendation Evidence is insufficient to provide a recommendation for or against the intervention. It is advisable to perform individualized risk stratification of the risk for thrombotic events vs. haemorrhagic events. Consider extended anticoagulation prophylaxis for patients with a low risk of bleeding and elevated risk for VTE (active malignancy, immobility, history of VTE, recent major surgery, thrombophilia). ## Should physical or pulmonary rehabilitation be offered to patients, and when? A meta-analysis and systematic review of RCTs was conducted to evaluate the effectiveness of pulmonary rehabilitation in interstitial lung disease in general, including COVID-19. This metaanalysis demonstrated improved walking distance in the 6MWT with the intervention (pooled effect size estimate for pulmonary rehabilitation: 44.55; 95% CI, 32.46e56.64), improved quality of life (effect size: 0.52; 95% CI, 0.22e0.82), improved dyspnoea (effect estimate: 0.39; 95% CI, e0.08 to 0.87), and significant improvement in lung function as evaluated by forced vital capacity (effect size: 0.37; 95% CI, 0.02e0.71) [bib_ref] Effectiveness of pulmonary rehabilitation in interstitial lung disease including coronavirus diseases: a..., Reina-Guti Errez [/bib_ref]. One small RCT included in the metaanalysis evaluated elderly patients discharged from the hospital after COVID-19 and demonstrated significant improvement in PFT, 6MWT, quality of life scale, and anxiety score with the intervention [fig_ref] Table 8: Summary of studies addressing management of long-COVID/postCOVID-19 condition [/fig_ref] [bib_ref] Respiratory rehabilitation in elderly patients with COVID-19: a randomized controlled study, Liu [/bib_ref]. A living systematic review evaluated rehabilitation specifically in COVID-19, both acute and post-acute phases, with one of the addressed questions being "what is the evidence for effect of intervention for limitation(s) of functioning?" [bib_ref] Rehabilitation and COVID-19: the Cochrane Rehabilitation 2020 rapid living systematic review, Ceravolo [/bib_ref] [bib_ref] Rehabilitation and COVID-19: a rapid living systematic review by Cochrane Rehabilitation Field..., De Sire [/bib_ref]. Only three comparative studies were available for this question, addressing different patients and comparisons [fig_ref] Table 8: Summary of studies addressing management of long-COVID/postCOVID-19 condition [/fig_ref]. One of these studies is the RCT by Liu et al. described earlier [bib_ref] Respiratory rehabilitation in elderly patients with COVID-19: a randomized controlled study, Liu [/bib_ref] [bib_ref] Effectiveness of pulmonary rehabilitation in COVID-19 respiratory failure patients post-ICU, Chikhanie [/bib_ref] [bib_ref] Outcomes of a COVID-19 recovery program for patients hospitalized with SARS-CoV-2 infection..., Hameed [/bib_ref]. Additional studies presented in this systematic review included noncomparative studies, all reporting significant improvement in symptoms and respiratory and general function in response to the intervention [fig_ref] Table 8: Summary of studies addressing management of long-COVID/postCOVID-19 condition [/fig_ref]. Explicit timing of starting rehabilitation was not provided in the literature. The British Society of Rehabilitation Medicine recommends that rehabilitation start on patient admission and be continued throughout hospitalization and then after discharge. Other guidelines for rehabilitation after critical illness in general recommend initiating rehabilitation programs within the first 30 days (at the post-acute phase). Rehabilitation programs should include (according to the individual patient) exercise, pulmonary, cardiac, musculoskeletal, neurological, and psychological rehabilitation [bib_ref] The Stanford Hall consensus statement for post-COVID-19 rehabilitation, Barker-Davies [/bib_ref]. ## Recommendation Evidence is insufficient to provide a recommendation for or against the intervention specifically for COVID-19. No data regarding persistent long COVID were identified. Until further evidence accumulates, it is reasonable that clinicians follow available consensus statements regarding multidisciplinary rehabilitation in the post-acute stage [bib_ref] The Stanford Hall consensus statement for post-COVID-19 rehabilitation, Barker-Davies [/bib_ref]. How should persistent pulmonary symptoms/signs be managed? In one small, noncomparative, prospective study, 30 patients diagnosed with interstitial lung disease consistent with organizing pneumonia 6 weeks after discharge (persistent symptoms, functional or physiological abnormalities, and parenchymal abnormality on CT) were treated with corticosteroids (maximum initial dose of 0.5mg/kg prednisolone) for 3 weeks. All patients demonstrated significant symptomatic improvement, significant increase in gas transfer and forced vital capacity, and radiologic improvement [bib_ref] Persistent post-COVID-19 interstitial lung disease. An observational study of corticosteroid treatment, Myall [/bib_ref]. In another small study, the authors retrospectively reviewed the routine management of patients with abnormal CT findings over 4 weeks after COVID-19 and desaturation, treated with corticosteroids. At a follow-up at 12 to 14 weeks, 24 patients demonstrated improved fatigue, breathlessness, and cough, as well as improved modified Medical Research Council score, saturation at rest, 6MWT results, and imaging findings. However, others reported significant spontaneous recovery within 12 weeks for similar patients, raising the question of whether steroids are beneficial. Continuing steroids for patients with persistent hypoxemia and abnormal CT at discharge and/or follow-up has been suggested based on clinical experience but not tested in comparative clinical studies [bib_ref] Care of the postcoronavirus disease 2019 patient, Lafond [/bib_ref] [bib_ref] Post-COVID lung fibrosis: the tsunami that will follow the earthquake, Udwadia [/bib_ref]. Few cases of treatment of long-COVID lung fibrosis with antifibrotic agents have been reported [bib_ref] Usefulness of pirfenidone in COVID lung: a case series, Momen [/bib_ref]. This therapeutic option is currently being tested in clinical trials. Trials are ongoing to evaluate the use of the antifibrotic nintedanib and pirfenidone, as well as other drugs [104e106]. ## Recommendation Evidence is insufficient to provide a recommendation for or against any intervention. How should persistent cough be managed? There are no clinical studies evaluating the management of persistent cough after acute COVID-19. In a review discussing the possible pathophysiology and management of cough in patients with COVID-19, further investigation into the role of gabapentin and pregabalin, antimuscarinic drugs, and other novel drugs that interfere with the neuroinflammatory pathways has been suggested [bib_ref] Confronting COVID-19-associated cough and the post-COVID syndrome: role of viral neurotropism, neuroinflammation,..., Song [/bib_ref]. ## Recommendation Evidence is insufficient to provide a recommendation for or against any intervention. How should smell and taste disturbances be managed? A Cochrane systematic review aimed to assess interventions to treat persistent COVID-19erelated olfactory dysfunction. The search for RCTs for inclusion resulted in only one small trial comparing prednisone plus nasal irrigation (intranasal steroids with mucolytic and decongestant agents) for 15 days versus no treatment. The study included nine patients in each arm but was graded as high risk of bias, and the results were reported only up until 40 days, limiting the ability to draw conclusions [bib_ref] Interventions for the treatment of persistent post-COVID-19 olfactory dysfunction, O'byrne [/bib_ref]. Addison et al. conducted a systematic review evaluating the management of any postinfectious olfactory dysfunction. In total, 15 studies addressing this entity directly were included, but none specifically evaluated patients with COVID-19. The interventions tested included olfactory training and various topical and systemic treatments. All 11 studies evaluating olfactory training (not all comparative) showed a benefit of the intervention [bib_ref] Clinical Olfactory Working Group consensus statement on the treatment of postinfectious olfactory..., Addison [/bib_ref]. The manuscript included a consensus statement by the clinical olfactory working group, which recommended routine use of olfactory training, but was controversial regarding pharmacologic therapy with a recommendation to consider steroids (nasal or systemic), theophylline, and sodium citrate. A role of smoking and olfactory dysfunction in general has been discussed. The consensus document states that the benefit of smoking cessation in patients with long-COVID anosmia/ageusia is not clear, but an overall benefit justifies the recommendation. Other therapies described that need further study include oral and intranasal corticosteroids, theophylline, sodium citrate, N-methyl D-aspartate antagonist (caroverine), traditional Chinese acupuncture, a-lipoic acid, vitamin A, minocycline, and zinc sulphate [bib_ref] Clinical Olfactory Working Group consensus statement on the treatment of postinfectious olfactory..., Addison [/bib_ref]. One low-quality RCT including 100 patients recovering from COVID-19 evaluated topical corticosteroid nasal spray (mometasone furoate) for 3 weeks combined with olfactory training versus olfactory training alone. In this study, no difference between groups was demonstrated in rates or patients with olfactory recovery or duration of anosmia/hyposmia [bib_ref] Corticosteroid nasal spray for recovery of smell sensation in COVID-19 patients: a..., Abdelalim [/bib_ref]. An additional small, lowquality RCT evaluated insulin fast-dissolving film for intranasal delivery versus placebo in 40 post-COVID patients with olfactory loss. In this study, significantly higher olfactory detection scores were demonstrated with intervention (p ¼ 0.0163) [bib_ref] Insulin fast-dissolving film for intranasal delivery via olfactory region, a promising approach..., Mohamad [/bib_ref]. ## Recommendation Evidence is insufficient to provide a recommendation for or against any intervention. Due to its simplicity and safety, olfactory training should probably be suggested for all patients. Physicians should discuss the likelihood for spontaneous recovery with patients, and other interventions should be suggested only in clinical trials. Smoking cessation should be recommended. ## How should fatigue be managed? Clinical overlap has been suggested between long COVID and postviral fatigue syndromes/postinfectious myalgia encephalomyelitis/chronic fatigue syndrome. For the latter, various interventions have been suggested [bib_ref] NICE guideline on long COVID, Sivan [/bib_ref] [bib_ref] Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)eA systemic review and comparison..., Wong [/bib_ref]. Systematic reviews of such interventions included various medications, complementary and alternative medicine, cognitive behavioural therapy, and exercise. The included studies were heterogeneous and data were limited, although the drug rintatolimod, counselling therapies, and graded exercise therapy suggested a benefit [bib_ref] Treatment of myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review for a National..., Smith [/bib_ref] [bib_ref] A mixedmethods systematic review of post-viral fatigue interventions: are there lessons for..., Fowler-Davis [/bib_ref]. No evidence is available to support interventions for the management of fatigue in patients with long COVID. Graded exercise and cognitive behavioural therapy are controversial for the management of myalgia encephalomyelitis/chronic fatigue syndrome and should be further investigated for patients with long COVID prior to any recommendation [bib_ref] A mixedmethods systematic review of post-viral fatigue interventions: are there lessons for..., Fowler-Davis [/bib_ref]. ## Recommendation Evidence is insufficient to provide a recommendation for or against any intervention. How should neurological/cognitive long-COVID sequelae be managed? There are no clinical studies evaluating any pharmacological treatment for neurological sequelae of long COVID. The flavonoid luteolin has been suggested as a potential treatment, by inhibiting a proinflammatory cascade of mast cells and microglia activation in the hypothalamus. However, no studies have evaluated this intervention [bib_ref] Long-COVID syndromeassociated brain fog and chemofog: luteolin to the rescue, Theoharides [/bib_ref]. The cannabis derivatives cannabidiol and cannabivarin have been suggested to have the potential to bind to and downregulate central nervous system proteins related to long-COVID symptoms. These compounds have not been tested in clinical studies [bib_ref] Insilico inquest reveals the efficacy of cannabis in the treatment of post-COVID-19..., Sarkar [/bib_ref]. Methylene blue has been suggested as a possible therapy for neurocognitive impairment in long COVID due to its mitochondrial protective effects [bib_ref] Methylene blue: subduing the post-COVID-19 blues, Magoon [/bib_ref]. The therapeutic potential is theoretical, however, and without clinical evidence. ## Recommendation Evidence is insufficient to provide a recommendation for or against any intervention. How should emotional/psychiatric long COVID sequelae be managed? Clomipramine, a tricyclic antidepressant with antiinflammatory action and penetrance to the central nervous system, has been suggested as a potential drug to prevent postinfectious mental complications. Further studies are needed [bib_ref] The antiinflammatory effect of the tricyclic antidepressant clomipramine and its high penetration..., Nobile [/bib_ref]. ## Recommendation Evidence is insufficient to provide a recommendation for or against any intervention. Recommendations for future studies on long COVID As reflected in these guidelines, studies on long COVID are limited by the lack of a consistent definition of long COVID in terms of symptoms and timeframes, the absence of typical laboratory findings/diagnostic tests, and the absence of a comparison group in most studies. Selection bias might be pronounced due to the considerable portion of online recruitment studies [bib_ref] Causation or confounding: why controls are critical for characterizing long COVID, Amin-Chowdhury [/bib_ref]. In addition, the study design is usually retrospective, including symptomatic patients (rather than all recovering patients), thus limiting the ability to measure the scope of the problem and evaluate risk factors. Additional studies are needed, including studies following consecutive patients recovering from COVID-19, with various severities of the acute disease. Such studies should be designed to evaluate the incidence of long COVID and to identify risk factors for its development. The first priority should be to evaluate healthy, community-treated persons and to evaluate the scope of the problem in this population and the need for follow up. Considering the toll of a stressful pandemic, quarantine, and unemployment, Amin-Chowdhury et al. suggested prospective longitudinal cohort studies using a noninfected control group [bib_ref] Causation or confounding: why controls are critical for characterizing long COVID, Amin-Chowdhury [/bib_ref]. Clustering of symptoms may assist in evaluating the scope of illness compared with noninfected people, as well as risk factors. Amin-Chowdhury et al. described the following clusters in a large prospective cohort: sensory (ageusia, anosmia, loss of appetite, and blurred vision), neurological (forgetfulness, short-term memory loss, and confusion/brain fog), and cardiorespiratory (chest tightness/pain, unusual fatigue, breathlessness after minimal exertion/ at rest, and palpitations). Patients after ICU hospitalization should be addressed separately in studies, including studies assessing rehabilitation starting in the hospital and different interventions to prevent and treat lung injury. Patients with less severe disease should be investigated for interventions to resolve their leading symptom/cluster of symptoms (as described). Outcomes addressed should include return to work and return to previous activity level, including sports. Further research is also needed to elucidate the pathophysiology of various long-COVID symptoms. Additional studies should assess long-COVID prevalence and symptoms after different SARS-CoV-2 variants and vaccination. Long-term follow-up studies of symptomatic patients are needed to evaluate the assessment and management of interventions, using predefined patient-related outcomes, including quality of life, time to return to work and baseline physical activity, and cognitive and functional assessments. These studies should be in the form of RCTs. # Author contributions These guidelines were developed by a group of infectious diseases specialists who care for patients recovering from acute COVID-19. All members formulated the questions and aims of these guidelines. DYa, DYe, and IM performed the literature search, and all members were involved in the data extraction and writing of the manuscript. All panel members reviewed the last version of the manuscript. The guidelines were written under the guidance and support of LS (ESCMID Guidelines Director). # Transparency declaration All authors declare no conflicts of interest. No funding sources. ## Updating These are rapid guidelines aimed to capture current evidence on the topic. However, due to the rapid evolvement of the literature, the authors plan to conduct these as living guidelines to be modified with upcoming new evidence. The panel will meet monthly regarding the need for updates. The panel members will perform an updated search every 3 months and will update the guidelines once substantial evidence for changing any recommendation is observed. [table] Table 1: Summary of definitions for long COVID/post-acute COVID according to level of certainty of COVID-19 diagnosis Acute COVID-19 diagnosis a /time from acute COVID-19 diagnosis For asymptomatic patients: Confirmed acute COVID-19 diagnosis is considered a positive PCR test in a relevant epidemiological setting. [/table] [table] Table 4: Prevalence of long COVID symptoms in studies investigating patients regardless of disease severity and in studies in hospitalized patients [/table] [table] Table 5: Studies addressing assessment of long COVIDdPulmonary function tests AMSTAR, A MeaSurement Tool to Assess systematic Reviews; DLCO, carbon monoxide diffusing capacity; FEV; forced expiratory volume; FVC, forced vital capacity; TLC, total lung capacity. a Pooled prevalence (standard deviation). b Pooled prevalence (95% CI). [/table] [table] Table 6: Studies addressing assessment of long COVIDdChest imaging AMSTAR, A MeaSurement Tool to Assess systematic Reviews; CT, computed tomography; MRI, magnetic resonance imaging. a CT, high-resolution CT, chest radiography, and/or MRI. [/table] [table] Table 7: Studies addressing assessment of long COVIDdOthers Evidence is variable. Different rates of abnormal findings (diastolic dysfunction, systolic dysfunction, elevated pulmonary artery pressure with or without pericardial disease). Rates are higher in patients hospitalized for analysis or referred to cardiology for ongoing cardiac symptoms (25%e27.5% overall abnormal findings). In one study, EF was normal in a cohort of 215 patients, but left ventricular global longitudinal strain was reduced in 29%.Systematic review reporting reduced left ventricular EF in 0%e16%; left ventricular hypertrophy in 0%e0.5%; diastolic dysfunction in 0%e55%; pulmonary hypertension in 0%e10%; and pericardial effusion in 0%e6%. Abnormal MRI myocardial findings are common in the postacute period. A study of athletes showed abnormalities in 5 of 26 asymptomatic patients after mild disease (20%). In severe cases, abnormalities may be found in up to 70% of patients. No correlation was shown with ongoing symptoms.Systematic review reporting increased T1 in 0%e73%; increased T2 in 0% e60%; late gadolinium enhancement (myocardial or pericardial) in 0% e46% and up to 100%. In four studies reporting formal diagnoses, myocarditis was reported in 0%e37%, myopericarditis in 0%e11%, pericarditis in 0%e3%, and myocardial infarction in 0%e2%. SPPB were moderately/severely impaired in comparison with expected ranges for age and sex. Impairment is mostly dependent on disease severity, and patients after severe disease had lower SPO2 after testing. [/table] [table] Table 8: Summary of studies addressing management of long-COVID/postCOVID-19 condition [/table]	None	http://www.clinicalmicrobiologyandinfection.com/article/S1198743X22000921/pdf	None
2e48df17efe0bcbf3aad65a9d5d1f7eec8de862b	pubmed	2021 update of the EULAR points to consider on the use of immunomodulatory therapies in COVID-19	2021 update of the EULAR points to consider on the use of immunomodulatory therapies in COVID-19 # Introduction The use of immunomodulatory therapies in SARS-CoV-2 infection is a rapidly evolving field and it represents a challenge for the scientific community. New evidence informing best practice for clinical management of patients infected with SARS-CoV-2 and presenting COVID-19 are released on a weekly basis, leading to the continuous need for updated policies in the field. In this context, several scientific societies, including EULAR, have formulated guidance on treatment of COVID-19. [bib_ref] EULAR points to consider on pathophysiology and use of immunomodulatory therapies in..., Alunno [/bib_ref] In order to propose the most up-to-date treatment strategies to physicians and patients, efforts to update these recommendations in a timely manner must be undertaken. The aim of this project was to update the EULAR points to Consider (PtC) on the use of immunomodulatory therapies in COVID-19 from the rheumatology perspective through a systematic literature review (SLR)-based approach. ## Key messages What is already known about this subject? ► Results from the previous systematic literature review highlighted that glucocorticoids, mainly dexamethasone, is the only drug with proven efficacy in reducing COVID-19 mortality in patients requiring oxygen therapy and in critically ill patients. ► Other immunomodulatory treatments used in rheumatology may be beneficial in selected subgroups of patients with COVID-19 and in specific phases of the disease. What does this study add? We updated the existing EULAR points to consider (PtC) on immunomodulatory therapies in COVID-19 in light of the most recent literature available. ► Tocilizumab in combination with glucocorticoids is beneficial in COVID-19 cases requiring oxygen therapy and in critical COVID-19. Use of Janus kinase inhibitors (baricitinib and tofacitinib) is promising in the same populations. ► Anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma may find application in early phases of the disease and in selected subgroups of immunosuppressed patients. ► Other immunomodulators failed to consistently demonstrate efficacy on mortality and other clinical outcomes at any disease stage or confirmatory evidence for biomarker-based stratification is currently lacking. ## Miscellaneous # Methods The multidisciplinary task force (TF) that developed the first version of the PtC guided by the 2014 updated EULAR standardised operating procedures. [bib_ref] update of the EULAR standardised operating procedures for EULAR-endorsed recommendations, Van Der Heijde [/bib_ref] reconvened in a virtual meeting on 30 June 2021. Two fellow clinicians (AA and AN), guided by the methodologist (PMM), performed an update of the SLR retrieving individual studies on the management of SARS-CoV-2 infection with immunomodulatory therapies published between 11 December 2020 and 30 June 2021 (subsequently updated up to 14 July 2021) (online supplemental text 1). In addition, a search to retrieve individual studies on the management of SARS-CoV-2 infection with anti-SARS-CoV-2 monoclonal antibodies was performed (online supplemental text 2). The SLR is published separately, however, it forms an integral part of the project. Grey literature, namely randomised controlled trials (RCTs) published as full online non-peer-reviewed preprints or in part as press releases, was also included for the sake of completeness but did not inform the PtC. Statements updated by the steering group were presented to the TF, and discussed against the existing ones, based on the SLR results. The statements were accepted if more than 75% of the TF approved the wording in the first round (informal voting), 67% in the second voting round and more than 50% in the third round. The level of evidence (LoE) supporting each statement was assigned. Finally, TF members anonymously indicated their level of agreement with each PtC online (numerical rating scale ranging from 0='completely disagree' to 10='completely agree'). # Results The updated PtCs are shown in table 1, and the modifications compared with the previous ones are shown in table 2. The PtCs are intended to provide guidance on therapeutic aspects, and the target users are healthcare providers involved in the care of patients infected with SARS-CoV-2 infection, patients and policy-makers. ## Overarching principles The overarching principles remained unchanged compared with the 2020 version. More than a year after the start of the Overarching principles and points to consider on the use of immunomodulatory treatment in COVID-19, with levels of evidence (LoE) and levels of agreement (LoA) ## Loa mean (sd); % of votes ≥8/10 Overarching principles The phenotype of SARS-CoV-2 infection is heterogeneous ranging from asymptomatic to lethal disease due to multiorgan damage. [bib_ref] An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus..., Ader [/bib_ref].92 (0.3); 100 SARS-CoV-2 infection may need different treatment approaches, including antiviral, oxygen therapy, anticoagulation and/or immunomodulatory treatment at different stages of the disease. [bib_ref] An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus..., Ader [/bib_ref].92 (0.3); 100 Points to consider In non-hospitalised patients with SARS-CoV-2 infection there is currently no evidence to support the initiation of immunomodulatory therapy (LoE 2/3/4). 9.58 (1.0); 96 In hospitalised patients with SARS-CoV-2 infection that do not need oxygen therapy there is currently no evidence to support the initiation of immunomodulatory therapy to treat their COVID-19 (LoE 2/3/4). [bib_ref] An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus..., Ader [/bib_ref].04 (1.6); 88 Hydroxychloroquine should be avoided for treating any stage of SARS-CoV-2 infection since it does not provide any additional benefit to the standard of care, and could worsen the prognosis in more severe patients particularly if coprescribed with azithromycin (LoE 2). ## (0.3) 100 In patients with COVID-19 requiring supplemental oxygen, non-invasive or mechanical ventilation, systemic glucocorticoids should be used since they can decrease mortality; most evidence concerns the use of dexamethasone (LoE 2/3). ## (0.4) 100 In patients with COVID-19 requiring supplemental oxygen, non-invasive or mechanical ventilation combination of glucocorticoids and tocilizumab should be considered since it reduces disease progression and mortality (LoE 2). More data are needed to fully appreciate the effect of other IL-6R inhibitors (LoE 2/3). 9.17 (1.7) 87.5 In COVID-19 there is no robust evidence to support the use of anakinra or canakinumab at any disease stage (LoE 2). 9.16 (0.9) 96 In COVID-19 there is no robust evidence to support the use of low-dose colchicine at any disease stage (LoE 2) 9.5 (0.9) 96 In patients with COVID-19 requiring oxygen therapy, non-invasive ventilation or high-flow oxygen, the combination of glucocorticoids and baricitinib or tofacitinib could be considered since it might decrease disease progression and mortality (LoE 2). ## Key messages How might this impact on clinical practice or future developments? ► We propose for healthcare providers the most up-to-date treatment strategies of using immunomodulators in the treatment of moderate-to-severe and critical COVID-19. ► The updated PtCs open the way to a new paradigm: the treatment of severe and critical acute infections may benefit from immunomodulatory treatments usually reserved for autoimmune and inflammatory diseases. pandemic, the heterogeneity of SARS-CoV-2 infection clinical picture, reflecting different pathogenic mechanisms, is widely recognised. [bib_ref] Lessons learned 1 year after SARS-CoV-2 emergence leading to COVID-19 pandemic, To [/bib_ref] Patients infected by SARS-CoV-2 may experience a set of manifestations ranging from asymptomatic infection, mild disease to severe disease with acute respiratory distress syndrome, multiorgan failure and death. In this regard, response to immunomodulatory therapy varies according to disease stage, with the best efficacy of these compounds observed in severe but not critical disease . ## Points to consider Since the formulation of the original set of PtCs, over 300 articles with various LoE investigating immunomodulatory agents in SARS-CoV-2 infection were published. [bib_ref] Immunomodulatory therapies for SARS-CoV-2 infection: a systematic literature review to inform EULAR..., Alunno [/bib_ref] Besides studies with drugs already mentioned in the previous PtCs, such as tocilizumab (TCZ) or anakinra, studies with new drugs including sarilumab, tofacitinib (TOFA), baricitinib (BARI) and colchicine, among others, were available, either as monotherapy or in combination treatment with glucocorticoids (GC). On this basis, the steering group agreed to keep PtC-1 and PtC-2 unchanged since they remain valid statements supported by current evidence and formulate new statements based on the recent evidence (or lack thereof) for individual classes of compounds, whenever possible or single drugs (tables 1 and 2). PtC-1: In non-hospitalised patients with SARS-CoV-2 infection, there is currently no evidence to support the initiation of immunomodulatory therapy (LoE 2/3/4). PtC-2: In hospitalised patients with SARS-CoV-2 infection that do not need oxygen therapy, there is currently no evidence to support the initiation of immunomodulatory therapy to treat their COVID-19 (LoE 2/3/4). Comparison of the 2020 and 2021 points to consider on the use of immunomodulatory treatment in SARS-CoV-2 infection ## (current) version changes performed 2020 (previous) version Overarching principles The phenotype of SARS-CoV-2 infection is heterogeneous ranging from asymptomatic to lethal disease due to multiorgan damage. ## Unchanged The phenotype of SARS-CoV-2 infection is heterogeneous ranging from asymptomatic to lethal disease due to multiorgan damage. SARS-CoV-2 infection may need different treatment approaches, including antiviral, oxygen therapy, anticoagulation and/or immunomodulatory treatment at different stages of the disease. Unchanged SARS-CoV-2 infection may need different treatment approaches, including antiviral, oxygen therapy, anticoagulation and/or immunomodulatory treatment at different stages of the disease. ## Points to consider In non-hospitalised patients with SARS-CoV-2 infection there is currently no evidence to support the initiation of immunomodulatory therapy (LoE 2/3/4). ## Unchanged In non-hospitalised patients with SARS-CoV-2 infection there is currently no evidence to support the initiation of immunomodulatory therapy (LoE 2/3/4). In hospitalised patients with SARS-CoV-2 infection that do not need oxygen therapy there is currently no evidence to support the initiation of immunomodulatory therapy to treat their COVID-19 (LoE 2/3/4). ## Unchanged In hospitalised patients with SARS-CoV-2 infection that do not need oxygen therapy there is currently no evidence to support the initiation of immunomodulatory therapy to treat their COVID-19 (LoE 2/3/4). Hydroxychloroquine should be avoided for treating any stage of SARS-CoV-2 infection since it does not provide any additional benefit to the standard of care, and could worsen the prognosis in more severe patients particularly if coprescribed with azithromycin (LoE 2). ## Unchanged Hydroxychloroquine should be avoided for treating any stage of SARS-CoV-2 infection since it does not provide any additional benefit to the standard of care, and could worsen the prognosis in more severe patients particularly if coprescribed with azithromycin (LoE 2). In patients with COVID-19 requiring supplemental oxygen, non-invasive or mechanical ventilation, systemic glucocorticoids should be used since they can decrease mortality; most evidence concerns the use of dexamethasone (LoE 2/3). ## Unchanged In patients with COVID-19 requiring supplemental oxygen, non-invasive or mechanical ventilation, systemic glucocorticoids should be used since they can decrease mortality; most evidence concerns the use of dexamethasone (LoE 2/3). In patients with COVID-19 requiring supplemental oxygen, non-invasive or mechanical ventilation combination of glucocorticoids and tocilizumab should be considered since it reduces disease progression and mortality (LoE 2). More data are needed to fully appreciate the effect of other IL-6R inhibitors (LoE 2/3). ## Modified An evolving RCT landscape cannot yet allow formal recommendation of the routine use of tocilizumab in patients with COVID-19 requiring oxygen therapy, non-invasive or invasive ventilation (LoE 2). In COVID-19 there is no robust evidence to support the use of anakinra at any disease stage (LoE 2/4). ## Modifies In COVID-19 there is no robust evidence to support the use of anakinra or canakinumab at any disease stage (LoE 2). In COVID-19 there is no robust evidence to support the use of low-dose colchicine at any disease stage (LoE 2) New Not applicable In patients with COVID-19 requiring oxygen therapy, non-invasive ventilation or high-flow oxygen, the combination of glucocorticoids and baricitinib or tofacitinib could be considered since it might decrease disease progression and mortality (LoE 2). ## Modified In patients with COVID-19 requiring non-invasive ventilation or high-flow oxygen, the combination of remdesivir plus baricitinib could be considered since it can decrease time to recovery and accelerate improvement in clinical status (LoE 2). ## Miscellaneous The group agreed to keep PtC-1 and PtC-2 unchanged since they remain valid statements supported by current evidence. PtC-3: Hydroxychloroquine should be avoided for treating any stage of SARS-CoV-2 infection since it does not provide any additional benefit to the standard of care, and could worsen the prognosis in more severe patients particularly if coprescribed with azithromycin (LoE 2). The group agreed to keep this PtC unchanged since further evidence against the use of hydroxychloroquine has emerged. [bib_ref] Safety and efficacy of favipiravir versus hydroxychloroquine in management of COVID-19: a..., Dabbous [/bib_ref] [bib_ref] Phase 2 randomized study on chloroquine, hydroxychloroquine or ivermectin in hospitalized patients..., Galan [/bib_ref] [bib_ref] An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus..., Ader [/bib_ref] [bib_ref] Hydroxychloroquine versus azithromycin for hospitalized patients with COVID-19. Results of a randomized,..., Brown [/bib_ref] [bib_ref] Effect of early treatment with hydroxychloroquine or lopinavir and ritonavir on risk..., Reis [/bib_ref] [bib_ref] Azithromycin and hydroxychloroquine in hospitalised patients with confirmed COVID-19-a randomised double-blinded placebo-controlled..., Sivapalan [/bib_ref] [bib_ref] Assessing the efficacy and safety of hydroxychloroquine as outpatient treatment of COVID-19:..., Schwartz [/bib_ref] [bib_ref] An open-label randomized controlled trial evaluating the efficacy of chloroquine/hydroxychloroquine in severe..., Réa-Neto Álvaro [/bib_ref] PtC-4: In patients with COVID-19 requiring supplemental oxygen, non-invasive or mechanical ventilation, systemic GC should be used since they can decrease mortality; most evidence concerns the use of dexamethasone (DEXA) (LoE 2/3). As PtC-1, the group agreed to keep this PtC unchanged but in this case on the basis of lack of new evidence. In fact, the three new RCTs gathered by the SLR update were underpowered, thereby providing unreliable results and therefore could not be used to formulate the PtC. One retrospective trial comparing the efficacy of methyprednisolone (MTP ≥1 mg/kg/ days for ≥3 days) vs DEXA (DEXA ≥6 mg for ≥7 days) showed a reduction of mortality in the group of patients receiving MV treated with MTP (relative risk (RR) 0.48 (95% CI 0.23 to 0.96). However, the small number of patients, retrospective design and high risk of bias for this study did not allow definitive conclusions regarding superiority of any compound and could therefore not inform the PtCs. [bib_ref] A comparison of methylprednisolone and dexamethasone in intensive care patients with COVID-19, Ko [/bib_ref] PtC-5: In patients with COVID-19 requiring supplemental oxygen, non-invasive or mechanical ventilation combination of GC and TCZ should be considered since it reduces disease progression and mortality (LoE 2). More data are needed to fully appreciate the effect of other IL-6R inhibitors (LoE 2/3). This PtC was modified encompassing not only TCZ but the entire class of IL-6R inhibitors. Four new RCTs pertained to TCZ [bib_ref] Tocilizumab in hospitalized patients with severe Covid-19 pneumonia, Rosas [/bib_ref] [bib_ref] Tocilizumab plus standard care versus standard care in patients in India with..., Soin [/bib_ref] [bib_ref] REMAP-CAP Investigators. Interleukin-6 receptor antagonists in critically ill patients with Covid-19, Gordon [/bib_ref] [bib_ref] Tocilizumab in patients admitted to hospital with COVID-19 (recovery): a randomised, controlled,..., Abani [/bib_ref] alongside the 90 days post hoc analysis of the CORIM-UNO-19 TOCI trial. [bib_ref] Effectiveness of tocilizumab in patients hospitalized with COVID-19: a follow-up of the..., Mariette [/bib_ref] Among these, RECOVERY, REMAP-CAP and the post hoc analysis of CORIMUNO-19 TOCI (the latter in the subgroup of patients with C reactive protein >15.0 mg/dL) showed reduction of death at day 21 (RR 0.27, 95% CI 0.12 to 0.72), day 28 (RR 0.82, 95% CI 0.75 to 0.90) and day 90 respectively (RR 0.79, 95% CI 0.63 to 0.97), respectively. In addition, a reduction of progression to invasive mechanical ventilation (IMV) or death at day 21 19 or day 90 20 or an increase in cardiovascular or respiratory support-free days 18 was observed. Of note, the proportion of patients receiving GC as part of the standard of care (SOC) was very heterogeneous among trials, with a difference observed between trials starting before and after the positive results of the GC arm of the RECOVERY trial. It is noteworthy that in contrast to two positive RCTs where a high percentage of patients were receiving concomitant GC (82%-93%), only up to 50% of patients were receiving concomitant GC in the COVACTA trial, which failed to show efficacy in reducing death or improving clinical status. [bib_ref] Tocilizumab in hospitalized patients with severe Covid-19 pneumonia, Rosas [/bib_ref] In addition, a recent meta-analysis of RCTs published in JAMA confirmed the efficacy of TCZ on all-cause mortality (OR 0.83, 95% CI 0.72 to 0.94) and progression to IMV, extracorporeal membrane oxygenation or death (OR 0.74, 95% CI 0.66 to 0.82) at day It is important to mention that the survival benefit at 28 days was essentially observed only in patients also on GC. Furthermore, the statistically significant benefit in survival at 90 days is the most relevant finding. Of note, much of what drove the statistical significance for improved mortality were the nonblinded larger randomised trials. The evidence regarding sarilumab (SARI) is scarcer although encouraging, with a small arm in REMAP-CAP trial (n=44 patients) showing a reduction in death and cardiovascular/respiratory organ-support free days 18 while another RCT comparing 200 mg or 400 mg of SARI and placebo showed no efficacy on death, progression to IMV or admission to intensive care unit. [bib_ref] Sarilumab in patients admitted to hospital with severe or critical COVID-19: a..., Lescure [/bib_ref] Of interest, in a meta-analysis of IL-6R inhibitors, in the subgroup of patients receiving GC compared with those who did not, mortality at day 28 was significantly reduced only in the GC group for TCZ (ratio of OR (ROR) 0.69, 95% CI 0.52 to 0.91 p=0.008), with only a non-significant trend for SARI (ROR 0.77, 95% CI 0.64 to 1.31 p=0.34). PtC-6) In COVID-19 there is no robust evidence to support the use of anakinra and canakinumab at any disease stage (LoE 2). The only RCT available in the 2020 version of the PtC on anakinra used at a high dose of 400 mg/day for 3 to 6 days (CORIMUNO-19 ANA) was negative in patients with mildto-moderate COVID-19 pneumonia requiring at least 3 L/min oxygen but not receiving non-invasive ventilation (NIV) or IMV at randomisation. [bib_ref] Effect of anakinra versus usual care in adults in hospital with COVID-19..., Tharaux [/bib_ref] In addition, one RCT looking into a specific group of COVID-19 patients, namely those with elevated soluble urokinase plasminogen activator equal to or above 6 ng/ mL which is considered as a predictor of unfavourable outcome. In this population, anakinra 100 mg subcutaneously for 7-10 days increased number of patients improving WHO CPS at day 28 (0.36 (95% CI 0.26 to 0.50) and decreased mortality at day 28: 3.2% vs 6.9% (HR=0.45, p=0.045). [bib_ref] Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor..., Kyriazopoulou [/bib_ref] Further studies are necessary to address the validity of this biomarker for predicting a possible effect of anakinra in this subgroup of patients. With regard to canakinumab, a 2020 press-release RCT indicated that it did not meet its primary and secondary endpoints. [bib_ref] Effect of canakinumab vs placebo on survival without invasive mechanical ventilation in..., Caricchio [/bib_ref] Large trials recruiting severe cases of COVID-19 are warranted. PtC-7: In COVID-19, there is no robust evidence to support the use of low-dose colchicine at any disease stage (LoE 2). Compared to 2020, the new SLR updated gathered two additional RCTs, a large study enrolling almost 5000 non-hospitalised patients with mild disease [bib_ref] Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded,..., Tardif [/bib_ref] and a small study including 72 hospitalised patients, most of whom required oxygen therapy. [bib_ref] Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded,..., Lopes [/bib_ref] The results of both studies were not rated solid enough to recommend in favour of colchicine. Moreover, both studies used a rather low dose, hence the group deemed appropriate to specify this in the PtC since it was not possible to rule out whether higher doses might be beneficial. In addition, a press release reported that the colchicine arm of the RECOVERY trial, enrolling hospitalised patients with COVID-19, has closed due to lack of evidence that further recruitment will prove a reduction of mortality. The interim results have been published as preprint.PtC-8: In patients with COVID-19 requiring oxygen therapy, NIV or high-flow oxygen, the combination of GC and BARI or TOFA could be considered since it might decrease disease progression and mortality (LoE 2). The only RCT available on BARI in SARS-CoV-2 infection included in the 2020 version [bib_ref] Baricitinib plus remdesivir for hospitalized adults with Covid-19, Kalil [/bib_ref] and compared remdesevir +BARI versus remdesevir +placebo. In addition, The Fourth iteration of the Adaptive COVID-19 Treatment Trial-4, although published in the grey literature and therefore not used to inform the PtCs; compared BARI+remdesivir+placebo versus remdesivir +DEXA+placebo and met predefined futility criteria in an interim analysis thereby closed enrollment in April 2021 according to a press release.In a new study (COV-BARRIER trial), BARI in addition to SOC (80% participants receiving GC (92% DEXA)) showed no significant efficacy in reducing progression to the composite primary endpoint defined by the proportion who progressed to high-flow oxygen, NIV/IMV or death by day 28. However, the all-cause 28-day mortality in the BARI group was decreased from 13% to 8% (HR=0.57 (95% CI 0.41 to 0.78); p=0.0018) and at day 60: 10% vs 15% (HR=0.62 (95% CI 0.47 to 0.83]; p=0.005). [bib_ref] Efficacy and safety of baricitinib for the treatment of hospitalised adults with..., Marconi [/bib_ref] One new RCT 32 comparing TOFA+SOC (n=144) to placebo +SOC (n=144) reported a significant improvement of the composite outcome of respiratory failure or mortality at day 28 (RR 0.63, 95% CI 0.41 to 0.97) vs placebo +SOC in a population where 90% of patients were receiving GC as part of SOC. No new evidence other than the previously published negative RCT on ruxolitinib was retrieved. PtC-9: An evolving RCT landscape cannot yet allow formal recommendation of the use of GM-CSF inhibitors (mavrilimumab, otilimab, lenzilumab) in COVID-19 (LoE 2) The 2020 SLR gathered only a few studies with low LoE on GM-CSF inhibitors. Although the SLR update identified only one RCT on mavrilimumab, the group discussed the large proportion of ongoing RCTs, not only on mavrilimumab but also on other GM-CSF inhibitors (otilimab, lenzilumab), available in the grey literature (both as press releases and as preprints). On this basis, they deemed appropriate to formulate a PtC conveying the message that the current lack of evidence to recommend either in favour or against is accompanied by an evolving body of evidence that will soon be available in peer-reviewed journals. PtC-10: In patients without hypogammaglobulinaemia and with symptom onset >5 days there is robust evidence against the use of convalescent plasma (CP) (LoE 2) Among the RCTs published on CP (n=7), four were retrieved by the SLR update. Of interest, a distinction was drawn by the TF based on the timing of CP administration (ie, before or after day 5 of symptom onset). In fact, a large RCT including more than 5000 patients in each treatment arm (CP +SOC vs placebo +SOC), CP was not effective in reducing the composite outcome of progression to IMV or death at day 28 (RR 0.99, 95% CI 0.93 to 1.05 p=0.79) when administered after this time frame. [bib_ref] Convalescent plasma in patients admitted to hospital with COVID-19 (recovery): a randomised..., Recovery Collaborative Group [/bib_ref] It is important to clarify that this PtC was informed by robust data against CP showing benefit while no evidence about CP being harmful was retrieved by SLR. PtC-11: In patients at risk of severe COVID-19 course, with symptom onset <5 days or still seronegative, monoclonal antibodies against SARS-CoV-2 spike protein should be considered (LoE 2) The new SLR conducted to gather studies on monoclonal antibodies against SARS-CoV-2 spike protein, retrieved four RCTs, three of which enrolled non-hospitalised patients with mild to moderate COVID-19 [bib_ref] Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral..., Gottlieb [/bib_ref] [bib_ref] REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19, Weinreich [/bib_ref] [bib_ref] Bamlanivimab plus etesevimab in mild or moderate Covid-19, Dougan [/bib_ref] and one enrolling hospitalised patients with moderate-to-severe COVID-19.The combination of bamlanivimab and etesevimab as well as of casirivimab and imdevimab administrated within the first week after symptom onset were able to significantly reduce viral load. However, casirivimab and imdevimab were effective only in patients seronegative at baseline. Conversely, bamlanivimab monotherapy failed to significantly reduce viral load in non-hospitalised patients, and failed to provide any benefit on clinical outcomes (eg, 90 days mortality) in hospitalised patients.It is important to mention that the specific monoclonal antibodies have different activities against variants, so in addition to the above-mentioned data, regional prevalence of variants must be taken into account when selecting a particular product. PtC-12: In patients with COVID-19, there is currently insufficient evidence to recommend the use of other immunomodulatory drugs, including interferon alpha, interferon beta, interferon kappa, interferon lambda, leflunomide, non-SARS CoV-2 IVIg (LoE 2), eculizumab and cyclosporine (LoE 3). Interferon lambda has been added since no RCT was available in the previous SLR and the two RCTs retrieved by the SLR update were not solid enough to formulate a new PtC. A change of LoE was done for interferon alpha since a small RCT was retrieved by the search update. [bib_ref] Efficacy and safety of pegylated interferon alfa-2b in moderate COVID-19: a phase..., Pandit [/bib_ref] The group did not comment on drugs for which published literature was of LoE <3. # Discussion Since the release of the first EULAR-endorsed PtCs on immunomodulatory therapy of SARS-CoV-2 infection, new evidence has accumulated on the efficacy and safety of various compound with most evidence pertaining to moderate to severe/critical COVID-19. The aim of this update was to provide clinicians involved in the care of people with SARS-CoV-2 infection with an update on the use of immunomodulatory therapies in COVID-19, based on available literature and as seen from the rheumatology perspective. All the statements are based on a thorough SLR and on conclusions of an international rheumatology/multidisciplinary team. All studies, although RCTs, were highly heterogeneous and at high or unclear risk of bias, hence the experts' opinion was instrumental to reach consensus on if and how to update the existing statements. Until now, only three drugs have been recommended by WHO for COVID-19, DEXA and TCZ for patients requiring oxygen therapy and critical patients and the combination of casirivimab and imdevimab for early patients at risk of severe form and not vaccinated or having not responded to vaccination.Besides the three statements on HCQ, GCs and anakinra, the group developed several new PtCs and modified the existing ones since more evidence about numerous drugs has accrued . Moreover, the discontinuation of some RCTs for futility and the availability of interim data of some successful RCTs from the grey literature, clarified the role of some immunomodulatory compounds in the scenario of the pandemic although these could not be used to formulate recommendations in favour or against. In particular, it was possible to formulate statements in favour of TCZ in combination with GCs and against CP, except in specific in subgroups of patients based on a consistent number of peer-reviewed RCTs. Based on the evidence on CP and monoclonal antibodies against SARS-CoV-2 spike protein, it is tempting to speculate that a polyclonal response may be better to activate effector functions than a monoclonal response. Data on Janus kinase inhibitors are promising in some subgroups. Lastly, the use of colchicine and GM-CSF inhibitors is pending the release of more solid evidence. In conclusion, the update of these EULAR PtCs provide relevant and updated guidance on immunomodulatory therapy utilisation from the rheumatology perspective and opens the way to a new paradigm: the treatment of immunopathology associated with severe and critical acute infections may benefit from immunomodulatory treatments usually given for autoimmune and inflammatory diseases. This article is made freely available for use in accordance with BMJ's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.ORCID iDsCompeting interests AA, AN, HB, FC, GDM, RG, CM-C and JRC have nothing to declare. PMM has received consulting and/or speaker's fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript. G-RRB has received consulting and/or speaker's fees from Abbvie, Gilead, Lilly, Roche, Sanofi, Pfizer all unrelated to this manuscript. IK-P has received consulting and/or speaker's fees from Novartis, SOBI, Amgen, CHUGAI, Pfizer, LFB, Novimmune, Abbvie and PAtent for AIDAI score AVR has received speaker fees/Honoraria from Abbvie, Lilly, Roche, UCB, SOBI and Novartis all unrelated to this manuscript. DGM has received consulting and/or speaker's fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche and UCB, all unrelated to this manuscript. XM has received consulting and/or speaker's fees from BMS, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Novartis, Pfizer, Servier and UCB, all unrelated to this manuscript.Patient and public involvement statementPatients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research.Patient consent for publication Not applicable.Provenance and peer review Not commissioned; externally peer reviewed.Data availability statement Data sharing not applicable as no datasets generated and/or analysed for this study. All data relevant to the study are included in the article or uploaded as online supplemental information.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.	None	None	Objectives To update the EULAR points to consider (PtCs) on the use of immunomodulatory therapies in COVID-19. Methods According to the EULAR standardised operating procedures, a systematic literature review up to 14 July 2021 was conducted and followed by a consensus meeting of an international multidisciplinary task force. The new statements were consolidated by formal voting. Results We updated 2 overarching principles and 12 PtC. Evidence was only available in moderate to severe and critical patients. Glucocorticoids alone or in combination with tocilizumab are beneficial in COVID-19 cases requiring oxygen therapy and in critical COVID-19. Use of Janus kinase inhibitors (baricitinib and tofacitinib) is promising in the same populations of severe and critical COVID-19. Anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma may find application in early phases of the disease and in selected subgroups of immunosuppressed patients. There was insufficient robust evidence for the efficacy of other immunomodulators with further work being needed in relation to biomarker-based stratification for IL-1 therapy Conclusions Growing evidence supports incremental efficacy of glucocorticoids alone or combined with tocilizumab/Janus kinase inhibitors in moderate to severe and critical COVID-19. Ongoing studies may unmask the potential application of other therapeutic approaches. Involvement of rheumatologists, as systemic inflammatory diseases experts, should be encouraged in clinical trials of immunomodulatory therapy in COVID-19.
f8b591cb9b4f281d0f8a9fc32700e1399e584596	pubmed	Clinical Practice Guideline for the Evaluation of Fever and Infection in Older Adult Residents of Long‐Term Care Facilities: 2008 Update by the Infectious Diseases Society of America	Clinical Practice Guideline for the Evaluation of Fever and Infection in Older Adult Residents of Long‐Term Care Facilities: 2008 Update by the Infectious Diseases Society of America ## Resources Most LTCFs have limited diagnostic equipment on site and are staffed by nursing personnel (primarily certified nurse assistants . Specific data are available to make recommendations for personnel, but no data are available to guide minimal requirements for diagnostic equipment. 1. LTCFs should employ sufficient staff to adequately care for all residents (B-III). ## Symptoms and signs of suspected infection Typical symptoms and signs of infection are frequently absent in LTCF residents, and as one ages and becomes more frail, basal body temperature decreases, making it less likely that one will achieve classic definitions of fever. Infection should be suspected in residents with the following characteristics: 2. Infection should be suspected in LTCF residents with: A. Decline in functional status, defined as new or increasing confusion, incontinence, falling, deteriorating mobility, reduced food intake, or failure to cooperate with staff (B-II Blood Cell Count 9. A complete blood cell (CBC) count, including peripheral white blood cell (WBC) and differential cell counts (preferably a manual differential to assess bands and other immature forms), should be performed for all LTCF residents who are suspected of having infection within 12-24 h of onset of symptoms (or sooner, if the resident is seriously ill), consistent with local standards of practice (B-II). [bib_ref] A perspective on cellular immunity in the elderly, Khanna [/bib_ref]. The presence of an elevated WBC count (WBC count, 14,000 cells/mm 3 ) or a left shift (percentage of band neutrophils or metamyelocytes, 46%; or total band neutrophil count, 1,500 cells/mm 3 ) warrants a careful assessment for bacterial infection in any LTCF resident with suspected infection, with or without fever (B-II). 11. In the absence of fever, leukocytosis and/or left shift, or specific clinical manifestations of a focal infection, additional diagnostic tests may not be indicated, because of the low potential yield (C-III). Nonbacterial infections, however, cannot be excluded. ## Urinalysis and urine culture 12. Urinalysis and urine cultures should not be performed for asymptomatic residents (A-I). [bib_ref] Age-associated defect in human TLR-1/2 function, Van Duin [/bib_ref]. In noncatheterized residents, the diagnostic laboratory evaluation of suspected UTI should be reserved for those with acute onset of UTI-associated symptoms and signs (e.g., fever, dysuria, gross hematuria, new or worsening urinary incontinence, and/or suspected bacteremia) (A-II). 14. In residents with long-term indwelling urethral catheters, evaluation is indicated if there is suspected urosepsis (i.e., fever, shaking chills, hypotension, or delirium), especially in the context of recent catheter obstruction or change (A-II). 15. Appropriately collected urine specimens include a midstream or clean-catch specimen obtained from elderly men who are cooperative and functionally capable; however, it is often necessary to use a freshly applied, clean condom external collection system, with frequent monitoring of the urine bag (B-II). Specimen collection from women will often require an in-and-out catheterization (B-III). [bib_ref] Risk factors for resistance to antimicrobial agents among nursing home residents, Loeb [/bib_ref] ## Evaluation of gi infection 28. In the absence of an outbreak of GI illness, residents with symptoms of gastroenteritis consistent with small bowel infection and a stable clinical status should be evaluated before 7 days for volume assessment, but no laboratory evaluation is required unless the resident is severely ill or symptoms persist beyond 7 days. In such cases, presence of Giardia species and other protozoa should be examined in stool specimens (B-III). 29. If the resident exhibits symptoms of colitis (e.g., severe fever, abdominal cramps, and/or diarrhea, with or without blood and/or WBCs in the stool), initial evaluation for C. difficile should be performed, especially if the patient has received antibiotics within the previous 30 days. Submit a single diarrheal stool specimen to the laboratory for a C. difficile toxin assay. If diarrhea persists and if the assay result is negative, submit 1 or 2 additional stool specimens for the toxin assay (A-II). 30. In a patient with symptoms of colitis but no history of antibiotic use within the previous 30 days and/or a negative C. difficile evaluation result, one should submit a stool sample for culture for isolation of the most frequent invasive enteropathogens (i.e., Campylobacter jejuni, Salmonella and Shigella species, and Escherichia coli O157:H7) (A-II). 31. Local public health authorities should be consulted if rates of gastroenteritis or colitis exceed baseline thresholds in the facility (if these thresholds are known), if 2 cases occur at the same time in the same unit, or if a reportable pathogen is isolated (B-III). 32. Intra-abdominal infections and abscesses can occur in LTCF residents as a consequence of GI pathology. These complications are relatively uncommon but are associated with substantial morbidity and mortality; evaluation and treatment of possible abscesses should be performed in an acute care setting (B-III). ## Suspected outbreak A broad description of an outbreak investigation is beyond the scope of these guidelines, but a general guide is provided, including circumstances in which appropriate authorities (e.g., the Centers for Disease Control and Prevention) should be notified. An important aspect of the outbreak investigation is that residents with advanced directives that prohibit testing can and often should be tested if the goal is not for care of that specific patient but reduction in the risk of illness in others. [bib_ref] Fever response in elderly nursing home residents: are the older truly colder?, Castle [/bib_ref]. During a possible outbreak of infection, testing of residents, regardless of advanced directive status, may be warranted for diagnostic and infection-control purposes for the protection of other residents and staff (B-III). ## Practice guidelines and update methodology ## Practice guidelines Practice guidelines are systematically developed statements to assist practitioners and patients in making decisions about appropriate health care for specific clinical circumstances.Attributes of good guidelines include validity, reliability, reproducibility, clinical applicability, clinical flexibility, clarity, multidisciplinary process, review of evidence, and documentation. 1 ## Panel composition The Infectious Diseases Society of America (IDSA) Standards and Practice Guidelines Committee (SPGC) convened experts in the evaluation of residents with fever and infection in LTCFs. The Panel's expertise included infectious diseases, geriatrics, primary care, long-term care, and epidemiology/infection control. ## Literature review and analysis ## Process overview In assessing the evidence regarding the evaluation of fever and infection in LTCF residents, the Expert Panel followed a process used in the development of other IDSA guidelines. The process included a systematic weighting of the quality of the evidence and the grade of recommendation [fig_ref] Table 1: Infectious Diseases Society of America-U [/fig_ref]. 2 ## Consensus development based on evidence The Expert Panel met on four occasions via teleconference to complete the work of the guidelines. The purpose of the teleconferences was to discuss the questions to be addressed, to make writing assignments, and to discuss recommendations. All members of the Expert Panel participated in the preparation and review of the draft guidelines. Feedback from external peer reviews was obtained. The guidelines were reviewed and approved by the SPGC and the Board of Directors prior to dissemination. ## Guidelines and conflicts of interest All members of the Expert Panel complied with the IDSA policy on conflicts of interest, which requires disclosure of any financial or other interest that might be construed as constituting an actual, potential, or apparent conflict. Members of the Expert Panel were provided the IDSA's conflict of interest disclosure statement and were asked to identify associations with companies developing products that may be affected by promulgation of the guidelines. Information was requested regarding employment, consultancies, stock ownership, honoraria, research funding, expert testimony, and membership on company advisory committees. The Expert Panel made decisions on a case-bycase basis as to whether an individual's role should be limited as a result of a conflict. Potential conflicts are listed in the Acknowledgments section. # Introduction In 2000, the IDSA published clinical practice guidelines on the evaluation of fever and infection in LTCFs. [bib_ref] Practice guideline for evaluation of fever and infection in longterm care facilities, Bentley [/bib_ref] The IDSA updates its guidelines when new data or publications might change a prior recommendation or when the Expert Panel feels clarifications or additional guidance is warranted. The previous document is a source for a more detailed review of earlier studies, [bib_ref] Practice guideline for evaluation of fever and infection in longterm care facilities, Bentley [/bib_ref] The aged human population is undergoing unprecedented growth in the United States and globally. Multiple nations have 42 million older citizens each, and the number is expected to grow within the next few decades, with the greatest burden in the developing world. [bib_ref] A new paradigm for clinical investigation of infectious syndromes in older adults:..., High [/bib_ref] By the year 2030, it is estimated that 20% of the U.S. population will be aged 65 years, among whom almost 30 million persons are anticipated to have functional limitations within the ensuing decade. [bib_ref] Infection Management for Geriatrics in Long Term Care Facilities, Yoshikawa [/bib_ref] These estimates are linked to the rising need for long-term care, particularly in nursing homes/facilities, in the United States. Currently, in the United States, there are 416,000 nursing homes/facilities for long-term care in which 1.5 million older adults reside. More than 90% of these facilities are either proprietary or voluntary nonprofit, with the majority housing 50-200 residents each. Care providers within facilities are primarily nursing staff, with an average of 7 registered nurses (RNs), 13 licensed practical nurses (LPNs), and 35 CNAs per 100 resident beds.The minority (19.6%) have physician providers on fulltime staff. The majority have contracts with group practices or use private physicians from the local community. Select specialty services and diagnostic testing are most often provided through contracts with outside providers (e.g., dental care, podiatry, and imaging services).Other more complex or technical services require hospitalization of the resident. Overall, care needs are becoming increasingly complex for this population, which consists primarily of elderly women (median age, 85 years) who are afflicted with a variety of comorbid conditions (e.g., dementia, stroke, or congestive heart failure) and who have functional limitations in mobility and dependence in activities of daily living (e.g., bathing, dressing, and toileting). 9 ## Multifactorial risks of infection in older adults in ltcfs The convergence of age-associated impairments in immunity, increasing prevalence of comorbid disease, functional limitations of extreme age, and residence in group quarters within a nursing home/facility increase the risk burden for infectious disease. [bib_ref] A new paradigm for clinical investigation of infectious syndromes in older adults:..., High [/bib_ref] [bib_ref] A perspective on cellular immunity in the elderly, Khanna [/bib_ref] [bib_ref] Community-acquired pneumonia in older people: the need for a broader perspective, Loeb [/bib_ref] The specific nature of senescence of the immune system with normal aging has been an area of increasing investigation, with evidence supporting impairments in adaptive (e.g., B and T cell function) and innate immunity (e.g., surface expression or function of Toll-like receptors) that may relate to the increased risk of disease due to specific pathogens (e.g., Listeria species, Mycobacterium tuberculosis, and varicella-zoster virus) and an impaired response to vaccination (e.g., influenza, pneumococcus, and zoster vaccines). 7,12-15 Concomitant comorbidities (e.g., diabetes mellitus, obstructive lung disease, urinary obstruction, impaired swallowing, poor dentition, and implanted prosthetic devices) further enhance the risk for common healthcare-associated infectious syndromes in the urinary tract, lung, and soft tissue. The common use of empirical antibiotic therapy for these conditions results in the additional complications of infections with antibioticresistant pathogens (e.g., methicillin-resistant S. aureus, vancomycin-resistant Enterococcus species, multidrug-resistant gram-negative bacilli) and C. difficile colitis. [bib_ref] Risk factors for resistance to antimicrobial agents among nursing home residents, Loeb [/bib_ref] As a result, the LTCF has become a reservoir for antibioticresistant pathogens in which elderly residents requiring periodic hospitalization may carry resistant organisms across sites of care. ## Burden of infection Although UTI, pneumonia, soft-tissue infection, gastroenteritis, and indwelling deviceFassociated infections are well-recognized problems among elderly nursing home residents, UTI and pneumonia represent the greatest infectious disease burden. For example, UTI is the most commonly reported bacterial infection in nursing home residents, with an incidence of 0.1-2.4 cases per 1,000 resident-days, and it is a leading source of sepsis and death. [bib_ref] Urinary tract infection in long-term-care facility residents, Nicolle [/bib_ref] Similarly, pneumonia develops among elderly nursing home residents at a rate of 1 episode per 1,000 days of care, which is 10-fold greater than the rate of pneumonia among elderly community dwellers. At the current rate, by the year 2030, there will be almost 2 million episodes of nursing home-acquired pneumonia annually, with its inherent consequences of mortality, morbidity, functional decline, and healthcare expenditures. [bib_ref] Nursing home-acquired pneumonia, Medina-Walpole [/bib_ref] ## Evidence summary When clinicians evaluate suspected infection in hospitalized patients, diagnostic technologies are usually readily available, and there are a variety of staff trained in acutely evaluating changes in health status. In contrast, the overarching goals of care for LTCF residents are patient comfort, maintenance or improvement of functional status, stabilization of chronic illnesses, and prevention of new health problems, and care is most often provided by the nursing staff (primarily CNAs) under the direction of a director of nursing. LTCF resident-to-healthcare staff ratios are considerably lower than patient-to-staff ratios at acute care hospitals. Although there is no federal standard for specific levels of nurse staffing in a nursing home, the Centers for Medicare and Medicaid Services requires nursing homes to employ sufficient staff to adequately care for all residents. [bib_ref] Evaluation of infections in long-term care facilities versus acute care hospitals, Joaquin [/bib_ref] Staffing guidelines should be adjusted according to case mix and acuity of the residents. A threshold for acceptable ratios of nursing staff to residents can be recommended on the basis of this study, as follows: ratio of CNAs to residents, 1:12; ratio of RNs plus LPNs to residents, 1:30; and ratio of RNs to residents, 1:120. [bib_ref] Evaluation of infections in long-term care facilities versus acute care hospitals, Joaquin [/bib_ref] Relatively few physicians practice in an LTCF, and routine physician visits are infrequentFoften monthly or even less frequent, depending on state or federal regulations. Some visits may be made by cross-covering physicians or physician extenders (i.e., physician assistants and advance-practice nurses). Between these visits, initiation of diagnostic testing and changes in medications and other treatments are usually accomplished by telephone communication. [bib_ref] Medical care of nursing home residents, Evans [/bib_ref] [bib_ref] Physician evaluation and management of nursing home residents, Ouslander [/bib_ref] [bib_ref] SHEA Long-Term-Care Committee and APIC Guidelines Committee. Infection prevention and control in..., Smith [/bib_ref] Technologies available for the prompt diagnosis of infection in hospitals are often difficult to access in the LTCF. Vital signs generally are obtained on a weekly basis for stable residents who require long-term maintenance care; however, more frequent measurements can be obtained on the basis of nursing judgment or physician order. Criteria for infections that rely less on diagnostic studies and more on patient symptoms and signs and on resources that are more readily available in LTCFs have been developed and widely used but not validated. [bib_ref] Definitions of infection for surveillance in long-term care facilities, Mcgeer [/bib_ref] [bib_ref] Consensus conference on nosocomial infections in longterm care facilities, Smith [/bib_ref] There is no minimum requirement that diagnostic equipment be present on-site for evaluation of fever and suspected infection in LTCFs other than for equipment used for clinical assessment. Immediately available laboratory tests and radiography equipment are sometimes located on-site, but personnel to operate these devices are almost never available every day, 24 h per day. Contract organizations often provide services, and subspecialty or surgical consultation is very rarely available except for LTCFs attached to acute care hospitals. Cost and capitated care may influence decisions to transport patients off site for diagnostic evaluation. . However, clinical findings in infected elderly residents in LTCFs may also be absent or too subtle to be recognized by the staff, or infection may manifest atypically as a change in mental or cognitive function or a decline in physical functional status (e.g., the person is unable to perform the usual activities of daily living). Berman et al. [bib_ref] The atypical presentation of infection in old age, Berman [/bib_ref] determined that infection is present in 77% of episodes of ''decline in function,'' defined as new or increasing confusion, incontinence, falling, deteriorating mobility, or failure to cooperate with rehabilitation. Ascertaining the functional status or functional capacity of older persons with infection before, during, and after resolution of infection is an essential aspect of managing the health care in the geriatric population. [bib_ref] A new paradigm for clinical investigation of infectious syndromes in older adults:..., High [/bib_ref] Thus, LTCF residents may have typical or atypical presentations of infection. [bib_ref] The atypical presentation of infection in old age, Berman [/bib_ref] [bib_ref] Nursing home-acquired pneumonia: a casecontrol study, Marrie [/bib_ref] [bib_ref] Pyrexia in infection in the elderly, Mcalpine [/bib_ref] [bib_ref] Clinical manifestations of disease in the elderly, Samiy [/bib_ref] For example, Brooks et al. [bib_ref] The physician decision-making process in transferring nursing home patients to the hospital, Brooks [/bib_ref] found ''typical'' symptoms and signs of UTI, such as fever (30%; absolute temperature criterion for fever was not defined), were not sensitive indicators of infection in LTCF residents. In contrast, persons with respiratory tract infection (RTI) more often presented with classic manifestations (cough, 75%; fever, 62%; and rales, 55%). In another large study, just 44% of nursing home residents with possible or probable pneumonia noted on a chest radiograph had a temperature of 381C, but only 7.5% had no respiratory symptoms. 32 ## Fever criteria in residents of ltcfs There are several methods to determine whether fever is present in the LTCF resident. Basal body temperatures in frail, elderly persons may be lower than the well-established mean value of 371C or 98.61F. [bib_ref] Fever response in elderly nursing home residents: are the older truly colder?, Castle [/bib_ref] In a study by in which all temperatures were determined orally or rectally with use of an electronic thermistor probe and in which subjects were mostly male veteran nursing-facility residents, a single temperature reading of 1011F (38.31C) had a sensitivity of only 40% for predicting infection. Lowering the criterion to 1001F (37.81C) raised the sensitivity to 70% for predicting infection while maintaining excellent speci-ficity at 90%. Thus, according to Castle et al., [bib_ref] Lowering the temperature criterion improves detection of infections in nursing home residents, Castle [/bib_ref] a single temperature reading of 1001F (37.81C) is both a sensitive and specific predictor of infection, with a positive predictive value of 55%, in LTCF residents. Other suggested temperature criteria indicative of possible infection in LTCF residents are an increase in temperature of at least 21F (1.11C) over baseline or an oral temperature of 991F (37.21C) or a rectal temperature of 99.51F (37.51C) on repeated measurements. [bib_ref] Lowering the temperature criterion improves detection of infections in nursing home residents, Castle [/bib_ref] [bib_ref] Fever in the elderly, Norman [/bib_ref] Although temperatures in LTCF residents are most often measured in the mouth, there is some evidence that rectal measurements of temperatures may be more accurate than either the oral or axillary method and that electronic techniques are better than standard mercury thermometry. [bib_ref] The febrile response to mild infections in elderly hospital inpatients, Darowski [/bib_ref] [bib_ref] Silent'' pyrexia in the elderly, Downton [/bib_ref] Another alternative method for measuring temperature is tympanic membrane thermometry. In one study of nursing home residents, the correlation of tympanic membrane thermometry versus rectal thermometry was somewhat better than oral versus rectal thermometry. [bib_ref] The equivalency of infrared tympanic membrane thermometry with standard thermometry in nursing..., Castle [/bib_ref] However, there are insufficient data to recommend the tympanic membrane method for measuring fever in older persons. ## Iii. who should perform the initial evaluation of the resident with suspected infection? Recommendations 3. The initial clinical evaluation of infection should be a three-tiered approach involving a CNA, the on-site nurse, and an advanced-practice nurse, physician assistant, or physician (B-III). 4. CNAs should measure vital signs (temperature, heart rate, blood pressure, and respiratory rate). Residents who are suspected of having an infection or who have fever, as defined previously, should be reported immediately to the on-site nurse (B-II). ## Evidence summary Once infection is suspected or fever is established by the criteria outlined above, clinical evaluation of LTCF residents with suspected infection (i.e., clinical manifestations of infection or decline in functional status) should be a three-tiered level of evaluation that includes CNAs, the onsite nurse (charge nurse), and the responsible physician or physician extender (i.e., advanced-practice nurses or physician assistant). A number of studies have reported use of advanced-practice nurses (e.g., nurse practitioners) to assess acute problems in residents of LTCFs as an approach to improve evaluation. [bib_ref] Physician evaluation and management of nursing home residents, Ouslander [/bib_ref] [bib_ref] Medical care in the nursing home, Ouslander [/bib_ref] [bib_ref] Effects of a geriatric nurse practitioner on process and outcome of nursing..., Kane [/bib_ref] [bib_ref] Identifying clues to infections in nursing home residents: the role of the..., Jackson [/bib_ref] Evidence suggests that geriatric nurse practitioners (GNPs) can enhance identification of acute medical problems (including fever) and improve activities of daily living, nursing therapies, and drug treatments, compared with the absence of GNPs. [bib_ref] Effects of a geriatric nurse practitioner on process and outcome of nursing..., Kane [/bib_ref] However, GNPs do not alter overall outcomes, as measured by the resident's functional status, physical condition, and satisfaction. [bib_ref] Impact of geriatric nurse practitioners on nursing-home residents' functional status, satisfaction, and..., Garrard [/bib_ref] Specific outcome data do not exist for infection. It is unknown whether NPs without geriatric certification will perform equally well. CNAs often have the first opportunity to assess a resident in an LTCF. Jackson and Schafer 41 surveyed 50 CNAs and asked which symptoms or signs of pneumonia warranted notification of the charge nurse. For temperature elevation, cough, and shortness of breath, the response rates were 30%, 24%, and 12%, respectively. These investigators then determined the agreement/disagreement between GNPs (the number is not specified in the paper) and CNAs regarding the presence of infection. There were 110 assessments made among 75 nursing facility residents. In 76 instances (69%), both groups agreed that there was no infection, and in 4% of assessments, both groups agreed that an infection was present. However, in the remaining 27% of assessments, there was disagreement between the GNPs and CNAs about whether infection was present or absent or about the type of infection; CNAs often attributed any symptoms and signs to ''colds,'' even when the GNPs found UTIs, skin infections, and pneumonia. The final diagnoses were not confirmed by a physician. To our knowledge, no studies have compared LPNs, RNs, advance-practice nurses, or physician assistants with physicians or have examined the impact of specific training on the ability of CNAs to correctly identify infections. Several authors suggest the use of specific protocols to assist nurses and GNPs with evaluation of fever, 23,43 but information on the utility of such protocols in LTCF residents has not been published. Thus, at present, the role of CNAs is to recognize and report significant changes in the clinical condition of LTCF residents or abnormalities in vital signs; the role of physician extenders and physicians is to initiate appropriate diagnostic and therapeutic interventions. ## Iv. what clinical evaluation should be performed for an ltcf resident with suspected infection? Recommendation 5. Initial clinical evaluation should involve assessment of respiratory rate, hydration status, mental status, oropharynx, conjunctiva, skin (including sacral, perineum, and perirectal areas), chest, heart, abdomen, and indwelling devices (if present) (B-III). ## Evidence summary No specific studies have addressed the utility of a focused history and physical examination, but a general approach to the clinical evaluation of fever in residents of LTCFs can be suggested on the basis of the most likely sources of infection. [bib_ref] Approach to fever and infection in the nursing home, Yoshikawa [/bib_ref] [bib_ref] Systemic antibiotic use in nursing homes: a quality assessment, Zimmer [/bib_ref] Attention should be directed toward the following: mental status, oropharynx, conjunctiva, skin (including turning the patient to look for pressure ulcers), chest, heart, abdomen, perineum and perirectal area, and CNS. [bib_ref] Approach to fever and infection in the nursing home, Yoshikawa [/bib_ref] Several groups have outlined general guidelines for evaluation of suspected infection, including clinical recommendations. [bib_ref] Definitions of infection for surveillance in long-term care facilities, Mcgeer [/bib_ref] [bib_ref] Consensus conference on nosocomial infections in longterm care facilities, Smith [/bib_ref] [bib_ref] Systemic antibiotic use in nursing homes: a quality assessment, Zimmer [/bib_ref] Although these guidelines have not been validated, they represent a consensus of representatives from various organizations interested in or involved with care of LTCF residents with infection. An English study from the 1980s suggested that a respiratory rate of 425 breaths/min was both sensitive and specific for diagnosis of pneumonia. [bib_ref] Raised respiratory rate in elderly patients: a valuable physical sign, Mcfadden [/bib_ref] In an observational study of 87 English LTCF residents, the normal respiratory rate was 16-25 breaths/min. In a follow-up prospective study of 60 consecutive residents acutely admitted to a geriatric unit, pneumonia was diagnosed in 21 (35%), 19 (90%) of whom had respiratory rates of 425 breaths/min. The respiratory rate of 12 residents with UTIs were not elevated, and of those residents without infection, only 1 of 27 had a respiratory rate of 425 breaths/min. However, in a study of 2,334 residents of 36 Missouri nursing homes who were evaluated for a possible lower RTI, 19% of those with no radiographic evidence of pneumonia had a respiratory rate of 30 breaths/min. [bib_ref] Clinical findings associated with radiographic pneumonia in nursing home residents, Mehr [/bib_ref] Dehydration commonly accompanies fever in elderly residents of LTCFs; this is perhaps a result of impaired vasopressin responses in elderly subjects. [bib_ref] Hypernatremia in the acutely ill elderly patients: role of impaired arginine-vasopressin secretion, Sonnenblick [/bib_ref] [bib_ref] Plasma arginine vasopressin in arginine-vasopressin secretion, Kirkland [/bib_ref] In a study of 40 febrile residents in a hospital-based LTCF, [bib_ref] Dehydration and death during febrile episodes in the nursing home, Weinberg [/bib_ref] [bib_ref] SHEA Long-Term-Care Committee and APIC Guidelines Committee. Infection prevention and control in..., Smith [/bib_ref] (60%) had evidence of hypernatremia and/or an elevated ratio of blood urea nitrogen level to serum creatinine level. Most of the 40 residents had UTI, urosepsis, or pneumonia, but a significant proportion (25%) had an upper respiratory viral syndrome. No single physical finding is of particular value in assessing dehydration, [bib_ref] Dehydration and death during febrile episodes in the nursing home, Weinberg [/bib_ref] [bib_ref] Clinical indicators of dehydration severity in elderly patients, Gross [/bib_ref] although tongue dryness, tongue furrows, and dry mucous membranes provide the best correlation. In one study, [bib_ref] Dehydration and death during febrile episodes in the nursing home, Weinberg [/bib_ref] a reference in the chart by staff regarding poor oral intake was observed in 11 residents, and 9 (82%) were found to be dehydrated according to the laboratory criteria noted above. Thus, LTCF residents with poor oral intake are likely to be at enhanced risk for dehydration in the setting of fever, and this historic clue may indicate a population in whom baseline electrolyte, blood urea nitrogen, and serum creatinine determinations are of particular importance. In addition, medications such as diuretics may lead to dehydration and hence, drug evaluation is important. In LTCF residents, special attention should be noted for specific underlying disorders or conditions that predispose them to select infections, such as diabetes mellitus (a predisposition for skin infection and UTI), chronic obstructive pulmonary disease (for pneumonia), poor swallowing or gag reflex (for aspiration pneumonia), long-term indwelling urinary catheters (for UTI), prosthetic devices (e.g., artificial joints leading to septic arthritis), altered mental status (for aspiration pneumonia), or chronic immobility (for pressure ulcers). For example, the presence of an indwelling bladder catheter is associated with a 39-fold increase in the risk of bacteremia over a 1-year period in residents of LTCFs. [bib_ref] Clinical correlates of bacteremia in a Veterans Administration extended care facility, Rudman [/bib_ref] ## Adequacy of the clinical evaluation of fever in ltcfs Several studies suggest that fever is inadequately evaluated or, at the very least, inadequately documented in residents of LTCFs. In one study, 241 infections were identified among 227 residents in LTCFs in Maryland. [bib_ref] Prevalence and characteristics of nursing home-acquired infections in the aged, Magaziner [/bib_ref] The criteria for all infections included measurement of temperature, examination by a physician, and microbiologic culture of specimens from the suspected sites; a chest radiograph was considered to be appropriate for all those who had pneumonia or were suspected of having pneumonia or for those who had fever without a clear source. On the basis of these criteria, only 21% of residents with infection were ''appropriately'' evaluated. Pneumonia was the most likely infection to be adequately evaluated (53%). When the same records [bib_ref] Prevalence and characteristics of nursing home-acquired infections in the aged, Magaziner [/bib_ref] were reviewed regarding antibiotic use, it was found that RNs and LPNs examined 36% of residents for whom antibiotics were prescribed, that 47% of residents were assessed by physicians, and that the remaining 17% were not examined before the prescription of antibiotics. [bib_ref] Incidence and characteristics of antibiotic use in aged nursing home patients, Warren [/bib_ref] Some of the lack of evaluation and intervention may reflect conscious decisions of the health providers neither to assess nor to treat the more debilitated residents; [bib_ref] Nontreatment of fever in extended-care facilities, Brown [/bib_ref] it is also possible that the standards of evaluation of acute care facilities may influence the criteria and decisions on appropriateness of care of residents in LTCFs. Advance directives may greatly impact the initiation or extent of evaluation in febrile episodes in LTCF residents. It has been reported that evaluation and antibiotic treatment were provided far less often to ''comfort care only'' residents with UTI, RTI, or skin infections. [bib_ref] Treatment decisions for infections occurring in nursing home residents, Mott [/bib_ref] However, some data suggest that there are distinct differences of evaluation based not just on advance directives but also on the type of care facility. None of the procedures (including a physical examination) outlined as ''appropriate'' were performed for 71 (31%) of the 227 patients noted above; 51 however, the definition of ''appropriate'' was based on the opinion of practitioners who more often practice in a hospital setting, and this definition may not be accurate for evaluation of fever in persons in LTCFs. A multivariate analysis of factors contributing to ''no evaluation'' in that study showed that dementia, residing in a larger facility (4150 beds), and residing in an urban facility were significantly associated with an absence of a medical evaluation. It has also been suggested that the type of facility influenced fever evaluation: a quicker response to persons with fever and more thorough assessment and treatment were found in hospital-based nursing homes (where there was more physician involvement) than in community-based nursing homes. [bib_ref] Documentation and evaluation of fevers in hospital-based and communitybased nursing homes, Franson [/bib_ref] However, no difference was noted with regard to outcome in hospital-based versus communitybased homes (survival rates were 87% and 88%, respectively; early mortality rates were 3% and 4%, respectively; and the percentages of patients who were transferred to a hospital were 11% and 8%, respectively). Thus, it is not clear whether evaluation of fever in residents of LTCFs by a physician alters outcome. ## Evidence summary Long-term care staff often need to communicate among themselves and, subsequently, with a clinician (physician, nurse practitioner, or physician assistant) to initiate patient evaluation and management. Clinician access for timely direct patient assessment of fever or other symptoms remains a vexing problem for many LTCFs. Consequently, fever is a common antecedent to the decision to transfer patients to a higher level of care. Although direct care staff often make the initial clinical observations, calls to clinicians are typically made by supervising staff (an LPN or RN), because they are the ones licensed to take physician orders over the telephone. Multiple issues can impede effective communication about a possible infection in a facility or with a clinician, such as failure to communicate a change in condition at a shift change, difficulty contacting an on-call physician after hours, or a difficult relationship between a nurse and a physician. [bib_ref] Barriers to timely care of acute infections in nursing homes: a preliminary..., Longo [/bib_ref] Skills of direct care staff in recognizing symptoms of infection and communicating them to a supervisor may be influenced by experience, education, and language skills (for nonnative speakers). The LPN or RN should independently assess the resident to be certain that key information on the resident's condition is available when the nurse calls the clinician. Clinicians practicing in the LTCF need to participate in setting and reinforcing standards for consistent collection and reporting of clinical information, so that adequate detail is communicated when there are overt or subtle signs suggesting an infection or other acute change in condition. Acute or subacute changes in functional status, such as new urinary incontinence, falls, decreased oral intake, or delirium, may be the initial and/or only clinical manifestation of infection in elderly persons. [bib_ref] A new paradigm for clinical investigation of infectious syndromes in older adults:..., High [/bib_ref] When calling the clinician, certain minimum information should be available to report at the time of the call. In addition to vital signs and acute or subacute changes in functional status, depending on the presenting symptom, a directed review of systems will help with an over-the-phone determination of what needs to be done next. Presence of a urinary catheter or any other indwelling device (e.g., vascular devices) should always be reported, along with whether entry sites are erythematous or tender. Similarly, staff should report breathlessness and cough (or a change in these if chronically present), most recent bowel movement and its character, and any urinary symptoms. Assessment should also include the following: an assessment of respiratory status, including use of accessory muscles, retractions, and quality of breath sounds; presence of bowel sounds; and any wounds or areas of tenderness or redness. Any abnormal vital signs should be repeated. An example of what should be reported for a variety of conditions can be found in the American Medical Directors Association patient evaluation guideline. ## Evidence summary There are several site-specific considerations that must be addressed in making recommendations for diagnostic laboratory and radiologic tests for suspected infections in LTCF residents. Appropriate diagnostic tests for evaluation of fever and infection in LTCF residents have not been established and, when recommended, have not been systematically studied. [bib_ref] Definitions of infection for surveillance in long-term care facilities, Mcgeer [/bib_ref] [bib_ref] Systemic antibiotic use in nursing homes: a quality assessment, Zimmer [/bib_ref] Furthermore, the guidelines from ''expert panels,'' including physicians with experience in LTCFs, are often influenced by diagnostic standards used routinely in acute care settings (e.g., site-specific bacterial cultures for suspected skin infection, UTI, and lower RTIs and urine and blood cultures for fever of unknown source). [bib_ref] Prevalence and characteristics of nursing home-acquired infections in the aged, Magaziner [/bib_ref] [bib_ref] Antimicrobial use in long-term-care facilities, Nicolle [/bib_ref] However, obtaining specimens adequate for microbiologic studies in LTCFs can be problematic. Residents suspected of having an RTI may not be able to produce expectorated sputum. When respiratory secretions are available, they may be misleading, because sputum samples or nasopharyngeal aspirate specimens are often contaminated with respiratory pathogens that colonize the oropharynx. [bib_ref] Factors predisposing to oropharyngeal colonization with gram-negative bacilli in the aged, Valenti [/bib_ref] Although urine specimens are more frequently obtained, the prevalence of asymptomatic bacteriuria is 15%-50% in noncatheterized LTCF residents and is essentially 100% in residents with long-term urinary catheters. [bib_ref] Management of complicated urinary tract infection in older patients, Yoshikawa [/bib_ref] [bib_ref] Urinary tract infections in long-term care facilities, Nicolle [/bib_ref] [bib_ref] A prospective microbiologic study of bacteriuria in patients with chronic indwelling urethral..., Warren [/bib_ref] Thus, some diagnostic tests with poor positive and negative predictive values must be accepted in the evaluation of LTCF residents suspected of having infection. Infectious diseases physicians with considerable experience in LTCFs have noted that clinicians must weigh the benefits of diagnostic tests versus their direct costs. This is especially relevant for LTCFs operating under the current Prospective Payment System. These physicians recommend that tests only be performed if they have a reasonable diagnostic yield, are of low risk, are reasonable in cost, and improve patient management. If a test will not cause the clinician to reassess his or her treatment strategy, then there is little justification for ordering the laboratory examination. [bib_ref] Aging and Clinical Practice Infectious Diseases Diagnosis and Treatment, Yoshikawa [/bib_ref] Others with similar expertise and experience have noted that additional diagnostic tests should be performed only for clinical presentations or manifestations that are unusual or that fail to respond to initial therapy or in circumstances in which prolonged antimicrobial therapy is considered. [bib_ref] Antimicrobial use in nursing homes in Manitoba, Montgomery [/bib_ref] Moreover, explicit plans (or as implied by directives to limit interventions) to not perform or to limit diagnostic studies in severely debilitated or ill residents with poor survival prognosis shall always be considered to be appropriate, unless a risk is posed to other residents and staff. [bib_ref] Treatment decisions for infections occurring in nursing home residents, Mott [/bib_ref] Blood Cell Count Recommendations 9. A CBC count, including peripheral WBC and differential cell counts (preferably a manual differential to assess bands and other immature forms), should be performed for all LTCF residents who are suspected of having infection within 12-24 h of onset of symptoms (or sooner, if the resident is seriously ill), consistent with local standards of practice (B-II). 10. The presence of an elevated WBC count (WBC count, 14,000 cells/mm 3 ) or a left shift (percentage of band neutrophils or metamyelocytes, 46%; or total band neutrophil count, 1,500 cells/mm 3 ) warrants a careful assessment for bacterial infection in any LTCF resident with suspected infection, with or without fever (B-II). 11. In the absence of fever, leukocytosis and/or left shift, or specific clinical manifestations of a focal infection, additional diagnostic tests may not be indicated, because of the low potential yield (C-III). Nonbacterial infections, however, cannot be excluded. ## Evidence summary Suspected Symptomatic Infection in LTCF Residents. Provided that there are no prior directives (in advance or currently expressed by the resident or caregiver) limiting diagnostic or therapeutic medical interventions, all residents in LTCFs with suspected symptomatic infection should have appropriate diagnostic laboratory studies performed promptly, provided that the tests have reasonable yield, are of low cost and risk, and may improve the resident/patient management. Findings should be discussed with the primary care clinician as soon as results are available. CBC Count with Differential. In a prospective cohort analytic study of 4200 older persons who presented to a community-based hospital emergency department, 33 persons had documented bacterial infection, including 50% of persons with no fever. [bib_ref] Utility of fever, white blood cells, and differential count in predicting bacterial..., Wasserman [/bib_ref] Evaluation of the total WBC count (with leukocytosis defined as a leukocyte count 14,000 cells/mm 3 ), number of band forms, and the percentage of neutrophils and band forms revealed that an elevated total band count ( 1,500 cells/mm 3 ) had the highest likelihood ratio (14.5) for detecting documented bacterial infection; an increase in the percentage of neutrophils ( 90%) and band neutrophils (46%; i.e., left shift) had likelihood ratios of 7.5 and 4.7, respectively. Leukocytosis with a leukocyte count 14,000 cells/mm 3 had a likelihood ratio of 3.7. Thus, this study and others [bib_ref] A simple index to identify occult bacterial infection in adults with acute..., Mellors [/bib_ref] [bib_ref] Afebrile bacteremia: a phenomenon in geriatric patients, Gleckman [/bib_ref] demonstrate that there is a high probability of an underlying bacterial infection in an older person if the WBC count is elevated, with or without fever; has a high percentage of neutrophils or left shift (even in the presence of a normal total leukocyte countFi.e., o10,000 cells/mm 3 ); or shows an elevated total band count. In observational studies, leukocytosis has been associated with increased mortality among LTCF residents with nursing home-acquired pneumonia (WBC count, 415,000 cells/mm 3 ) and bloodstream infection (WBC count, 420,000 cells/mm 3 ). [bib_ref] Does hospitalization impact survival after lower respiratory infection in nursing home residents?, Kruse [/bib_ref] [bib_ref] Epidemiology of bloodstream infection in nursing home residents: evaluation in a large..., Mylotte [/bib_ref] Urinalysis and Urine Culture Recommendations 12. Urinalysis and urine cultures should not be performed for asymptomatic residents (A-I). 13. In noncatheterized residents, the diagnostic laboratory evaluation of suspected UTI should be reserved for those with acute onset of UTI-associated symptoms and signs (e.g., fever, dysuria, gross hematuria, new or worsening urinary incontinence, and/or suspected bacteremia) (A-II). 14. In residents with long-term indwelling urethral catheters, evaluation is indicated if there is suspected urosepsis (i.e., fever, shaking chills, hypotension, or delirium), especially in the context of recent catheter obstruction or change (A-II). 15. Appropriately collected urine specimens include a midstream or clean-catch specimen obtained from elderly men who are cooperative and functionally capable; however, it is often necessary to use a freshly applied, clean condom external collection system, with frequent monitoring of the urine bag (B-II). Specimen collection from women will often require an in-and-out catheterization (B-III). 16. Residents with long-term indwelling urethral catheters and suspected urosepsis should have catheters changed prior to specimen collection and institution of antibiotic therapy (A-II). 17. The minimum laboratory evaluation for suspected UTI should include urinalysis for determination of leukocyte esterase and nitrite level by use of a dipstick and a microscopic examination for WBCs (B-II). If pyuria (410 WBCs/high-power field) or a positive leukocyte esterase or nitrite test is present on dipstick, only then should a urine culture (with antimicrobial susceptibility testing) be ordered (B-III). 18. If urosepsis is suspected, urine and paired blood specimens should be obtained, if feasible, for culture and antimicrobial susceptibility testing, and a Gram stain of uncentrifuged urine should be requested (B-III). ## Evidence summary Symptomatic UTI in LTCF residents may present as fever and clinical pyelonephritis or as irritative symptoms (e.g., dysuria, frequency, urgency, nocturia, and increased incontinence). [bib_ref] Urinary tract infection in long-term-care facility residents, Nicolle [/bib_ref] [bib_ref] Urinary tract infections in long-term care facilities, Nicolle [/bib_ref] The evaluation of these symptoms and signs is difficult, because they are frequently observed in residents and are not necessarily associated with bacteriuria (410 5 cfu/mL) or altered with antimicrobial therapy. [bib_ref] Lack of association between bacteriuria and symptoms in the elderly, Boscia [/bib_ref] The majority of elderly persons with bacteriuria are asymptomatic. [bib_ref] Urinary tract infection in long-term-care facility residents, Nicolle [/bib_ref] [bib_ref] Urinary tract infections in long-term care facilities, Nicolle [/bib_ref] [bib_ref] Infectious Diseases Society of America guidelines for the diagnosis and treatment of..., Nicolle [/bib_ref] Moreover, residents are often treated for UTIs when nonspecific symptoms, including low-grade fever, increased confusion, incontinence, anorexia, or functional decline, are noted, but limited studies suggest that these symptoms may not be associated with UTIs. [bib_ref] The atypical presentation of infection in old age, Berman [/bib_ref] Residents who are suspected of harboring an infection will often undergo urinalysis and urine culture as part of the evaluation to determine the cause of infection. These tests, however, frequently demonstrate bacteria because of the noted high prevalence (10%-50%) of asymptomatic bacteriuria. [bib_ref] Management of complicated urinary tract infection in older patients, Yoshikawa [/bib_ref] [bib_ref] Urinary tract infections in long-term care facilities, Nicolle [/bib_ref] Prospective studies have shown that untreated asymptomatic bacteriuria in LTCF residents without longterm indwelling urinary catheters persist for as long as 1-2 years without evidence of increased morbidity or mortality. [bib_ref] Bacteriuria in elderly institutionalized men, Nicolle [/bib_ref] [bib_ref] Prospective randomized comparison of therapy and no therapy for asymptomatic bacteriuria in..., Nicolle [/bib_ref] Microscopic pyuria ( 10 WBCs/high-power field of spun urine) or a dipstick test positive for leukocyte esterase are not highly predictive of bacteriuria, but the absence of pyuria or even a dipstick test negative for leukocyte esterase and nitrite can exclude bacteriuria (i.e., the negative predictive value approaches 100%). [bib_ref] Pyuria: its predictive value of asymptomatic bacteriuria in ambulatory elderly men, Norman [/bib_ref] [bib_ref] Epidemiologic and diagnostic aspects of bacteriuria: a longitudinal study in older women, Monane [/bib_ref] [bib_ref] Role of dipstick testing in the evaluation of urinary tract infection in..., Juthani-Mehta [/bib_ref] [bib_ref] Diagnostic accuracy of criteria for urinary tract infection in a cohort of..., Juthani-Mehta [/bib_ref] In persons with neutropenia or, on rare occasions, with a normal peripheral WBC count, significant bacteriuria may occur without pyuria. Thus, although the presence of pyuria has a relatively low predictive value for UTI, both a negative urinalysis for WBCs and dipstick tests for leukocyte esterase and nitrite are useful to exclude a urinary source for a suspected infection. However, in residents suspected of having urosepsis because of, for example, high fever, shaking chills, and hypotension, urine culture is recommended along with blood culture. For residents with new indwelling urinary catheters, catheter-associated UTI, defined as new pyuria and bacteriuria, develops on average within 4 days and are rarely symptomatic. [bib_ref] Catheter-associated urinary tract infection is rarely symptomatic: a prospective study of 1,497..., Tambyah [/bib_ref] In residents with chronic indwelling urinary catheters, the presence of bacteriuria and pyuria is virtually universal. For residents with long-term indwelling urethral catheters, fever, and symptomatic UTI, a prospective randomized trial of 54 nursing home residents demonstrated that replacement of the catheter prior to the institution of antimicrobial therapy was associated with improved clinical outcomes. [bib_ref] Chronic indwelling catheter replacement before antimicrobial therapy for symptomatic urinary tract infection, Raz [/bib_ref] Frail elderly LTCF residents are often unable to provide a midstream voided urine specimen for diagnostic testing. For men, it is frequently necessary to apply a clean condom external collection device. However, this validated method for urine collection requires carefully trained personnel and frequent monitoring of the urine bag. [bib_ref] An accurate method to obtain urine for culture in men with external..., Ouslander [/bib_ref] If appropriately collected voided urine cannot be obtained from women, in-and-out catheterization should be used to obtain urine specimens for culture. [bib_ref] Urinary tract infections in long-term care facilities, Nicolle [/bib_ref] The benefit of antimicrobial or antiseptic coated catheters in LTCF residents has not been directly assessed. ## Blood culture recommendation ## In a study of older adult nursing home residents, blood cultures were demonstrated to have a low yield and rarely to influence therapy; thus, they are not recommended for most residents of LTCFs (B-II) (note: this may not apply to all types of residents or all types of LTCFs). Blood cultures may be appropriate for residents in whom bacteremia is highly suspected and if the LTCF has quick access to laboratory facilities, adequate physician coverage to respond to positive culture results, and a capacity to administer parenteral antibiotics. ## Evidence summary Bacteremia is documented infrequently in LTCFs, with an incidence of 5-40 episodes per 100,000 resident-days; 82 the proportion of infections complicated by secondary bacteremia in this setting is 6%. [bib_ref] Bacteremia in a 170 longterm-care facility: a five-year prospective study of 163..., Muder [/bib_ref] These rates were documented primarily in large LTCFs (often associated with Veterans Affairs medical centers) with full-time medical staff and 24-h on-site physician coverage; there are no comparable studies reported from the more representative smaller proprietary or the not-for-profit community-based LTCFs. As expected, the most frequent sites of infection with LTCF-acquired bacteremias are as follows: the urinary tract (50%-55%), the respiratory tract (10%-11%), skin or soft tissue (10%), intra-abdominal foci (5%), infected intravenous catheters (3%), and unknown site (15%-22%). [bib_ref] Bacteremia in a 170 longterm-care facility: a five-year prospective study of 163..., Muder [/bib_ref] The overall mortality rates associated with bacteremia in LTCF residents range from 18% to 50%; the highest rates are for patients with bacteremic pneumonia. [bib_ref] Epidemiology of bloodstream infection in nursing home residents: evaluation in a large..., Mylotte [/bib_ref] [bib_ref] Bacteremia in a 170 longterm-care facility: a five-year prospective study of 163..., Muder [/bib_ref] [bib_ref] Bacteremia in a long-term care facility: spectrum and mortality, Setia [/bib_ref] Despite appropriate therapy, 50% of deaths occur within 24 h after the diagnosis of bacteremia. [bib_ref] Bacteremia in a 170 longterm-care facility: a five-year prospective study of 163..., Muder [/bib_ref] In retrospective studies, nonspecific symptoms, such as lethargy, confusion, falls, abdominal pain, nausea, vomiting, and incontinence, are frequently noted in older persons at the onset of documented bacteremia. [bib_ref] Bacteremia in the elderly, Richardson [/bib_ref] Fever ( 1001F [ 37.81C]) is usually present in bacteremic older persons; in 1 series, however, 15% of older persons had ''afebrile'' bacteremia, including many of the nosocomial bacteremias for which they were already receiving antimicrobial therapy. [bib_ref] Afebrile bacteremia: a phenomenon in geriatric patients, Gleckman [/bib_ref] In a prospective study, older patients in a geriatric hospital had predictors of bacteremia, with higher relative risks (3.4-15.7) than was noted for nonbacteremic older patients. These predictors were: fever (temperature, 4101.31F [4381C]), in community-acquired cases only; bladder catheter removal, in hospital-acquired cases only; and shaking chills, shock, total band neutrophil count 1,500 cells/mm 3 , and lymphocyte count o1,000 cells/ mm 3 in both groups. [bib_ref] Predicting bacteremia in older patients, Pfitzenmeyer [/bib_ref] A prospective observational study of elderly adults (3% of whom were from LTCFs; C. L. Chen, personal communication) with bloodstream infection found that, although the elderly persons were less likely to present with fever or tachycardia, they were more likely to have acute renal failure or respiratory failure, compared with younger adults (age, o65 years). [bib_ref] Comparison of clinical manifestations and outcome of community-acquired bloodstream infections among the..., Lee [/bib_ref] Other studies, using case-control methods in hospital and emergency department settings, however, have also noted that older bacteremic patients have fewer symptoms or signs than do younger bacteremic patients and that clinical indicators alone are unreliable predictors of bacteremia in older patients. [bib_ref] Is presentation of bacteremia in the elderly the same as in younger..., Chassagne [/bib_ref] [bib_ref] Difficulty in predicting bacteremia in elderly emergency patients, Fontanarosa [/bib_ref] In a retrospective study of 166 cases of nursing home-acquired bloodstream infection among patients who were subsequently hospitalized, predictors of mortality were pulmonary source of infection, hypotension, and leukocytosis (leukocyte count, 420,000 cells/mm 3 ). [bib_ref] Nursing home-acquired bloodstream infection, Mylotte [/bib_ref] Blood cultures could potentially be helpful in establishing a definitive microbiologic diagnosis in LTCF residents with selected conditions, such as (1) suspected polymicrobial bacteremia in older residents with probable urosepsis and long-term indwelling urethral catheters or in those with infected pressure ulcers, [bib_ref] Antimicrobial use in long-term-care facilities, Nicolle [/bib_ref] (2) suspected urosepsis when polymicrobial bacteriuria is present, 59 or (3) suspected pneumonia (or other suspected bacterial infections) when the resident appears ill enough to warrant hospitalization but will be cared for in the LTCF. [bib_ref] Silent'' pyrexia in the elderly, Downton [/bib_ref] Blood samples should be obtained for cultures prior to transfer to an acute care facility, if feasible. Although obtaining blood samples for culture within 24 h after presentation has been associated with improved 30-day survival in communityacquired pneumonia, [bib_ref] Nursing home-acquired bloodstream infection, Mylotte [/bib_ref] there are no comparable studies in LTCFs. However, because of the high mortality rates within 24 h after onset and because 50% of deaths among nursing home residents with positive blood culture results occur within the first 3 days after onset, it is doubtful that blood cultures would significantly impact mortality risk for most nursing home residents, and they would provide little opportunity for starting or adjusting effective antimicrobial therapy. [bib_ref] Epidemiology of bloodstream infection in nursing home residents: evaluation in a large..., Mylotte [/bib_ref] [bib_ref] Influence of blood culture results on antibiotic choice in the treatment of..., Arbo [/bib_ref] Blood cultures may be appropriate if the LTCF has quick access to laboratory facilities, adequate physician coverage to respond to positive culture results, and capacity to administer parenteral antibiotics. ## Pneumonia evaluation If pneumonia is clinically suspected and resources are available, the following diagnostic studies should be performed. Recommendations 20. Pulse oximetry should be performed for residents with respiratory rates of 425 breaths/min, to document hypoxemia (oxygen saturation, o90%) in residents with suspected pneumonia and to guide transfer to an acute care facility pending the resident's or family's wishes (B-II). 21. Chest radiography should be performed if hypoxemia is documented or suspected, to identify the presence of a new infiltrate compatible with acute pneumonia and to exclude other complicating conditions (e.g., multilobe infiltrates, large pleural effusions, congestive heart failure, or mass lesions) (B-II). ## Evidence summary Pulse Oximetry. Hypoxemia (arterial oxygen partial pressure, o60 mmHg) is one of the important indicators in the Pneumonia Prognosis Index of acute severity and shortterm mortality for patients with community-acquired pneumonia, which included residents with LTCF-acquired pneumonia. [bib_ref] A prediction rule to identify low-risk patients with community-acquired pneumonia, Fine [/bib_ref] This index has been further validated in nursing home populations. [bib_ref] Validation and application of the pneumonia prognosis index to nursing home residents..., Mylotte [/bib_ref] In a prospective cohort study of risk factors for 30-day mortality in nursing home residents with lower RTI, oxygen saturation of o90% was associated with higher mortality rate in bivariable analysis but was not part of a multivariate prediction model. However, the oxygen saturation value was missing in the majority of cases evaluated; this may have affected its significance in a multivariate model. [bib_ref] Clinical findings associated with radiographic pneumonia in nursing home residents, Mehr [/bib_ref] More recently, oxygen saturation of o90% was a strong predictor of hospitalization but was not significantly associated with mortality in a nested cohort study of nursing home pneumonia in residents of nine Ontario, Canada, nursing homes. [bib_ref] Pneumonia and lower respiratory infections in nursing home residents: predictors of hospitalization..., Carusone [/bib_ref] Hypoxemia is a predictor of impending respiratory failure requiring intensive care unit admission. [bib_ref] Community-acquired pneumonia, Bartlett [/bib_ref] Impending respiratory failure can be suspected at the bedside if the patient has a respiratory rate of 425 breaths/min, and it can be confirmed by an oxygen saturation of o90% on pulse oximetry, as advised in the recent modification and validation study of the Pneumonia Prognosis Index in nursing home residents. [bib_ref] Validation and application of the pneumonia prognosis index to nursing home residents..., Mylotte [/bib_ref] Finally, in febrile nursing home residents, pulse oximetry may also assist in differentiating pneumonia from other infectious processes. A case-control study comparing nursing home residents with pneumonia versus residents with other infections found that an oxygen saturation of o94% had a sensitivity of 80%, specificity of 91%, and positive predictive value of 95% for diagnosis of pneumonia. [bib_ref] Utility of pulse oximetry in diagnosing pneumonia in nursing home residents, Kaye [/bib_ref] Chest Radiographs. An abnormal chest radiograph demonstrating a new infiltrate compatible with pneumonia is often considered to be the most reliable method of diagnosing suspected LTCF-acquired pneumonia. [bib_ref] Nursing home-acquired pneumonia, Medina-Walpole [/bib_ref] [bib_ref] Definitions of infection for surveillance in long-term care facilities, Mcgeer [/bib_ref] [bib_ref] Nursing home-acquired pneumonia: a casecontrol study, Marrie [/bib_ref] [bib_ref] Systemic antibiotic use in nursing homes: a quality assessment, Zimmer [/bib_ref] [bib_ref] Prevalence and characteristics of nursing home-acquired infections in the aged, Magaziner [/bib_ref] More recently, radiographic diagnosis of pneumonia in nursing homes was associated with both death and hospitalization. [bib_ref] Pneumonia and lower respiratory infections in nursing home residents: predictors of hospitalization..., Carusone [/bib_ref] However, practice patterns in LTCFs show considerable variability with respect to performing chest radiographs, ranging from 20% to 35% in communitybased nursing facilities [bib_ref] Systemic antibiotic use in nursing homes: a quality assessment, Zimmer [/bib_ref] [bib_ref] Prevalence and characteristics of nursing home-acquired infections in the aged, Magaziner [/bib_ref] [bib_ref] Aging and Clinical Practice Infectious Diseases Diagnosis and Treatment, Yoshikawa [/bib_ref] to as high as 85% in university medical center-affiliated nursing facilities. [bib_ref] Provider practice patterns in nursing home-acquired pneumonia, Medina-Walpole [/bib_ref] Although most LTCFs have contract services to provide chest radiography, several problems remain, including (1) the inability of frail older persons to maintain a stationary, upright sitting position; (2) the relatively poor quality of portable radiography techniques (compared with standard techniques using the posterior-to-anterior projection); and (3) a lack of availability of previous films for comparison. Despite these concerns, evidence of acute pneumonia is present on 75%-90% of chest radiographs obtained for residents with suspected LTCF-acquired pneumonia. [bib_ref] Systemic antibiotic use in nursing homes: a quality assessment, Zimmer [/bib_ref] [bib_ref] Provider practice patterns in nursing home-acquired pneumonia, Medina-Walpole [/bib_ref] However, there are no prospective trials evaluating the impact of chest radiography on outcomes of LTCF-acquired pneumonia. The clinical diagnosis of pneumonia can be exceedingly difficult. [bib_ref] Diagnosing pneumonia by physical examination: relevant or relic?, Wipf [/bib_ref] Excluding bacteremia from all sources, pneumonia is the only infection that is an important contributor to mortality for residents in LTCFs; 82 thus, it is important to document this serious condition by chest radiography whenever possible. Moreover, the chest radiograph may demonstrate other high-risk conditions (e.g., multilobe infiltrate, congestive heart failure, large pleural effusions, and mass lesions) that should warrant considering for transfer to an acute care facility, depending on the wishes of the resident or their family or caregiver. Respiratory Secretions. The diagnosis of suspected pneumonia in LTCF residents is usually based on clinical criteria alone (e.g., fever, tachypnea [425 breaths/min], and new or increased cough with purulent respiratory secretions). [bib_ref] Approach to fever and infection in the nursing home, Yoshikawa [/bib_ref] Retrospective studies of nursing-facility practices indicate that sputum examinations are ordered for only 5%-10% of residents with the diagnosis of pneumonia. [bib_ref] Prevalence and characteristics of nursing home-acquired infections in the aged, Magaziner [/bib_ref] [bib_ref] Provider practice patterns in nursing home-acquired pneumonia, Medina-Walpole [/bib_ref] Even in carefully performed prospective studies of radiographically confirmed LTCF-acquired pneumonias, using recommended methods for screening prior to culture of expectorated sputum, sputum samples are obtained from o30% of residents; 28 when sputum is obtained, o50% of specimens demonstrate o25 squamous epithelial cells/lowpower field on microscopic examination of Gram-stained specimens. [bib_ref] Microscopic and bacteriological comparison of paired sputa and transtracheal aspirates, Geckler [/bib_ref] In addition, the single-most frequent causative agent ( 35%) is ''mixed flora'' (i.e., 2 respiratory pathogens or normal throat flora only). [bib_ref] Pneumococcal vaccine in the institutionalized elderly: design of a nonrandomized trial and..., Bentley [/bib_ref] No prospective studies have been done to determine whether a more rigorous microbiologic study of respiratory secretions will lead to improved outcomes (i.e., cure, a reduced number hospital transfers, or a patient still alive 30 days after diagnosis of pneumonia). In a retrospective study of 99 nursing home-acquired pneumonias in a single large nursing home with on-site bacteriology testing facilities, only 14 adequate sputum samples were obtained. Although the overall 30day mortality rate for the cohort was 10%, none of the residents from whom a sputum sample was obtained died within 30 days, suggesting that the ability to obtain sputum may actually be a marker for better outcomes or higher functional status. [bib_ref] Sputum bacteriology in nursing home pneumonia: a retrospective study, Gauerke [/bib_ref] Urinary Antigen Testing. There are few specific data on LTCF residents regarding the performance characteris-tics of urinary antigen testing to detect Streptococcus pneumoniae or Legionella pneumophila (serogroup I), the 2 pathogens for which U.S. Food and Drug Administrationapproved test kits are available. Thus, specific recommendations cannot be provided. However, the tests may be useful in LTCF residents in selected circumstances, particularly if sputum specimens cannot be obtained. Older adults have been included in studies of hospitalized patients with pneumonia. The sensitivity of urinary antigen testing for S. pneumoniae in those studies was 75%, whereas the specificity approached 90%. Performance characteristics are similar for L. pneumophila, but it is important to recognize that only serogroup I is detected by this test, and the sensitivity may be lower for nosocomial legionellosis (and, by implication, perhaps also in LTCF residents), even when illness is caused by serogroup I. [bib_ref] Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management..., Mandell [/bib_ref] Several studies have examined the utility of Legionella urinary antigen tests in outbreak settings and for diagnosis of legionellosis in regions where it is highly endemic (e.g., western Pennsylvania). The proportion of LTCF-associated cases of pneumonia caused by L. pneumophila ranged from 0% to 6.5%; thus, the organism is relatively rare even in areas in which community-acquired legionellosis is common. It is likely that Legionella urinary antigen testing would prove to be most useful in LTCF outbreaks of pneumonia due to unclear etiology. [bib_ref] Legionnaires' disease in longterm care facilities: overview and proposed solutions, Seenivasan [/bib_ref] ## Respiratory viral infection evaluation recommendation ## At the onset of a suspected respiratory viral infection outbreak, nasopharyngeal wash or swab samples obtained from the throat and nasopharynx (combined with refrigerated viral transport media in a single tube) should be obtained from several acutely ill residents for transport to an experienced laboratory for virus isolation and rapid diagnostic testing for influenza A virus and other common viruses (A-III). ## Evidence summary Influenza is the most serious viral respiratory infection for older persons; clusters or outbreaks of influenza occur frequently in LTCFs, with attack rates ranging from 20% to 70%. During outbreaks, complication rates among unvaccinated residents of LTCFs are substantial, approaching 32% (range, 5-84%); 7% (range, 5%-42%) pneumonia, including pneumonia due to methicillin-resistant S. aureus; 4% (range, 3%-26%) hospitalization; and 4% (range, 0%-73%) death. [bib_ref] Long-Term-Care Committee of the Society for Healthcare Epidemiology of America. Prevention of..., Bradley [/bib_ref] Recent studies suggest that the consequences of respiratory syncytial virus infection are just as severe in older populations. [bib_ref] Respiratory syncytial virus infection in elderly and high-risk adults, Falsey [/bib_ref] [bib_ref] Winter respiratory viruses and health care use: a population-based study in the..., Neuzil [/bib_ref] [bib_ref] Mortality associated with influenza and respiratory syncytial virus in the United States, Thompson [/bib_ref] The diagnosis of influenza and respiratory syncytial virus infection is frequently made on the basis of clinical and epidemiologic findings during a community outbreak. However, additional diagnostic efforts are warranted in LTCF outbreaks, because of the increased frequency of other respiratory viruses that can cause severe illness in this setting (e.g., parainfluenza virus, metapneumovirus, coronaviruses, and rhinoviruses). [bib_ref] Mortality associated with influenza and respiratory syncytial virus in the United States, Thompson [/bib_ref] [bib_ref] Viral pneumonia in older adults, Falsey [/bib_ref] Of all the respiratory viruses mentioned, influenza virus is the most easily detected. In frail elderly patients, spec-imens for viral isolation by culture are best obtained by nasopharyngeal swab, because it is simpler to perform, with acceptable sensitivity, compared with nasopharyngeal wash. [bib_ref] Viral pneumonia in older adults, Falsey [/bib_ref] [bib_ref] Infection management for geriatrics in longterm care facilities, Dumyati [/bib_ref] The swabs are combined in a single refrigerated tube containing viral transport media and are transported (preferably on ice and within 1-2 h after collection) to an experienced laboratory for viral culture and rapid diagnostic testing. [bib_ref] Viral pneumonia in older adults, Falsey [/bib_ref] However, not all LTCFs will find it feasible to obtain and transfer the specimens. Of all the respiratory viruses mentioned, influenza is the most readily isolated by culture technique, particularly if the specimen is obtained within 24-48 h after onset of clinical illness. [bib_ref] Viral pneumonia in older adults, Falsey [/bib_ref] In general, rapid antigen testing for respiratory viruses in adults has been insensitive. For influenza, the sensitivity of rapid antigen tests has ranged from 40% to 80%, with specificity of 85%. [bib_ref] Viral pneumonia in older adults, Falsey [/bib_ref] [bib_ref] Infection management for geriatrics in longterm care facilities, Dumyati [/bib_ref] However, confirmation of influenza in LTCFs by rapid testing assisted with decisions about isolation and initiation of antiviral prophylaxis, with significant reductions in duration of the outbreak and hospitalization costs. [bib_ref] Clinical and economic evaluation of rapid influenza a virus testing in nursing..., Church [/bib_ref] Very sensitive and specific RT-PCR tests for multiple respiratory viruses are available but expensive. [bib_ref] Viral pneumonia in older adults, Falsey [/bib_ref] [bib_ref] Infection management for geriatrics in longterm care facilities, Dumyati [/bib_ref] Evaluation of SSTI Recommendations 23. Bacterial cultures should be performed only under select conditions. Surface swab cultures are not indicated for the diagnosis of most bacterial SSTIs (A-II), with the exception of conjunctivitis (B-III). Needle aspiration (only skilled physicians should perform this procedure) or deep-tissue biopsy to obtain samples for Gram stain and culture may be appropriate in special circumstances in which unusual pathogens are suspected, fluctuant areas suggest an abscess is present, or initial antimicrobial treatment has been unsuccessful (C-III). 24. If a pressure ulcer demonstrates poor healing and/or persistent purulent drainage, obtain deep specimens for culture of tissue and bone specimens at the time of surgical debridement or biopsy (B-II). MRI is the most sensitive imaging modality to detect osteomyelitis, but bone biopsy for histopathologic examination definitively confirms the diagnosis and is most useful in guiding antimicrobial therapy (A-III Evidence Summary SSTI is the third most common infection seen in LTCFs; rates of 1%-9% and a prevalence of 0.9-2.1 cases per 1,000 patient-days have been reported. [bib_ref] Infection control in long-term care facilities, Nicolle [/bib_ref] SSTI typically results when breaks in skin or mucosa occur as a consequence of physical trauma, maceration, pressure, or use of devices. Wounds may become secondarily infected with pathogens found among the resident's own endogenous flora or exogenously via the hands of personnel, from other residents, or by contact with contaminated environment or fomites. Although bacteria are the most common causes of SSTI in LTCF residents, viruses, fungi, and parasites must also be considered. The 3 most common types of SSTI in LTCF residents include cellulitis, infected pressure ulcer, and scabies. Primary infections of skin and mucosa, reactivation of latent herpetic infection, ectoparasitic infection, and secondary infection of pressure ulcers also occur. Primary SSTI. The primary SSTIs seen in LTCF residents include erysipelas, cellulitis, folliculitis, and impetigo. Primary infections of deep soft tissue involving fascia and muscle rarely occur and typically do so as part of an outbreak. Common bacterial etiologies of primary SSTI include S. aureus and beta-bhemolytic streptococci, especially Streptococcus pyogenes. Diagnosis and treatment decisions are made primarily on the basis of clinical characteristics. When the presentation is atypical or the patient is not responding to empirical therapy, Gram stain and culture of pus, blister fluid, or deep-tissue specimens can be useful to confirm a bacterial cause and antimicrobial susceptibilities. [bib_ref] Drug treatment of skin and soft tissue infections in elderly long-term care..., Lertzman [/bib_ref] [bib_ref] Infection management for geriatrics in long-term care facilities, Schmader [/bib_ref] Secondary SSTI. Twenty percent of nursing home residents will develop secondary infection of a pressure ulcer within 2 years after admission; 6% of those ulcers will become infected, at a rate of 1.4 infections per 1,000 resident-days. [bib_ref] Infected pressure ulcers in elderly individuals, Livesley [/bib_ref] Infection of pressure ulcers is diagnosed primarily by clinical symptoms and signs. These local findings may range from nonhealing to overt presence of surrounding erythema, warmth, tenderness, and purulent discharge to presence of necrotic tissue and even crepitus. [bib_ref] Infected pressure ulcers in elderly individuals, Livesley [/bib_ref] [bib_ref] Infected pressure ulcers in the longterm-care facility, Smith [/bib_ref] [bib_ref] Infection management for geriatrics in long-term care facilities, Reynolds [/bib_ref] Signs of systemic inflammation, such as fever and leukocytosis, may be absent. SuggestedFalthough unval-idatedFcriteria for diagnosis of infected pressure ulcer include presence of purulent discharge plus 4 of the following characteristics: fever (temperature, 381C), worsening mental or functional status, warmth, redness, swelling, localized tenderness/pain, or serous drainage. The surfaces of pressure ulcers are always colonized with bacteria; thus, cultures of specimens obtained from superficial swabs cannot differentiate between colonization and infection. The utility of fine-needle aspiration and deeptissue biopsy has been debated. Irrigation with saline and massage of the area followed by needle aspiration have been found to be very sensitive and specific in some studies; however, aspirates of clinically uninfected ulcers yield bacteria in 30% of instances. Correlations between swabs, aspiration, and deep-tissue biopsy specimen culture results have been poor. In general, deeper specimens are preferred for culture; however, positive culture results must be interpreted in conjunction with clinical and laboratory evidence that infection is present. Although a positive probe-to-bone test result has been shown to be predictive of osteomyelitis in patients with diabetes mellitus and lowerextremity ulcers, in pressure ulcers, the presence of exposed bone and of positive swab culture results is not diagnostic of osteomyelitis. Unfortunately, confirmation of osteomyelitis in pressure ulcers with exposed bone using histopathology, the gold standard for the diagnosis, yields positive results in only o20% of cases, perhaps because of sampling error. Imaging may also provide supporting evidence that osteomyelitis is present; MRI is the most sensitive (98%) and specific (89%) diagnostic method. [bib_ref] Infected pressure ulcers in elderly individuals, Livesley [/bib_ref] [bib_ref] Infected pressure ulcers in the longterm-care facility, Smith [/bib_ref] [bib_ref] Infection management for geriatrics in long-term care facilities, Reynolds [/bib_ref] Most pressure ulcer infections are polymicrobial; aerobic gram-negative bacilli (e.g., E. coli, Proteus species, and Pseudomonas species), gram-positive cocci (e.g., streptococci and staphylococci), and anaerobic flora (e.g., bacteroides, peptostreptococci, and Clostridium perfringens) are found most commonly. Although blood cultures are not generally recommended for evaluation in nursing home-acquired infection, the presence of polymicrobial infection may provide supporting evidence that an infected pressure ulcer is the source. [bib_ref] Infected pressure ulcers in elderly individuals, Livesley [/bib_ref] [bib_ref] Infected pressure ulcers in the longterm-care facility, Smith [/bib_ref] [bib_ref] Infection management for geriatrics in long-term care facilities, Reynolds [/bib_ref] Most evaluations for acute osteomyelitis should be done in the acute care setting. Conjunctivitis. Conjunctivitis is another common SSTI that occurs in 0.3% to 3.4% of LTCF residents or at a rate of 0.1-1.0 cases per 1,000 resident-days. [bib_ref] Conjunctivitis in a long-term care facility, Boustcha [/bib_ref] Conjunctivitis is primarily defined as the presence of purulent exudate or new or worsening redness in 1 or both eyes for at least 24 h; allergy and trauma should be excluded. Ideally, treatment should be based on Gram stain results, culture results, and antibiotic susceptibilities of purulent discharge specimens obtained from the conjunctival sac. A cause may be established in o40% of cases; most are due to S. aureus, Moraxella catarrhalis, Haemophilus species, epidemic strains of S. pyogenes, and, during outbreaks, adenovirus infection. Thus, therapy is often empirical, and close follow-up should be conducted for treatment failure. Mucocutaneous Fungal Infection. SSTI may also result from the overgrowth of endogenous resident fungi in moist macerated skin and in association with use of antimicrobials and corticosteroids; infection with Candida spe-ciesFtypically Candida albicansFand dermatophytes may result. In one study, 84% of LTCF residents were colonized with yeast. [bib_ref] Risk factors for colonization with yeast species in a Veterans Affairs long-term..., Hedderwick [/bib_ref] Mucocutaneuous candidiasis may present as thrush, denture stomatitis, chelitis, paronychia, and intertrigo. Dermatophyte infection may manifest as tinea corporis, tinea pedis, tinea cruris, and tinea ungium (onychomycosis). Microscopic examination of scrapings following digestion with 10% potassium hydroxide can confirm the presence of Candida species or dermatophytes. [bib_ref] Infection management for geriatrics in long-term care facilities, Kauffman [/bib_ref] If candidal infection fails to respond to empirical treatment, cultures and speciation of yeast should be performed. Azole-resistant Candida glabrata has been isolated with greater frequency from older adults with systemic fungal infection than from young adults, [bib_ref] Fungal infections in older adults, Kauffman [/bib_ref] but there are no data for cutaneous disease. Mucocutaneous Viral Infection. Reactivation of latent viral infection occurs with increasing age and waning immunity; 10,500-16,500 cases of herpes zoster occur in LTCF residents each year. [bib_ref] Infection management for geriatrics in long-term care facilities, Schmader [/bib_ref] Herpes simplex virus infections typically present as vesicles or ulcerations involving nasolabial, genital, or rectal skin or mucosa. Reactivation of zoster presents as a painful vesicular rash typically in a dermatomal distribution. Presence of giant cells on Tzanck smear is diagnostic for herpes virus infection, and speciation between simplex and zoster can be confirmed by obtaining vesicle fluid specimens for immunofluorescence antigen testing, culture, or PCR. Differentiation between the two viral infections is important because of infection control issues and because of the increased doses of antivirals required for treatment of herpes zoster. [bib_ref] Infection management for geriatrics in long-term care facilities, Schmader [/bib_ref] [bib_ref] Herpes zoster in older adults, Schmader [/bib_ref] The role of zoster vaccine in LTCF residents is undefined. [bib_ref] A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults, Oxman [/bib_ref] Ectoparasitic Infection. Scabies (Sarcoptes scabiei) and lice (Pediculus humanus capitus, P. humanus corporis, and Phthirus pubis) are acquired by LTCF residents from other infected persons or contaminated fomites. [bib_ref] Clinical practices: scabies, Chosidow [/bib_ref] The clinical presentation of scabies infection in nursing home patients can be atypical. Burrows, inflammatory changes in intertrigenous areas, and pruritis may be absent. Debilitated patients may present only with hyperkeratosis, papules, or vesicles. [bib_ref] Atypical presentation of scabies among nursing home residents, Wilson [/bib_ref] Diagnosis of scabies is often made when the typical rash occurs in healthcare workers or visitors. [bib_ref] Infection management for geriatrics in long-term care facilities, Schmader [/bib_ref] [bib_ref] Scabies in long-term care facilities, Degelau [/bib_ref] Debilitated older adults are often heavily infested with scabies mites. Scabies outbreaks are usually suspected by the occurrence of 1 unexplained rash in residents. [bib_ref] Scabies in long-term care facilities, Degelau [/bib_ref] Although it may be necessary to make the diagnosis on the basis of clinical findings alone, an incorrect diagnosis can often lead to pseudo-outbreaks, with widespread ''psychogenic'' scabies (itching but no skin lesions), especially among staff or family members. Therefore, once scabies is suspected, an etiologic diagnosis should be attempted in several residents or staff. Skin should be scraped six or seven times with a scalpel, and examination of the scrapings under immersion oil by low-power microscopy readily detects mites, ova, and feces. [bib_ref] Clinical practices: scabies, Chosidow [/bib_ref] [bib_ref] Atypical presentation of scabies among nursing home residents, Wilson [/bib_ref] Lice are typically found at the base of hair follicles (nits), in the scalp (head lice), or in the seams of clothing (body lice). ## Evaluation of gi infection recommendations 28. In the absence of an outbreak of GI illness, residents with symptoms of gastroenteritis consistent with small bowel infection and a stable clinical status should be evaluated before 7 days for volume assessment, but no laboratory evaluation is required unless the resident is severely ill or symptoms persist beyond 7 days. In such cases, presence of Giardia species and other protozoa should be examined in stool specimens (B-III). 29. If the resident exhibits symptoms of colitis (e.g., severe fever, abdominal cramps, and/or diarrhea, with or without blood and/or WBCs in the stool), initial evaluation for C. difficile should be performed, especially if the patient has received antibiotics within the previous 30 days. Submit a single diarrheal stool specimen to the laboratory for a C. difficile toxin assay. If diarrhea persists and if the assay result is negative, submit 1 or 2 additional stool specimens for the toxin assay (A-II). 30. In a patient with symptoms of colitis but no history of antibiotic use within the previous 30 days and/or a negative C. difficile evaluation result, one should submit a stool sample for culture for isolation of the most frequent invasive enteropathogens (i.e., C. jejuni, Salmonella and Shigella species, and E. coli O157:H7) (A-II). 31. Local public health authorities should be consulted if rates of gastroenteritis or colitis exceed baseline thresholds in the facility (if these thresholds are known), if 2 cases occur at the same time in the same unit, or if a reportable pathogen is isolated (B-III). 32. Intra-abdominal infections and abscesses can occur in LTCF residents as a consequence of GI pathology. These complications are relatively uncommon but are associated with substantial morbidity and mortality; evaluation and treatment of possible abscesses should be performed in an acute care setting (B-III). ## Evidence summary Gastroenteritis and Diarrhea. Gastroenteritis and diarrhea are the most commonly encountered GI infections in LTCF residents. Diarrhea may be attributable to increased susceptibility or exposure to pathogens. Increased achlorhydria and reduced intestinal motility with age may allow the organism to survive in the stomach with slowed egress from the GI tract. Many medications and underlying diseases affect gastric acidity and slow gut motility in aged persons. Enteric pathogens may be acquired from environmental sources, direct contact with infected residents and hands of personnel, and ingestion of contaminated food and water. Visits by children and animals have also been associated with outbreaks. Devices such as feeding tubes or thermometers may provide an efficient means to introduce pathogens directly into the GI tract. [bib_ref] CME article: management and treatment of infectious diarrhea in the elderly, Mishkin [/bib_ref] [bib_ref] Infectious disease outbreaks in nursing homes: an unappreciated hazard for frail elderly..., Strausbaugh [/bib_ref] Although the exact incidence of infectious diarrhea in LTCF is not known, numerous outbreaks reported from individual facilities suggest that the problem is common. It has been estimated that one-third of nursing home residents will have an episode of diarrhea annually. More than onehalf of all diarrheal deaths involve adults aged 74 years; one-third of these deaths occur in LTCF residents. [bib_ref] CME article: management and treatment of infectious diarrhea in the elderly, Mishkin [/bib_ref] [bib_ref] Infectious disease outbreaks in nursing homes: an unappreciated hazard for frail elderly..., Strausbaugh [/bib_ref] Gastroenteritis and diarrhea can be caused by the organism itself or by the elaboration of toxins. Causes of diarrhea in the LTCF may be bacterial, viral, or, less commonly, parasitic. A commonly used case definition of diarrhea includes the presence of 3 watery, loose, or unformed stools per day for 448 h. In general, GI infection can be classified by the organ involved. Infection of the small bowel or gastroenteritis is most commonly associated with mid abdominal pain and large-volume watery stools; blood and pus in stool are rare. Typical small bowel pathogens include viruses and the protozoa Giardia lamblia and Cryptosporidium and Cyclospora species. [bib_ref] Practice guidelines for the management of infectious diarrhea, Guerrant [/bib_ref] In contrast to upper GI tract disease, infection of the large bowel is associated with lower abdominal or rectal pain; mucosal ulcers, blood, and fecal leukocytes or stool lactoferrin may be present. Causes of large-bowel infections described in LTCFs include C. difficile, toxigenic enterohemorrhagic E. coli, Shigella species, Salmonella species, Campylobacter species, Yersinia species, and Entamoeba histolytica. Campylobacter, Yersinia, and Salmonella species also cause disease in the terminal ileum. [bib_ref] Practice guidelines for the management of infectious diarrhea, Guerrant [/bib_ref] Infections of the Small Intestine/Gastroenteritis. Viruses account for the majority of outbreaks of gastroenteritis that typically occur in the winter time in association with vomiting, respiratory symptoms, and headaches. [bib_ref] Infectious disease outbreaks in nursing homes: an unappreciated hazard for frail elderly..., Strausbaugh [/bib_ref] Viral causes, such as norovirus, calciviruses, adenoviruses, enteroviruses, and rotavirus infections, are common. Viral diarrheas resolve with supportive treatment. Diagnosis is generally not required unless there is a prolonged outbreak that does not resolve with appropriate isolation techniques. Most new laboratory methods rely on the detection of viral antigens in stool by RT-PCR or enzyme immunoassay. [bib_ref] Practice guidelines for the management of infectious diarrhea, Guerrant [/bib_ref] Norovirus, a particularly prevalent and highly contagious agent, deserves specific comment for several reasons. First, fatal cases of norovirus infection occur the majority of the time among LTCF residents.Second, very small numbers of virus particles are infectious and can be transmitted by direct contact, by fomites, or by aerosolization during vomiting. This mandates stringent infection control procedures. [bib_ref] A norovirus outbreak at a longtermcare facility: the role of environmental surface..., Wu [/bib_ref] Third, as with C. difficile (see below), alcohol hand preparations may not completely inactivate the organism, and vigorous handwashing with soap, friction, and running water is still preferred. [bib_ref] Norovirus outbreaks in nursing homes, Drinka [/bib_ref] Enterotoxin-producing foodborne strains of Bacillus cereus, C. perfringens, and S. aureus have caused epidemics of nausea and vomiting in nursing homes. The diagnosis of infection is made solely on the basis of the abrupt onset of nausea, vomiting, abdominal cramps, and diarrhea within 1-72 h after ingestion of suspect foods in multiple patients. Fever and inflammatory signs are lacking, and the episodes resolve in 24-48 h with supportive care. [bib_ref] Infectious disease outbreaks in nursing homes: an unappreciated hazard for frail elderly..., Strausbaugh [/bib_ref] [bib_ref] Foodborne disease outbreaks in nursing homes, Levine [/bib_ref] The parasites G. lamblia and Cryptosporidium parvum have been identified less often in association with contaminated food and water and with child-care programs. [bib_ref] Infectious disease outbreaks in nursing homes: an unappreciated hazard for frail elderly..., Strausbaugh [/bib_ref] [bib_ref] Cryptosporidiosis: an unrecognized cause of diarrhea in elderly hospitalized patients, Neill [/bib_ref] Diagnosis of infection with these organisms by antigen detection is more sensitive than examination of stool specimens for trophozoites and for cysts. [bib_ref] Diagnostic advantages and therapeutic options for giardiasis, Mank [/bib_ref] Standard examinations of stool specimens for ova and parasites do not include the acid-fast staining required to detect Cryptosporidium, Cyclospora, or Isospora species. [bib_ref] Cryptosporidium species: new insights and old challenges, Leav [/bib_ref] C. difficile Infection. C. difficile is the most common readily identifiable cause of infectious diarrhea in LTCF residents. [bib_ref] Infectious disease outbreaks in nursing homes: an unappreciated hazard for frail elderly..., Strausbaugh [/bib_ref] [bib_ref] Clostridium difficile in long-term-care facilities for the elderly, Simor [/bib_ref] [bib_ref] Burden of Clostridium difficile-associated diarrhea in a long-term care facility, Laffan [/bib_ref] Most other diarrheal pathogens are identified only after an outbreak is suspected. Rates of asymptomatic C. difficile colonization in LTCFs approach 10%-30%, [bib_ref] Burden of Clostridium difficile-associated diarrhea in a long-term care facility, Laffan [/bib_ref] in part because of decreases in protective antibody to toxin A with increasing age. [bib_ref] Clostridium difficile in long-term-care facilities for the elderly, Simor [/bib_ref] Rates of symptomatic infection appear to be highest in subacute and rehabilitative units, especially after recent admission from a hospital. [bib_ref] Burden of Clostridium difficile-associated diarrhea in a long-term care facility, Laffan [/bib_ref] Under the selective pressure of antibiotics, growth of toxin-producing C. difficile occurs, with resulting diarrhea. One-third of nursing home residents already colonized with C. difficile will acquire symptomatic C. difficile-associated diarrhea within 2 weeks after receiving antibiotic therapy, [bib_ref] Clostridium difficile in long-term-care facilities for the elderly, Simor [/bib_ref] highlighting the need to avoid unnecessary antibiotic use in this cohort. Alcohol preparations used for hand sanitizing in hospitals and LTCFs do not inactivate the spores of C. difficile; thus, strict handwashing (which mechanically removes the spores) is recommended after caring for patients with C. difficile illness. Nosocomial transmission of C. difficile by personto-person contact is now well recognized in institutional settings such as LTCFs. Therefore, outbreaks of diarrhea in LTCFs should prompt consideration of C. difficile-associated diarrhea as the diagnosis. [bib_ref] Burden of Clostridium difficile-associated diarrhea in a long-term care facility, Laffan [/bib_ref] [bib_ref] A predominantly clonal multiinstitutional outbreak of Clostridium difficile-associated diarrhea with high morbidity..., Loo [/bib_ref] Clinical manifestations of C. difficile infection range from mild diarrhea to pseudomembranous colitis to toxic megacolon. Recent C. difficile-associated diarrhea strains are clearly associated with increased incidence and severity of disease in the older adult, leading to increased rates of hospitalization, intensive care, surgical intervention, and death. [bib_ref] A predominantly clonal multiinstitutional outbreak of Clostridium difficile-associated diarrhea with high morbidity..., Loo [/bib_ref] The diagnosis of C. difficile should be strongly considered if the patient has received antibiotics or chemotherapy in the previous 4-6 weeks and for any older patient with severe leukocytosis (430,000 cells/mm 3 ), even in the absence of abdominal pain, diarrhea, or recent antibiotic use. An EIA positive for toxins A or B in diarrheal stool specimens is diagnostic. Toxin assays are 60%-90% sensitive and 75%-100% specific for detection of the organism, particularly if multiple specimens are tested. Stool cultures are not performed for patients without diarrhea, because C. difficile is part of normal GI flora. Sigmoidoscopy is less useful than assays for detection of toxin in stool specimens, because not all cases of C. difficile infection have pseudomembranes, and isolated right-side disease can be missed. [bib_ref] Clostridium difficile in long-term-care facilities for the elderly, Simor [/bib_ref] Patients with signs of ileus or peritonitis should be transferred to a hospital for urgent imaging by CT and monitoring, if appropriate. E. coli 0157:H7 and other Shiga toxin-producing enterohemorrhagic strains have been associated with foodborne outbreaks of bloody diarrhea without fever and hemolytic uremic syndrome. [bib_ref] Escherichia coli O157: H7 infection in nursing homes: review of literature and..., Reiss [/bib_ref] Diarrhea due to toxigenic strains of E. coli is diagnosed primarily with an assay of Shiga toxin or the presence of colorless colonies on Sorbitol-MacConkey agar cultures of stool specimens. [bib_ref] CME article: management and treatment of infectious diarrhea in the elderly, Mishkin [/bib_ref] Diarrhea due to invasive pathogens, such as Salmonella, Shigella, and Campylobacter species, have been associated with fever and prominent inflammatory signs, in addition to bloody stool, and are readily diagnosed by stool culture. [bib_ref] Infectious disease outbreaks in nursing homes: an unappreciated hazard for frail elderly..., Strausbaugh [/bib_ref] Rarely, parasites such as Entamoeba histolytica have been identified as a cause of bloody diarrhea in this setting. [bib_ref] Infectious disease outbreaks in nursing homes: an unappreciated hazard for frail elderly..., Strausbaugh [/bib_ref] Intra-Abdominal Infection and Abscesses. Complications of biliary tract and GI disease, such as appendiceal, hepatic, and diverticular abscesses, are uncommon but should be considered in febrile, older LTCF residents. The manifestations of these infections in this population are atypical, with a resulting delay in treatment and increased morbidity and mortality. Fever and focal findings on physical examination may be lacking, leading to perforation, abscess formation, and death.Compared with young adults, rates of diverticulitis and cholecystitis increase several-fold among older persons. [bib_ref] Infection management for geriatrics in longterm care facilities, Campbell [/bib_ref] Leading causes of intra-abdominal infections in older adults include appendicitis (28%), diverticulitis (28%), cholecystitis (12%), cholangitis (12%), and intra-abdominal abscess (9%).Appendicitis is less common with aging but accounts for 15% of surgical emergencies among persons in this age group. [bib_ref] Infection management for geriatrics in longterm care facilities, Campbell [/bib_ref] Intra-abdominal abscess is also a leading diagnosis in older adults with fever of unknown origin. Evaluation for these infections should be considered to be a medical emergency that requires admission to an acute care facility. ## Evidence summary Although a broad description of outbreak investigation is beyond the scope of these guidelines, LTCFs commonly experience outbreaks of disease above endemic levels (i.e., epidemics). The role of the LTCF physician is to recognize an outbreak; to take immediate action regarding isolation, if required; and to notify the medical director and infectioncontrol practitioner or appropriate authorities (e.g., local public health department or the Centers for Disease Control and Prevention) for further assistance, if needed. [bib_ref] SHEA/APIC guideline: infection prevention and control in the long-term care facility, Smith [/bib_ref] Importantly, testing of LTCF residents, even those with advanced directives prohibiting such measures in their own care, may be done when the goal is to benefit the community of the LTCF. [bib_ref] Treatment decisions for infections occurring in nursing home residents, Mott [/bib_ref] To facilitate early recognition of an outbreak, facilities should monitor their baseline infection rates using standard definitions. The following initial steps should be initiated in recognizing an outbreak: Confirm the diagnosis of disease in the index patient. Decide and define key variables to study (before chart review) and involve a multidisciplinary team in planning the study. Derive a uniform case definition to be used in chart review and patient evaluation. With use of the case definition, perform a chart review and prospectively observe newly suspected cases. Plot an epidemic curve (number of cases over time) that includes a sufficient pre-epidemic period to establish that an outbreak truly exists. Determine whether the outbreak is a ''pseudo-outbreak'' (presence of positive laboratory results in the absence of clinical disease) that is now recognized because of a change in surveillance, laboratory and/or specimen collection methods, or altered procedures rather than a true increase in the number of cases. Review the relevant literature. Inform appropriate administrative personnel (director of nursing or department heads) of isolation procedures, if required. Seek assistance from local epidemiology personnel in the health department, the Centers for Disease Control and Prevention, or a hospital. ## Performance measures 1. In LTCF residents suspected of having an infection, the temperature, pulse, blood pressure, and respiratory rate should be obtained by nursing home/facility personnel within 30 min. 2. In LTCF residents suspected of having an infection and in whom no prior advance directive prohibits further evaluation, a CBC count, including peripheral WBC count and differential cell counts, should be performed within 12-24 h (or sooner if the patient is seriously ill), consistent with local standards of practice. [table] Table 1: Infectious Diseases Society of America-U.S. Public Health Service Grading System for Ranking Recommendations in Clinical Guidelines [/table]	None	https://europepmc.org/articles/pmc7166905?pdf=render	Residents of long‐term care facilities (LTCFs) are at great risk for infection. Most residents are older and have multiple comorbidities that complicate recognition of infection; for example, typically defined fever is absent in more than one‐half of LTCF residents with serious infection. Furthermore, LTCFs often do not have the on‐site equipment or personnel to evaluate suspected infection in the fashion typically performed in acute care hospitals. In recognition of the differences between LTCFs and hospitals with regard to hosts and resources present, the Infectious Diseases Society of America first provided guidelines for evaluation of fever and infection in LTCF residents in 2000. The guideline presented here represents the second edition, updated by data generated over the intervening 8 years. It focuses on the typical elderly person institutionalized with multiple chronic comorbidities and functional disabilities (e.g., a nursing home resident). Specific topic reviews and recommendations are provided with regard to what resources are typically available to evaluate suspected infection, what symptoms and signs suggest infection in a resident of an LTCF, who should initially evaluate the resident with suspected infection, what clinical evaluation should be performed, how LTCF staff can effectively communicate about possible infection with clinicians, and what laboratory tests should be ordered. Finally, a general outline of how a suspected outbreak of a specific infectious disease should be investigated in an LTCF is provided.
2498113d5a1f94be7ec23add6617b5ee4cd42839	pubmed	Clinical genetics evaluation in identifying the etiology of autism spectrum disorders	Clinical genetics evaluation in identifying the etiology of autism spectrum disorders Disclaimer: This guideline is designed primarily as an educational resource for medical geneticists and other health care providers to help them provide quality medical genetics services. Adherence to this guideline does not necessarily assure a successful medical outcome. This guideline should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.The autism spectrum disorders are a collection of conditions, which have, in common, impaired socialization and communication in association with stereotypic behaviors. The reported incidence of autism spectrum disorders has increased markedly over the past decade. In addition, a large amount of attention has been paid to these conditions among lay and professional groups. These influences have resulted in a marked increase in the number of referrals to clinical geneticists for evaluation of persons with autism spectrum disorders. The primary role of the From the geneticist in this process is to define etiology, if possible, and to provide counseling and contribute to case management based on the results of such investigations. In deciding upon the appropriate evaluation scheme for a particular patient, the geneticist must consider a host of different factors. Such considerations would include [bib_ref] Genetic landmarks through philately -autism spectrum disorders: a genetic update, Chudley [/bib_ref] Assuring an accurate diagnosis of autism before proceeding with any investigation. (2) Discussing testing options, diagnostic yields, and patient investment before proceeding with an evaluation. Autism spectrum disorders (ASDs), also known as pervasive developmental disorders (PDD), are a behaviorally defined group of neurodevelopmental disorders that are usually diagnosed in early childhood. They are characterized by varying degrees of restrictions in communication and social interaction and by atypical, repetitive behaviors. The phenotype of ASDs is extremely heterogeneous with differences from person to person in a wide range of symptoms and severity as well as differences between the various subtypes of ASDs (e.g., autistic disorder, Asperger, PDD . Multiple lines of epidemiologic evidence support the strong role of genetics in the etiology of ASDs. 1-3 Results of population studies of unselected cases of autism are consistent with multifactorial inheritance. The reported recurrence risk for full siblings is 4% if the affected child is a girl and 7% if the affected child is a boy. Overall, 2-3% of families have more than one affected child (potentially because of a decreased occurrence of subsequent pregnancies). If a second child has autism, the recurrence risk is on the order of 25-35%. The calculated relative recurrence risks are 22.3 for autism and 13.4 for Asperger syndrome. The sibling risk ratio ( s ) is estimated to be 100 -150. The calculated heritability (the proportion of phenotypic variance explained by the genotype) is around 90%. There is an excess of twins reported in affected sib pairs. Population stud-ies show a concordance of 70% in monozygotic twins; 90% if the broader phenotypic definition is used. This is in contrast to a 3% concordance in dizygotic twins. [bib_ref] Genetics of autism, Cook [/bib_ref] [bib_ref] The genetics of autism, Muhle [/bib_ref] [bib_ref] The neurobiology and genetics of infantile autism, Lotspeich [/bib_ref] [bib_ref] The genetics of autism, Spence [/bib_ref] As a group, ASDs occur three to four times more commonly in men. Such a sexual dimorphism suggests that X-linked genes play a major role in the etiology of the spectrum. However, whole genome screens have found only four minor linkages to the X chromosome, and X chromosome genes seem to account for a only a small portion of the overall genetic contribution. Evidence of linkage has been found to most autosomes, suggesting marked genetic heterogeneity. The most consistently reported linkages have been with chromosomal locations 15q11-13, 7q 22-31 (two loci with parent of origin effect), 13q, 17q 11 (male-specific locus), 2q, and 16p. Over the past decade, the reported incidence of ASDs has increased markedly with some estimates suggesting a quadrupling in 10 years. The current estimates for autism are now reported to be on the order of 10 -60 per 10,000 individuals, if all forms of ASDs are considered. In fact, the Center for Disease Control and Prevention has recently estimated the prevalence of ASDs in the United States at approximately 5.6 per 1000 (1 of 155 to 1 of 160) children. [bib_ref] The prevalence of autism, Fombonne [/bib_ref] This rise in the reported prevalence of ASDs is unlikely to represent a true "epidemic " of the condition as has been suggested by some. Rather, it seems that, this reported increase can be attributed to better knowledge of the disease and its variability, broader diagnostic criteria, improved public and professional awareness, and a higher level of acceptance of the diagnosis. The role of the clinical geneticist is to determine the etiology of the ASDs, if possible, and to provide counseling for the family. In recent years, there has been an explosion of new diagnostic options and tools available to the clinician. Several recent publications have also reported a host of "expanded phenotypes" for genetic and metabolic conditions in association with ASDs phenotypes. These factors have led to an increase in the number of referrals to the clinical geneticist and an increase in the diagnostic yield. Now, more than ever, medical genetics services are available to help families answer the question "Why?" In deciding upon an evaluation plan, the clinical geneticist has the difficult task of balancing an ever-expanding list of available tests and possible diagnoses with the issues of cost, practicality, and expected yield. The guidelines put forth here outline a strategy of a tiered evaluation of the etiology of autism. These recommendations use evidence-based conclusions from the current available literature and cumulative clinical experience. ## Rationale for an evaluation The rationale for a clinical genetics evaluation for persons with ASDs has been questioned by some. Concerns have been expressed over the high cost of such an evaluation coupled with the fact that the information obtained typically will not change interventions for the patient. The rationale for performing a clinical genetics consultation for a patient with an ASD is clear to the clinical geneticist. Clinical geneticists can contribute to the process by examining and evaluating the patient, the parents, and siblings, as necessary, in establishing the etiology. A definitive diagnosis helps the patient acquire needed services, and is helpful in many other ways for the family. Many families are greatly empowered by knowledge of the underlying cause of a relative's disorder. Depending on the etiology, associated medical risks may be identified that lead to screening and the potential for prevention of morbidity. Specific recurrence risk counseling-beyond general multifactorial informationcan be provided, and targeted testing of at risk family members can be offered. In a limited number of cases (e.g., metabolic disorders) targeted therapies may be or become available. These significant positive benefits strongly justify a medical genetics consultation for all patients with ASDs. One of the best strategies for integrating clinical genetics services into the care of patients with ASDs can be the participation of the geneticist on an interdisciplinary "autism team. " This allows the geneticist to work alongside other professionals involved in the care of persons with ASDs with access to detailed, specific diagnostic information about the patient. ## Reported approaches and yields The generally reported rate of success for identifying a specific (unifactorial) diagnosis in persons with autism is 6 -15%. This range is applicable even for evaluations of patients with PDD (NOS), atypical autism, Asperger syndrome, or autistic features, which did not necessarily meet the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, criteria for PDD. Many factors seem to influence the diagnostic yield. The use of newer diagnostic modalities and the aggressiveness of the evaluation seem to be the most critical. Not surprisingly, the skill and experience of the geneticist also factor heavily into the yield. A critical review of the potential contribution of newer testing techniques suggests that yield can be significantly higher than 15%. Chromosomal studies are consistently reported as giving one of the highest diagnostic yields in persons with ASDs. [bib_ref] Cytogenetic abnormalities and fragile-X syndrome in autism spectrum disorder, Reddy [/bib_ref] [bib_ref] Etiologic yield of autistic spectrum disorders: a prospective study, Shevell [/bib_ref] [bib_ref] Chromosomes in autism and related pervasive developmental disorders: a cytogenetic study, Weidmer-Mikhail [/bib_ref] Continued improvements in cytogenetic approaches including higher resolution studies have further increased the diagnostic yield. Numerous submicroscopic deletions and duplications have been reported in association with an autism phenotype. In general, the most commonly reported loci mirror the reported linkage data. Some of the most frequently reported regions with abnormalities in association with ASDs include 15q pericentromeric 11-13 region, 17p11, 22q11, 22q13, and 2q37. Most recently, changes in the 16p11.2 region have been reported as occurring in a significantly high frequency in patients with ASDs-prompting the designation of this region as a "hot spot of genetic instability." Currently, array comparative genomic hybridization (aCGH) has emerged as a powerful new tool that promises further revolution of clinical genetic testing. The technology of assessing submicroscopic rearrangements is evolving at a mind-bog-gling rate. New platforms are being developed at rates faster than clinical studies can define their use. The availability of multiple platforms further complicates the ability to compare studies from various sites. Relatively few studies have been published that provide an actual estimate of the diagnostic yield of aCGH in evaluating patients with autism. One study found a 27.5% yield in the study of aCGH in patients with "syndromic " autism. [bib_ref] Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in..., Jacquemont [/bib_ref] Preliminary data from many sites suggests that the cumulative yield of aCGH will prove to be the highest yield test that is clinically available. If the estimates of the frequency of the most commonly reported anomalies are pooled, current aCGH platforms can be estimated to identify abnormalities on the order of 10%, beyond what would be identified by standard chromosomal testing (G. Schaefer, unpublished data). Until definitive, large-scale studies provide confirmation of the use of aCGH, its role in the evaluation of ASDs may not be fully appreciated. Realistic predictions suggest that the time in which this will occur may be just a few years. The strong association of autism with Fragile X syndrome has been confirmed in almost every large reported series. [bib_ref] Autism spectrum phenotype in males and females with fragile X full mutation..., Clifford [/bib_ref] [bib_ref] Autistic behavior in children with fragile X syndrome: prevalence, stability, and the..., Hatton [/bib_ref] [bib_ref] Fragile X in a survey of 75 autistic males, Watson [/bib_ref] Mutations in the Methyl-CPG-Binding Protein 2 (MECP2) gene are reported in a significant number of women with autism. [bib_ref] The diagnostic utility of a genetics evaluation in children with pervasive developmental..., Abdul-Rahman [/bib_ref] [bib_ref] Identification of MeCP2 mutations in a series of females with autistic disorder, Carney [/bib_ref] To date, no male with idiopathic autism has been reported with a mutation in the MECP2 gene. Mutations in the phosphatase and tensin homolog (PTEN) gene are reported to occur frequently in the subgroup of patients with autism with a head circumference 2.5 SDs greater than age-appropriate means. 14 Clinically recognizable syndromes and metabolic disorders are other identifiable causes. [bib_ref] Genetics evaluation for the etiologic diagnosis of autism spectrum disorders, Schaefer [/bib_ref] A synthesis of the published literature suggests that the following diagnostic yields would be projected in the genetic evaluation of ASDs: ## Evaluation scheme The first (and most critical) step in the clinical genetic evaluation of ASDs is the pre-evaluation. Several pieces of critical information need to be obtained before beginning any investigation. An accurate ASD diagnosis is mandatory. The diagnosis of ASDs should be made by appropriately trained professionals using objective criteria. Normal hearing should be documented because children with significant hearing loss tend to have difficulties with socialization and communication that may be misidentified as autism. Recently published guide-lines from the American Academy of Pediatrics suggest that primary care providers obtain chromosome and Fragile X studies at the time an ASD is diagnosed. [bib_ref] American Academy of Pediatrics Council on Children with Disabilities. Identification and evaluation..., Johnson [/bib_ref] Thus, part of the evaluation may already have been accomplished before referral to the geneticist. As with all clinical evaluations, an etiologic evaluation must be tailored to the individual patient. The design of the evaluation must take into consideration focused information from the history and physical as well as clinical experience. There is no single approach or algorithm that can be applied to all cases. For practical reasons, a step-wise (tiered) evaluation is considered by many to be the preferred approach. In general, a nontiered evaluation in which a large battery of tests is ordered as part of the initial testing scheme is poorly tolerated by the patient and family and less acceptable to third-party payers. A stepwise evaluation can be designed such that tests obtained in higher (earlier) tiers have a greater expected diagnostic yield, lower invasiveness of testing, better potential of intervention, and easier overall practicality. [bib_ref] Genetics evaluation for the etiologic diagnosis of autism spectrum disorders, Schaefer [/bib_ref] A model for such a tiered evaluation is provided in [fig_ref] Table 1: Template for the clinical genetic diagnostic evaluation of autism spectrum disordersPre-evaluationConfirmation of... [/fig_ref]. This scheme will evolve with continued advancements in diagnostic testing and improved understanding of the ASD phenotype. Additional conditions have already been reported in association with an ASD phenotype, but to date none of these have been evaluated in a large prospective cohort. Thus, the possibility of a fourth (extended) tier of evaluation is a distinct possibility in the near future. Alternatively, advances in technology may permit bundling of individual tests into an extended, more readily accessible, and lessexpensive platform. ## Recommendations 1. Accurate diagnosis: It is critically important that a firm diagnosis of ASD is made before initiating any genetic evaluation. Although the diagnosis of autism may seem straightforward, many neurodevelopmental disorders have overlapping phenotypes. The diagnosis should be made by a professional trained in the diagnosis of autism. The patient's parents, siblings, and offspring may also need to be evaluated. Objective criteria with the application of generally accepted tools should be used. All persons with apparent autism should have a formal audiogram to rule out a significant hearing loss. 2. Role of the primary care physician: All persons with autism should have a designated primary care physician (PCP). Often the PCP will be the first professional to raise the question of ASD as a possible diagnosis. Depending on training and comfort level, the PCP may be prepared to make a diagnosis of an ASD. Alternatively, the PCP may make a referral to a school team or mental health professional for diagnostic confirmation. Recent guidelines from the American Academy of Pediatrics suggest that the PCP obtain high-resolution chromosome studies (peripheral karyotype) and Fragile X studies when the diagnosis of an ASD is confirmed. After clinical genetics consultation, the PCP and the clinical geneticist should be prepared to partner in ordering, scheduling, and coordination of recommended diagnostic testing. 3. Referral for clinical genetics evaluation: Defining the etiology of an ASD can be of great benefit to the patient and family. Information gained from an identified etiology can help with family counseling, medical management, preventative health strategies, and empowerment of the family. Clinical geneticists have much to offer in this process beyond the initial assessments made by the PCP or mental health professionals working with the individual or family with ASD. As such, a genetic consultation should be offered to all persons and families with ASDs. Evaluations should be considered for any individual along the full autism spectrum. The referring professional should discuss expectations and possible outcomes of such an evaluation before making the referral. The referring professional should be aware of what is involved in such a consultation and the potential diagnostic yields and share this information with the patient and family. 4. Tiered evaluation: The clinical genetic evaluation of an individual with an ASD must be customized to the clinical situation. A patient may be referred to the geneticist with a specific diagnosis that is being considered-seeking confirmation. Alternatively, a syndromic diagnosis may be apparent to the geneticist upon the initial visit. In either case, the diagnosis should be confirmed using accepted clinical criteria and laboratory testing (if available). Many recognizable syndromes have a firmly documented association with autism. For these conditions, further investigation into the etiology of the ASD is unnecessary. There are, however, genetic conditions that have been reported in association with ASDs in which the reported association is not as convincing. For patients with these conditions, it is recommended that an etiologic evaluation for the ASD proceed as an independent condition. [fig_ref] Table 2: Partial list of genetic syndromes with a reported association with autism Lujan-Fryns... [/fig_ref] provides a partial list of these two groups of conditions. If the clinical geneticist does not identify a specific disorder upon the initial evaluation, further testing can be accomplished as outlined in [fig_ref] Table 1: Template for the clinical genetic diagnostic evaluation of autism spectrum disordersPre-evaluationConfirmation of... [/fig_ref]. 5. Counseling: Upon completion of the clinical genetics evaluation, two groups of individuals will have been identified: those with and those without an identifiable major single etiology. Definitive counseling should be provided to both groups. For those without an identifiable etiology, counseling should be provided for multifactorial inheritance. The best available published empiric recurrence risks for full siblings are 4% if the affected child is a girl and 7% if the affected child is a boy. If a second child has autism, the reported recurrence risk has been from 25% to 50%. A reasonable synthesis of published reports would be around 30%. 6. Follow-up: Clinical geneticists differ greatly in their degree of involvement with patients after completion of diagnostic consultations. Intervening changes in technology and in phenotypes often aid in ultimately obtaining a diagnosis. At a minimum, periodic reevaluations should be considered for patients in whom a definitive etiology is not initially discovered. The timing of interval follow-ups should be a negotiation between the patient and family, the PCP, and the geneticist. ## Resources [fig] 3: Communication and coordination with the patient's medical home. (4) Assessing the continuously expanding and evolving list of available laboratory testing modalities in light of evidence-based medicine. (5) Recognizing expanded phenotypes of well-described syndromic and metabolic conditions that encompass autism spectrum disorders. (6) Defining an individualized evaluation scheme based on the unique history and clinical features of a given patient. The guidelines in this article have been developed to assist the clinician in the consideration of these factors. Genet Med 2008:10(4):301-305. [/fig] [fig] •: High-resolution chromosome studies (5%) aCGH-beyond what would be detected by chromosomal analysis (10%) Fragile X (5%) MECP2 (5%-women only) PTEN (3%-if head circumference Ͼ2.5 SDs) Other (10%)Thus, using current knowledge and technology, a thorough clinical genetics evaluation of persons with ASDs will result in a positive answer in up to 40% of individuals. [/fig] [table] Table 1: Template for the clinical genetic diagnostic evaluation of autism spectrum disordersPre-evaluationConfirmation of diagnosis of autism by trained professional using objective criteria and tools Initial evaluation to identify known syndromes or associated conditionsExamination with special attention to dysmorphic features Should include Woods lamp evaluation If specific diagnosis is suspected, proceed with targeted testing Rubella titers-if clinical indicators present "Standard" metabolic screening-if clinical indicators present and if suspected condition was not assessed by newborn screening Urine mucopolysaccharides and organic acids Serum lactate, amino acids, ammonia, and acyl-carnitine profile High-resolution chromosomal analysis-if not already performed DNA for Fragile X-if not already performed Fibroblast karyotype if leukocyte karyotype is normal and clonal pigmentary abnormalities are noted Comparative genomic hybridization (chromosomal microarray) a MECP2 gene testing (females only) PTEN gene testing (if the head circumference is 2.5 SD greater than the mean) Brain magnetic resonance imaging Serum and urine uric acid If elevated, Hypoxanthine-guanine phosphoribosyl transferase (HgPRT) and Phosphoribosylpyrophosphate (PRPP) synthetase superactivity testing If low, purine/pyrimidine panel (uracil excretion, xanthine, hypoxanthine) Extracted from Schaefer GB and Mendelsohn NJ. Genetics evaluation for the etiologic diagnosis of autism spectrum disorders. Genet Med 2008;10:4 -12. a Advances in microarray technology will likely elevate aCGH to a first tier study in the near future. [/table] [table] Table 2: Partial list of genetic syndromes with a reported association with autism Lujan-Fryns syndrome De Lange syndrome Extracted from Schaefer GB and Mendelsohn NJ. Genetics evaluation for the etiologic diagnosis of autism spectrum disorders. Genet Med 2008;10:4 -12. [/table]	None	https://europepmc.org/articles/pmc3111012?pdf=render	The autism spectrum disorders are a collection of conditions, which have, in common, impaired socialization and communication in association with stereotypic behaviors. The reported incidence of autism spectrum disorders has increased markedly over the past decade. In addition, a large amount of attention has been paid to these conditions among lay and professional groups. These influences have resulted in a marked increase in the number of referrals to clinical geneticists for evaluation of persons with autism spectrum disorders. The primary role of the geneticist in this process is to define etiology, if possible, and to provide counseling and contribute to case management based on the results of such investigations. In deciding upon the appropriate evaluation scheme for a particular patient, the geneticist must consider a host of different factors. Such considerations would include (1) Assuring an accurate diagnosis of autism before proceeding with any investigation. (2) Discussing testing options, diagnostic yields, and patient investment before proceeding with an evaluation. (3) Communication and coordination with the patient's medical home. (4) Assessing the continuously expanding and evolving list of available laboratory testing modalities in light of evidence-based medicine. (5) Recognizing expanded phenotypes of well-described syndromic and metabolic conditions that encompass autism spectrum disorders. (6) Defining an individualized evaluation scheme based on the unique history and clinical features of a given patient. The guidelines in this article have been developed to assist the clinician in the consideration of these factors.
15731755ea3f6fc0b1d8facdb6b87be43e11e16e	pubmed	Clinical practice guidelines for intraductal papilloma: Chinese Society of breast surgery (CSBrS) practice guidelines 2021	Clinical practice guidelines for intraductal papilloma: Chinese Society of breast surgery (CSBrS) practice guidelines 2021 [bib_ref] An analysis of breast cancer risk in women with single, multiple, and..., Lewis [/bib_ref] [bib_ref] Nonmalignant breast papillary lesions at coreneedle biopsy: a meta-analysis of underestimation and..., Wen [/bib_ref] [bib_ref] Management of breast papillary lesions diagnosed in ultrasound-guided vacuum-assisted and core needle..., Yamaguchi [/bib_ref] ## 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 The voting committee of this guideline comprised 76 members, including 63 (82.9%) breast surgeons, 3 (3.9%) oncologists, 4 (5.3%) radiologists, 2 (2.6%) pathologist, 2 (2.6%) radiation therapists, and 2 (2.6%) epidemiologists. ## Target audience The target audience is clinicians specializing in breast diseases in China. [bib_ref] Systematic review and meta-analysis of the diagnostic accuracy of ductoscopy in patients..., Waaijer [/bib_ref] [bib_ref] The role of breast ductoscopy in evaluation of nipple discharge: a chinese..., Yang [/bib_ref] I A 1.5 Cytological examination of nipple discharge [bib_ref] Ductoscopic detection of intraductal lesions in cases of pathologic nipple discharge in..., Ohlinger [/bib_ref] II A 1.6 Core needle biopsy [bib_ref] Nonmalignant breast papillary lesions at coreneedle biopsy: a meta-analysis of underestimation and..., Wen [/bib_ref] , ‡ I A * Ultrasound examination is performed to exclude other breast tumors for the central type and to locate tumor sites for the peripheral type. † Mammography can be used as an auxiliary examination, except for other breast tumors. ‡ Core needle biopsy (CNB) has diagnostic value for the peripheral type. Vacuum-assisted breast biopsy (VABB) [bib_ref] Consensus on diagnosis and treatment of intraductal papilloma of breast, Wu [/bib_ref] [bib_ref] Nipple discharge: is its significance as a risk factor for breast cancer..., Montroni [/bib_ref] , † I A * Simple tumor resection or lobular or quadrant resection including duct excision with nipple discharge as the main manifestation. † Suitable for intraductal papilloma visible on imaging. ## Recommendations ## Recommendation 2: surgical indications # Discussion The panel reviewed the literature and restated the standard for histological classification of breast tumors defined by the World Health Organization in 2003. According to its anatomical location and histological features, intraductal papilloma can be divided into the central and peripheral type. The central type originates from a large duct, is usually located under the areola; in contrast, the peripheral type originates from the terminal ductal-lobular unit.Most cases of intraductal papilloma are of the central type. Peripheral papilloma accounts for only about 10% of cases. [bib_ref] Breast papillomas: current management with a focus on a new diagnostic and..., Sarakbi1 [/bib_ref] Central intraductal papilloma mainly manifests as unilateral nipple discharge, which is often bloody or serous. In some patients, physical examination reveals palpable breast masses, most of which are located around the areola and compress the tumor area, bloody or serous liquid discharge is often present at the corresponding nipple ductal opening. [bib_ref] Consensus on diagnosis and treatment of intraductal papilloma of breast, Wu [/bib_ref] Peripheral intraductal papilloma is usually concealed and is characterized by nipple discharge or a breast mass that can be found by imaging examination. The typical clinical manifestation of both types is bloody or serous nipple discharge with or without a breast mass. The most common breast imaging methods show fewer specific signs of intraductal papilloma, and the sensitivity and specificity of different imaging methods for the diagnosis of intraductal papilloma are quite different. [bib_ref] Ductoscopic detection of intraductal lesions in cases of pathologic nipple discharge in..., Ohlinger [/bib_ref] [bib_ref] Diagnostic and therapeutic value of ductoscopy in nipple discharge and intraductal proliferations..., Kamali [/bib_ref] [bib_ref] Systematic review and meta-analysis of the diagnostic accuracy of ductoscopy in patients..., Waaijer [/bib_ref] [bib_ref] Diagnostic value of ductoscopy in the diagnosis of nipple discharge and intraductal..., Grunwald [/bib_ref] [bib_ref] Diagnostic performance of MRI versus galactography in women with pathologic nipple discharge:..., Berger [/bib_ref] [bib_ref] Role of radiological features in management of papillary lesions of the breast, Lam [/bib_ref] The sensitivity and specificity of ultrasound examination range from 67.3% to 82.9% and from 17.9% to 61.5% respectively, and the sensitivity of mammography ranges from 57.1% to 62.9%. [bib_ref] Ductoscopic detection of intraductal lesions in cases of pathologic nipple discharge in..., Ohlinger [/bib_ref] [bib_ref] Diagnostic and therapeutic value of ductoscopy in nipple discharge and intraductal proliferations..., Kamali [/bib_ref] However, calcification can be seen in malignant transformation of intraductal papilloma, and mammography is of significance in differentiating benign from malignant lesions. [bib_ref] Ductoscopic detection of intraductal lesions in cases of pathologic nipple discharge in..., Ohlinger [/bib_ref] [bib_ref] Diagnostic and therapeutic value of ductoscopy in nipple discharge and intraductal proliferations..., Kamali [/bib_ref] A metaanalysis of 921 cases among 10 studies showed that magnetic resonance imaging (MRI) was superior to galactography in the diagnosis of patients with negative ultrasound and mammography. [bib_ref] Role of radiological features in management of papillary lesions of the breast, Lam [/bib_ref] Ductoscopy is a highly sensitive diagnostic method for lesions in patients with nipple discharge that are not specifically found by ultrasound and mammography, especially for central intraductal lesions. One meta-analysis showed that the sensitivity and specificity of ductoscopy were 94% and 47%, respectively. [bib_ref] Systematic review and meta-analysis of the diagnostic accuracy of ductoscopy in patients..., Waaijer [/bib_ref] [bib_ref] The role of breast ductoscopy in evaluation of nipple discharge: a chinese..., Yang [/bib_ref] Cytological examination of nipple discharge exfoliation is also an available diagnostic method, but its sensitivity is only 22.8%; however, its specificity is as high as 85.5%. [bib_ref] Ductoscopic detection of intraductal lesions in cases of pathologic nipple discharge in..., Ohlinger [/bib_ref] According to China's national conditions and the anatomical characteristics of Chinese women's breasts, the panel recommends ultrasound examination as the first-choice imaging examination technique, with the addition of mammography and MRI to distinguish intraductal papilloma from other types of malignant tumors when necessary. Nipple discharge is a common manifestation of central intraductal papilloma, and ductoscopy or cytological examination of nipple discharge exfoliation is recommended for a definitive diagnosis. In contrast, the main manifestation of peripheral intraductal papilloma is a breast mass. For this type of tumor, imaging examination combined with core needle biopsy/vacuum-assisted breast biopsy (CNB/VABB) is recommended to obtain a histopathological diagnosis. Because galactography lacks highlevel research evidence, [bib_ref] Galactography is not an obsolete investigation in the evaluation of pathological nipple..., Istomin [/bib_ref] the panel does not recommend it as a diagnostic method. The diagnostic underestimation rates of CNB and VABB for intraductal papilloma are 15.7%-19.1% and 5.0%, respectively, [bib_ref] Nonmalignant breast papillary lesions at coreneedle biopsy: a meta-analysis of underestimation and..., Wen [/bib_ref] [bib_ref] Management of breast papillary lesions diagnosed in ultrasound-guided vacuum-assisted and core needle..., Yamaguchi [/bib_ref] [bib_ref] Benign papillomas of the breast diagnosed on large-Gauge vacuum biopsy compared with..., Seely [/bib_ref] and both central and peripheral intraductal papillomas are at risk of malignant transformation. [bib_ref] An analysis of breast cancer risk in women with single, multiple, and..., Lewis [/bib_ref] A study of 915 patients showed that lobular resection or quadrant resection including the duct excision was the most accurate diagnostic method (sensitivity and specificity of 100%) for patients with pathological nipple discharge. [bib_ref] Nipple discharge: is its significance as a risk factor for breast cancer..., Montroni [/bib_ref] The panel recommends that all clinically diagnosed intraductal papillomas should be treated surgically and that the tumor should be completely removed. The First and Second International Consensus Conference on lesions of uncertain malignant potential in the breast (B3 lesions) recommended that imaging-visible papilloma should be removed by VABB and that the patient should subsequently undergo surveillance.Open surgical resection is the first choice for patients with ADH.Larger lesions that cannot be completely removed by VABB should be treated by open surgery.According to the site of single intraductal papilloma as well as the accessibility and cost of CNB and VABB in Chinese primary hospitals, the panel equally recommends complete resection by open surgical resection and VABB for single intraductal papilloma without nipple discharge. For central intraductal papilloma with nipple discharge, open surgery is recommended and should include lobular resection or quadrant resection including the intraductal lesion [bib_ref] Consensus on diagnosis and treatment of intraductal papilloma of breast, Wu [/bib_ref] [bib_ref] Nipple discharge: is its significance as a risk factor for breast cancer..., Montroni [/bib_ref] ; open surgery or CNB/VABB can be performed for peripheral intraductal papilloma. [bib_ref] Consensus on diagnosis and treatment of intraductal papilloma of breast, Wu [/bib_ref] [bib_ref] Nipple discharge: is its significance as a risk factor for breast cancer..., Montroni [/bib_ref] When the lesions are multiple and involve the whole breast, prophylactic mastectomy or subcutaneous mastectomy with or without prosthesis reconstruction can be considered. [bib_ref] Clinical practice guidelines for sentinel lymph node biopsy in patients with early-stage..., Ye [/bib_ref] The panel believes that patients diagnosed with central or peripheral intraductal papilloma with ADH by CNB/VABB should be treated individually according to their specific conditions. If the patient has a single lesion and imaging shows that it has been completely removed, follow-up monitoring can be carried out; open extended resection is recommended in cases of uncertain complete resection. ## 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. [bib_ref] Breast papillomas: current management with a focus on a new diagnostic and..., Sarakbi1 [/bib_ref]	None	None	Intraductal papilloma of the breast is relatively common, Recommendations accounting for 5.3% of all benign breast diseases. However, relapse readily occurs with pathological changes such as atypical ductal hyperplasia (ADH) and canceration, and the rate of underestimation of biopsy diagnosis is high. Therefore, specific considerations are required for the diagnosis and treatment methods of intraductal papilloma, and some clinical problems with these methods remain controversial. To standardize the diagnosis and treatment of intraductal papillomaof the breast andprovide a reference for the clinicalworkof breast specialists, Chinese Society of Breast Surgery has determined the key clinical issues of the clinical practice guidelines for intraductal papilloma of the breast through a literature search and expert discussion. The relevant evidencewas evaluatedwith reference to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, and the Clinical Practice Guidelines for Intraductal Papilloma: Chinese Society of Breast Surgery (CSBrS) practice guidelines 2021 was formulated to provide a reference for the clinical work of breast surgeons in China.
f4007b8903f395c40c142c989969597025b84c09	pubmed	ACMG practice guideline: Genetic evaluation of short stature	ACMG practice guideline: Genetic evaluation of short stature Disclaimer: This guideline is designed primarily as an educational resource for health care providers to help them provide quality medical genetic services. Adherence to this guideline does not necessarily assure a successful medical outcome. This guideline should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient's record the rationale for any significant deviation from this guideline.Abstract: Short stature is a common indication for genetic evaluation. The differential diagnosis is broad and includes both pathologic causes of short stature and nonpathologic causes. The purpose of genetic evaluation for short stature is to provide accurate diagnosis for medical management and to provide prognosis and recurrence risk counseling for the patient and family. There is no evidence-based data to guide the geneticist in an efficient, cost-effective approach to the evaluation of a patient with short stature. This guideline provides a rubric for the evaluation of short stature evaluation and summarizes common diagnoses and clinical testing available. Genet Med 2009:11(6):465-470. ## Objective To provide guidance for medical geneticists and other physicians regarding genetic evaluation of pathologic short stature. # Background information Short stature is a common reason for referral for pediatric subspecialty evaluation. The purpose of genetic evaluation of short stature is to provide an accurate diagnosis and to provide information to the patient and family regarding natural history, prognosis, available treatment, genetic basis, and recurrence risk. Potential diagnoses include familial short stature, constitutional delay of growth, occult pulmonary, renal or gastrointes-tinal disease, endocrinopathies, and genetic disorders. These categories are not mutually exclusive, and the molecular basis of many causes of short stature has already been, and continues to be, elucidated. Depending on the availability of the various subspecialists in the geographic area and the presence or absence of associated physical or developmental concerns, the medical geneticist may be one of the first to evaluate an individual with a primary indication of short stature or may be asked to provide consultation regarding genetic testing once a diagnosis is made by other physicians. If the medical geneticist is the primary consultant in the evaluation of an individual with short stature, then he or she must be familiar with the common nonpathologic conditions associated with short stature in addition to the teratogenic and genetic causes. One study reported 353 patients referred for genetic evaluation with the primary indication of short stature (defined as height Ͻ3rd centile). Almost 50% of the patients were considered to have either constitutional delay of growth or familial short stature. The most common pathologic diagnosis was chromosome abnormality (19%), primarily Turner syndrome, and its variants. In 3% of cases, a diagnosis of a recognized multiple malformation syndrome was made, and in almost 2% a previously unrecognized endocrine cause was identified. [bib_ref] Evaluation of referrals for genetic investigation of short stature in Hong Kong, Lam [/bib_ref] The majority of information and guidelines for evaluation of individuals, usually children, with short stature comes from the pediatric endocrinology literature, particularly addressing evaluation for growth hormone deficiency and indications for growth hormone therapy. Although there are a multitude of publications regarding identification of genes associated with growth and gene defects associated with short stature, there is a paucity of information directed toward the medical geneticist's approach to short stature and appropriate genetic testing. The most recent publication that specifically addressed the diagnostic approach to genetic causes of short stature was issued more than 20 years ago. [bib_ref] A diagnostic approach to genetic causes of short stature, Hall [/bib_ref] More recently, Kant et al. [bib_ref] Genetic analysis of short stature, Kant [/bib_ref] suggested an algorithm for the molecular diagnosis of short stature, although syndromes that may present with only minor anomalies were not included. There is currently no evidence-based literature to support the diagnostic evaluation of short stature by the medical geneticist. This guideline will assume that nonpathologic familial short stature, constitutional delay of growth, hypothyroidism, and occult disease have been ruled out as a cause for short stature. This guideline is also meant to apply to patients who might present for genetic evaluation with the chief concern of short stature, although minor anomalies and some major anomalies may be identified. It is not intended to include all genetic conditions for which short stature may be a feature. Selected inborn errors of metabolism are included if they are associated with other physical features or skeletal changes. A brief review of nonpathologic causes of short stature is included. A diagnostic algorithm is presented along with information regarding availability and utility of molecular testing for specific genes associated with short stature and intrauterine growth restriction (IUGR). ## Analysis of growth and pertinent historical information The first assessment that must be made when a child presents with short stature is whether a pathologic diagnosis is likely to be present. There are several factors that one must consider in the evaluation of short stature, including genetic potential for growth, rate of growth, and pattern of growth. The definition most commonly used for short stature is height-for-age less than two standard deviations below average for gender, which is demonstrated on the standard growth curves as a length or height less than the 3rd centile. Standard growth curves used in the United States are based on a North American population; these curves may not apply to all racial and ethnic groups, for which specific growth curves may or may not be available. The single most common useful indicator, in addition to the absolute height, is growth velocity. Growth velocity is ideally assessed by reviewing previous growth points or by remeasurement over a 4 -6 month interval. Crossing of several centile lines between 3 years of age and late childhood or early adolescence suggests a pathologic diagnosis. Healthy large infants, however, often cross centiles in the first 3 years of life and establish a new growth curve more appropriate for their genetic potential. [bib_ref] The short child, Vogiatzi [/bib_ref] Genetic potential or target height is estimated for boys by calculating the (father's height [cm]) ϩ (mother's height [cm] ϩ 13)/2 and for girls (father's height [cm]) ϩ (mother's height Ϫ 13)/2. Most children will reach an adult height within 10 cm of the target height. The centile for this target height at age 18 years can be helpful to determine if the child is likely, at his or her present height and age, to reach that potential. Analysis of other growth parameters, including weight and head circumference, are also important in the overall analysis of a child's growth pattern. In many pathologic types of short stature, weight is affected first, then height velocity, and finally brain growth (documented by head circumference). Low weight for height is more likely due to nutritional deficiency, chronic or occult disease, or other pathologic conditions. Children with endocrine disorders often have short stature with normal weight for height, or even relative obesity. [bib_ref] The short child, Vogiatzi [/bib_ref] Bone age, as a measure of skeletal maturity, can also be useful, although a delayed bone age (Ͻ2 standard deviations compared to the chronologic age) is nonspecific and associated with many different causes of short stature. Finally, analysis of body proportions, such as arm span-to-height ratio and upper to lower segment ratio are also helpful in documenting disproportionate short stature. Another key component of the evaluation is the time of onset of short stature. The small for gestational age (SGA) infant presents a special challenge for the medical geneticist. In this case, detailed information regarding familial birth measurements and growth pattern, maternal stature, parity, presence of more than one fetus, potential teratogenic exposures, onset of growth deficiency, placental function, amniotic fluid volume, and the presence or absence of structural anomalies are crucial to the assessment and evaluation. Restriction in fetal growth in the later stages of pregnancy is suggestive of placental insufficiency. Maternal health and surgical history are important to determine potential contribution to fetal growth restriction (e.g., maternal vascular disease, history of gastric bypass, or other surgery that could lead to maternal nutritional deficiency). Pathologic examination of the placenta can yield important clues to factors contributing to deficient fetal growth. The classic definition of IUGR or SGA is a fetus or infant whose length and weight are less than the 10th centile for the gestational age. By definition, then, up to 10% of normal infants could be classified as SGA. A common alternative definition is similar to that for postnatal onset of short stature: two standard deviations below the average for the gestational age and sex. Using this latter definition would likely lead to a higher proportion of infants with true pathologic growth deficiency. Depending on the cause, duration, and severity of the IUGR, the infant may or may not exhibit "catch up" growth. This "catch up" growth in otherwise healthy infants is usually complete by 2 years of age. [bib_ref] International Small for Gestational Age Advisory Board consensus development conference statement: management..., Lee [/bib_ref] Knowledge of familial growth patterns is also important in the evaluation of the infant or child with short stature. Constitutional delay of growth is suggested by deceleration of length/ height in the first 3 years of life, a normal or near-normal height velocity during childhood (4 -7 cm/year), delayed bone age and pubertal development, and final adult height within the normal range. Constitutional delay of growth can be familial; careful questioning of the parents about their childhood growth patterns and onset of puberty can be helpful. Familial short stature can be characterized by early deceleration in linear growth depending on the infant's birth measurements, a normal or near-normal growth velocity in childhood, normal bone age and pubertal development, and height as an adult that is short, but appropriate for the target height. ## Pathologic short stature A diagnostic approach to pathologic short stature is presented in [fig_ref] Figure 1: Diagnostic algorithm for genetic evaluation of short stature [/fig_ref]. This approach first requires that one differentiates between isolated short stature and short stature that is associated with other physical and/or developmental abnormalities. If the child falls within the latter group, the physician must then differentiate between proportionate and disproportionate short stature. A careful physical examination with measurements is necessary to determine whether there is a disproportionate body habitus. The differential diagnosis of isolated short stature includes nonpathologic and pathologic familial short stature, constitutional growth delay (as discussed earlier), a primary endocrinopathy [fig_ref] Table 1: Short stature with endocrinopathy [/fig_ref] , short stature in girls with X chromosome abnormalities (i.e., Turner syndrome or its variants), or short stature secondary to mutations in the SHOX gene. Although most SHOX gene mutations result in characteristic skeletal changes (Madelung deformity and mesomelia), mutations have also been identified in familial and simplex cases of idiopathic short stature. [bib_ref] High incidence of SHOX anomalies in individuals with short stature, Huber [/bib_ref] The skeletal changes of dyschondrosteosis may not be apparent until late childhood or pubertal age and are less commonly noted in males. [bib_ref] High incidence of SHOX anomalies in individuals with short stature, Huber [/bib_ref] The reported frequency of SHOX gene mutations in children with idiopathic short stature has varied from 1.1% to 12.5% depending on selection criteria and testing methodology. [bib_ref] SHOX mutations in idiopathic short stature and Leri-Weill dyschondrosteosis: frequency and phenotypic..., Jorge [/bib_ref] For this reason, skeletal survey should be considered in some cases of familial short stature to look for subtle changes that might be diagnostic. If there are any clinical or radiographic findings suggestive of dyschondrosteosis, SHOX gene testing could be considered. Skeletal survey should also be considered in cases with significant short stature (Ͼ3 standard deviations) if no other diagnosis is apparent. Review of the clinical, developmental, and family histories and a detailed physical examination are required to document the presence of major and/or minor malformations, degree of developmental delay if present, and other features that would suggest an underlying chromosome abnormality or recognizable syndrome. If physical examination reveals disproportionate short stature, a skeletal survey [fig_ref] Table 2: Dysmorphology skeletal survey [/fig_ref] is recommended to look for evidence of a skeletal dysplasia. Molecular genetic testing is available for confirmation of some of these conditions [fig_ref] Table 3: Selected skeletal dysplasias/dysostoses [/fig_ref]. In some of the more mild skeletal dysplasias, a skeletal survey performed in the first years of life may not be diagnostic, and periodic clinical and radiographic reevaluation is necessary. In other disorders, e.g., chondrodysplasia punctata, the characteristic features may be missed by taking the radiographs too late. If physical examination reveals proportionate short stature, a detailed physical examination may reveal signs that are consistent with a recognizable genetic syndrome. Molecular genetic testing is available for confirmation of some of these conditions [fig_ref] Table 4: Short stature and other anomalies Testing not available in the United States... [/fig_ref]. If physical examination does not suggest a recognizable syndrome, then chromosome analysis should be performed, which has the added advantage of addressing the potential of mosaicism. If this analysis is negative, genomic array studies may be considered to evaluate for changes in genome copy number. For the children with intrauterine onset of short stature, the approach is similar to that of the older child with short stature. Comparison should be made of the infant's birth weight, birth length and birth head circumference, body proportions, and documentation of major and minor anomalies. Depending on the age at which the SGA infant is being evaluated, assessment of the postnatal growth pattern will also yield clues to the underlying etiology. Selected syndromes associated with IUGR for which the genetic basis is known are presented in [fig_ref] Table 5: Selected IUGR syndromes DHCR7 A, S, TM AR a Testing for these... [/fig_ref]. Testing useful in the evaluation of infant with prenatal onset growth deficiency is presented in [fig_ref] Table 6: Evaluation of IUGR [/fig_ref]. If no diagnosis is apparent after initial clinical evaluation and appropriate laboratory or radiographic studies, periodic reassessment is indicated. The timing of reassessment will depend on the child's age, whether or not there are other significant developmental or physical features present, the family's interest or anxiety, and changes in the family history. A specific diagnosis may become apparent or the differential diagnoses altered with evolution of the phenotype and additional family history that may become available. Furthermore, new diagnostic tests and techniques may allow diagnosis or confirmation of a clinical diagnosis in the future. [fig] Figure 1: Diagnostic algorithm for genetic evaluation of short stature. [/fig] [table] Table 1: Short stature with endocrinopathy [/table] [table] Table 2: Dysmorphology skeletal survey [/table] [table] Table 3: Selected skeletal dysplasias/dysostoses [/table] [table] Table 4: Short stature and other anomalies Testing not available in the United States at the time of manuscript preparation. Cyt, cytogenetic analysis; AD, autosomal dominant; AR, autosomal recessive; Del/Dup, deletion/duplication analysis; FISH, fluorescence in situ hybridization; S, gene sequencing; Sp, sporadic; TM, targeted mutation analysis; XLD, X-linked dominant; XLR, X-linked recessive. [/table] [table] Table 5: Selected IUGR syndromes DHCR7 A, S, TM AR a Testing for these other causes not available in the United States at the time of manuscript preparation. A, analyte (biochemical); AD, autosomal dominant; AR, autosomal recessive; Cyt, cytogenetic analysis; Methyl, methylation; S, gene sequencing; TM, targeted mutation analysis; UPD, uniparental disomy. [/table] [table] Table 6: Evaluation of IUGR [/table]	None	https://www.nature.com/articles/gim200966.pdf	Short stature is a common indication for genetic evaluation. The differential diagnosis is broad and includes both pathologic causes of short stature and nonpathologic causes. The purpose of genetic evaluation for short stature is to provide accurate diagnosis for medical management and to provide prognosis and recurrence risk counseling for the patient and family. There is no evidence-based data to guide the geneticist in an efficient, cost-effective approach to the evaluation of a patient with short stature. This guideline provides a rubric for the evaluation of short stature evaluation and summarizes common diagnoses and clinical testing available.
1fbcbcd4a6b838f55b8419f469ff3f1ca4de0c20	pubmed	Effectiveness guidance document (EGD) for Chinese medicine trials: a consensus document	Effectiveness guidance document (EGD) for Chinese medicine trials: a consensus document Background: There is a need for more Comparative Effectiveness Research (CER) on Chinese medicine (CM) to inform clinical and policy decision-making. This document aims to provide consensus advice for the design of CER trials on CM for researchers. It broadly aims to ensure more adequate design and optimal use of resources in generating evidence for CM to inform stakeholder decision-making.Methods: The Effectiveness Guidance Document (EGD) development was based on multiple consensus procedures (survey, written Delphi rounds, interactive consensus workshop, international expert review). To balance aspects of internal and external validity, multiple stakeholders, including patients, clinicians, researchers and payers were involved in creating this document.Results: Recommendations were developed for "using available data" and "future clinical studies". The recommendations for future trials focus on randomized trials and cover the following areas: designing CER studies, treatments, expertise and setting, outcomes, study design and statistical analyses, economic evaluation, and publication. Conclusion: The present EGD provides the first systematic methodological guidance for future CER trials on CM and can be applied to single or multi-component treatments. While CONSORT statements provide guidelines for reporting studies, EGDs provide recommendations for the design of future studies and can contribute to a more strategic use of limited research resources, as well as greater consistency in trial design. # Background Chinese medicine (CM) includes a broad range of medical practices that have many of their roots in China and share common theoretical concepts. According to the description by the National Center for Complementary and Alternative Medicine (NCCAM) CM 'encompasses many different practices, including acupuncture, moxibustion (burning an herb above the skin to apply heat to acupuncture points), Chinese herbal medicine, tuina (Chinese therapeutic massage), dietary therapy, and tai chi and qigong (practices that combine specific movements or postures, coordinated breathing, and mental focus). In general, CM follows a theoretical framework, and the etiology and pathogenesis of CM uses its own terminology. The processes of diagnoses and interventions of this medical system are different from those in conventional medicine, and both are guided by traditional principles of CM. CM is often used as a multi-component treatment in which cultural, philosophical, historical, temporal, and geographic aspects as well practitioner training, all influence its heterogeneity. From the practitioner's perspective, CM diagnoses (for example, bian zheng), often also called CM patterns or CM syndromes differentiation, inform CM interventions. To date, treatment individualization according to the CM diagnoses seems to have very little clinically relevant impact on the outcome of acupuncture treatment in clinical studies [bib_ref] A randomized trial comparing acupuncture, simulated acupuncture, and usual care for chronic..., Cherkin [/bib_ref] [bib_ref] The effect of prophylactic acupuncture treatment in women with recurrent cystitis: kidney..., Alraek [/bib_ref] , whereas it might be more relevant for clinical trials of CM pharmacotherapy [bib_ref] Treatment of irritable bowel syndrome with Chinese herbal medicine: a randomized controlled..., Bensoussan [/bib_ref] [bib_ref] Pattern differentiation in traditional Chinese medicine can help define specific indications for..., Lu [/bib_ref] , although evidence is still scarce. In practice, CM treatment is often individualized, and because CM diagnoses may change over time, interventions can also change during the course of treatment. Currently in China, standardization of CM diagnoses and treatment for practice and research is emphasized, whereas in the West, a trend toward more individualization in research protocols and in practice is observed. ## Aim of the document This document provides consensus advice for the design of comparative effectiveness research (CER) trials in CM for researchers. CER is the generation and synthesis of evidence that compares the benefits and harms of alternative treatment options to prevent, diagnose, treat, and monitor a clinical condition or to improve the delivery of care. The purpose of CER is to assist consumers, clinicians, purchasers, and policy makers to make informed decisions that will improve health care at both the individual and population levels. CER broadly aims to ensure more adequate design and optimal use of resources in generating evidence for CM to inform stakeholder decision-making. These consensus recommendations can be applied to single and multicomponent interventions. They are based on the assumption that a reduction of internal validity can be justified in order to increase authenticity of the intervention and setting, thereby enhancing generalizability, relevance, feasibility and timeliness of research results. # Methods The development of the Effectiveness Guidance Document (EGD) followed a structured and predefined consensus process, which included a pre-workshop online survey (April 2012), a consensus workshop (19 May 2012 in Portland, OR, USA), and three written Delphi rounds (August 2012, January 2013 and May 2013) utilizing written comments to finalize the document. Multiple stakeholders were involved in the consensus process for this EGD to balance aspects of internal and external validity in the recommendations. Participants of the workshop had the following backgrounds: one CM patient, one health insurance representative, nine experts in CM with experience in both CM practice and CM research (two from China, two with a Chinese background living in the USA, four from the USA, and one from UK), and 6 methodologists (with backgrounds in clinical research, statistics or epidemiology, 5 of them with experience in CM research). The consensus meeting utilized presentations, large group discussions and an adapted world café methodology. The world café method, as developed by Brown and Isaac, is a simple, effective, and flexible format for facilitating large group dialogue. It has been used in the development of prior EGDs [bib_ref] Effectiveness guidance document (EGD) for acupuncture research -a consensus document for conducting..., Witt [/bib_ref] to foster collaborative dialogue, knowledge sharing, and community participation in a setting that involves multiple stakeholder groups. Expert involvement was further broadened by the inclusion of nine international CM research experts who did not participate in the workshop, but who contributed to the survey and both Delphi rounds. The consensus process was finalized after feedback from all workshop participants and the external review experts. # Results The results of the consensus process are presented in two sections: I) Using available data, II) recommendations for future clinical studies. clarify whether the CM treatment is to be assessed as an "alternative" in direct comparison, using a superiority or non-inferiority hypothesis, or as an adjunct to a usual or standard care treatment. b) During the trial planning phase, time should be given to discuss and determine the trial's position along the efficacy-effectiveness continuum [bib_ref] How well do randomized trials inform decision making: systematic review using comparative..., Witt [/bib_ref]. Use of the PRECIS tool to support this process is recommended [bib_ref] A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers, Thorpe [/bib_ref]. [bib_ref] Improving the reporting of pragmatic trials: an extension of the CONSORT statement, Zwarenstein [/bib_ref]. b) Multi-arm trials may help to identify dosing effects, synergistic effects when combining different CM interventions, and effective components within one treatment modality (for example, isolating meditative and breathing components from comprehensive qigong/tai chi protocols). c) The complexity of therapeutic decision-making and treatment changes within the treatment process could be reflected by designs as demonstrated by Ritenbaugh et. al. [bib_ref] Reductions in pain medication use associated with traditional Chinese medicine for chronic..., Elder [/bib_ref] [bib_ref] Comparative effectiveness of traditional Chinese medicine (TCM) and psychosocial care in the..., Ritenbaugh [/bib_ref]. ## Study population 4) General eligibility criteria a) In the context of available resources, eligibility criteria should be as broad as possible. The SPIRIT for content of clinical trial protocols X X [bib_ref] SPIRIT 2013: new guidance for content of clinical trial protocols, Chan [/bib_ref] CONSORT for parallel group randomized trials X [bib_ref] CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised..., Moher [/bib_ref] CONSORT extension for pragmatic trials X [bib_ref] Improving the reporting of pragmatic trials: an extension of the CONSORT statement, Zwarenstein [/bib_ref] CONSORT for non-pharmacological trials X [bib_ref] Extending the CONSORT statement to randomized trials of nonpharmacologic treatment: explanation and..., Boutron [/bib_ref] CONSORT extension for cluster randomized trials X [bib_ref] CONSORT statement: extension to cluster randomised trials, Campbell [/bib_ref] CONSORT extension for acupuncture trials X [bib_ref] Revised standards for reporting interventions in clinical trials of acupuncture (STRICTA): extending..., Macpherson [/bib_ref] CONSORT extension for herbal interventions X [bib_ref] Reporting randomized, controlled trials of herbal interventions: an elaborated CONSORT statement, Gagnier [/bib_ref] CONSORT extension for non-pharmacological treatment interventions X [bib_ref] Methods and processes of the CONSORT Group: example of an extension for..., Boutron [/bib_ref] CONSORT extension for traditional Chinese medicine X [bib_ref] Consolidated standards of reporting trials (CONSORT) for traditional Chinese medicine: current situation..., Bian [/bib_ref] CONSORT extension for patient reported outcomes X [bib_ref] Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO extension, Calvert [/bib_ref] Guidelines for randomized controlled trials investigating Chinese herbal medicine X [bib_ref] Guidelines for randomised controlled trials investigating Chinese herbal medicine, Flower [/bib_ref] Extending the CONSORT statement to moxibustion X [bib_ref] Extending the CONSORT statement to moxibustion, Cheng [/bib_ref] CONSORT = Consolidated Standards of Reporting Trials. criteria should reflect the evidence of the pattern of usage and disease burden, and the study population should reflect all well-known relevant disease characteristics that may interact with the treatment (for example, gender, disease stage, comorbidities, co-medications). b) Patients with comorbidities should not be explicitly excluded from the study enrollment unless the comorbidities make them inappropriate candidates for the treatment, but safety and regulatory aspects have to be taken into account (for example, when using herbs). c) Both CM naïve and non-naïve patients should generally be considered eligible for study inclusion to reflect real-world patient population. If special groups are targeted, the rationale should be provided. ## 5) diagnosis a) The study disease/condition should be defined as clearly as possible from the Western medical approach as well the CM approach. b) In general, recruitment of patients should initially follow the Western diagnostic approach. c) CM diagnoses should subsequently be made in all treatment groups (before randomization in randomized studies) and documented whenever Treatment, expertise and setting 7) Defining treatment groups a) The treatment alternatives (CM treatments and non-CM treatments) should each provide value to the patient by having the potential to be "best practice". In the absence of a clear evidence base "best practice" of CM can be derived by 1) reviewing alternatives that have been effective in addressing similar issues in the past and could be applied to a current problem, and 2) integrating information from a number of sources (recommended research protocols, existing clinical data, reference to classical usage, and formal consensus procedures). If a direct "head-to-head" comparison is used, all treatment options should reflect usual care as much as possible, and ideally the extent of standardization should be similar in all treatment groups. [bib_ref] Effectiveness guidance document (EGD) for acupuncture research -a consensus document for conducting..., Witt [/bib_ref]. 9) Special aspects of qigong/tai chi a) A large number of Qigong/Tai Chi styles exist and the chosen style(s) for a research trial should represent to some extent the real world heterogeneity of practice in the country where the study is performed. b) If a very specific style is used, it must be justified (specific style or protocol found to be effective in prior studies, or potential for widespread adoption), and limits to generalizability should be acknowledged. c) The setting in which qigong and tai chi is offered should be accessible and reflect typical community-based programs; the longer-term (post-study) sustainability of the program should be considered (access to training, classes or instruction). d) qigong/tai chi should be provided by qualified instructors, with expertise in both protocol content and teaching. Training and teaching qualifications of all instructors should be reported. In studies of high-risk populations, treatment safety should play a prominent role, using more expert instructors and protocols validated with respect to safety. e) Studies should provide information that specifies exercises (names and style), dose (number and duration of classes, home exercise) and ancillary training materials offered (for example, books and audio-visual material). 10) Special aspects of herbal medicine a) Study designs must comply with local and national regulations regarding herbal medicines in the country of the clinical trial. Although widely used in everyday practice, and in spite of the fact that research is urgently needed, research on individualized, multi-herb formulations is very difficult to accomplish in most Western countries due to government regulations and Institutional Review Board approval. b) The treatment should be based on existing evidence (systematic review of Chinese as well as European and US-based databases, survey of normal practice, practitioner case records, etc.), should have "model validity" within CM, and provide a rationale for "good practice" in CM. c) It must be assured that the treatment does not include any endangered species. d) Herbal formulations that include different herbs need to be adequately defined (chemically to assure quality of herbs and negative consequences of the treatment experience, often seemingly unrelated to the main outcomes). 13) Timing a) Outcomes should be evaluated over a sufficient long period to capture true impact on chronicity of disease and to distinguish this from short term or intermittent relief. b) The use of multiple intervals to document and compare the trajectory and persistence of treatment effects is recommended. Data collection methods that do not have a direct influence on the treatment plan (for example, text messages, phone calls, smart phone applications) are recommended. However, the frequency of assessment should be balanced, so that relevant information is gained without major disruptions of treatment implementations or practice setting and with minimal risk of respondent overload. ## Study design and statistical analysis 14) Allocation methods a) Use of appropriate allocation methods is strongly recommended. Randomization at the level of individual patients is still the most frequently used method, but dynamic allocation procedures (for example, rank minimization) may be used as an alternative. The final choice depends on the design of the study and the sites at which the study will be conducted [bib_ref] Rank-minimization with a two-step analysis should replace randomization in clinical trials, Taves [/bib_ref]. b) Stratified randomization or adaptive allocation techniques may be used to prevent imbalances for relevant covariates and potential confounders in study arms [bib_ref] Statistical issues in the use of dynamic allocation methods for balancing baseline..., Pond [/bib_ref]. c) Partially randomized patient preference designs have an advantage in that they provide additional exploratory information as to whether the results observed for randomized patients are different from those who were not randomized because of treatment preferences. However, these designs, while adding potentially important outcome data to a clinical trial, are often not feasible because of the need for much larger sample sizes and higher costs [bib_ref] A two-stage trial design for testing treatment, self-selection and treatment preference effects, Rucker [/bib_ref]. d) Cluster randomization is the best approach under circumstances where the randomization of social units (for example, clinics) is advisable to avoid contamination of treatments between groups. When planning such a trial, it is necessary to consult the relevant literature and local institutional roles to determine from whom, when, and how informed consent must be obtained [bib_ref] Ethical issues posed by cluster randomized trials in health research, Weijer [/bib_ref] , and to take into account that a larger sample might be needed than in patient level randomized trials, because the trials are powered based on the number of participating units. e) Standard procedures ensuring allocation concealment (for example, central randomization or secure databases) should be employed. 15) Blinding a) Blinded outcome measurement (for example, a blinded rater) is recommended in order to reduce bias, especially for outcomes that, in usual clinical practice, are assessed by the practitioner (for example, physical assessments). Methods to minimize the risk of unblinding (for example, allocation concealment, rater training, standardized assessment protocol) should be employed. b) Data analyses should be blinded whenever possible. c) Outcomes data reported by patients for the study purpose (for example, quality of life assessment) should be kept inaccessible to the practitioner (for example, by using sealed envelopes or preferably by sending questionnaires directly to a study office independent of the study site or using a blinded interviewer). d) Recommendations for blinding the treatment (for example, when using a double dummy placebo for the comparison of herbal medicine with conventional drugs) are provided in the guidelines developed in the European Union funded GP-TCM project. 16) Patient preferences and expectations a) Patient preferences should, if appropriate, be acknowledged in the study design, e.g., by using a partially randomized patient preference design. If such a design is not feasible, then it is important to document both the patients' preferences regarding the treatment options available in the trial as well as the degree of their knowledge and experience with these treatment options. b) Assessing patient and practitioner preferences and expectations for the treatments offered in the study at baseline should be considered. In randomized trials they should be assessed before randomization and for all available treatment options. 17) Sample size a) Sample size should focus on the main outcome(s) and the minimum clinically important difference (MCID) for the respective outcome(s) and take into account greater heterogeneity in CER study populations. Because of this, researchers should specifically avoid conducting small trials (< 50 In order to assess real-world effectiveness of treatments, benefits and harms should be compared in relation to the treatment to which patients were assigned. b) Analyses should adjust for relevant potential confounders (for example, baseline value of the outcome measure, stratification variables, expectation, and baseline CM diagnosis). c) Especially in non-randomized studies, procedures to compensate for baseline differences must be used (for example, matching and/or adjusted analysis). ## Economic evaluations ## 20) Relevance a) Comparing the effectiveness of treatment options should be the primary aim of CER, but economic evaluations should be included whenever possible as a secondary aim. b) To allow realistic cost estimates, the setting(s) of the study should reflect the real-world clinical practice for each treatment as closely as possible. If a study includes a standardized and a non-standardized CM arm, it would be useful to compare their cost-effectiveness. 21) Methodological approach a) Standard effectiveness measures for economic evaluations should be employed that include both benefits and harms (for example, utility measures based on SF-36, SF-12 or EQ-5D). b) Economic evaluations should be designed to reflect stakeholder perspectives with sensitivity analysis performed, whenever possible, from different stakeholder perspectives (for example, society, payer and patient). Because CM is often paid out-of-pocket, the patient's perspective is highly relevant. c) Requirements of the local context (for example, guidelines by regulatory agencies) should be taken into account. d) Subgroup analyses should mainly focus on subgroups defined a priori for the effectiveness study. Additional analyses should be clearly described as exploratory. A subgroup analysis for gender is recommended since there is preliminary evidence that gender may influence the cost-effectiveness of CM treatment [bib_ref] Cost-effectiveness of acupuncture in women and men with allergic rhinitis: a randomized..., Witt [/bib_ref]. e) Exploratory analyses of factors that predict a better cost-effectiveness are suggested to develop future hypotheses. 22) Observation time a) Long-term observations with intermediate measurement time points are highly recommended for economic evaluations of chronic disease in order to evaluate development of cost-effectiveness over time. ## Publication ## 23) existing guidelines To ensure that CER on CM will fulfill reporting standards, the relevant CONSORT guidelines should be followed (see [fig_ref] Table 1: Relevant guidelines for design and reporting [/fig_ref]. 24) Content a) Publication of a detailed study protocol (design publication) should take place whenever possible prior to the recruitment of the last patient. b) The study should be registered in an internationally accessible trial database with as many details as possible provided. c) Publication of the completed study should describe why and how it qualifies as CER and make clear the phase of the study. d) The setting of the study should be described, including information about the typical care setting in the country where the study was performed (and, if relevant, in other countries). The procedure for selection of practitioners for each treatment group should be described, with an account of whether and how those included in the study differ from the average practitioner (for example, training, experience). e) Information on how patients were informed about the treatment options should be provided. f ) If a usual-care or standard-care comparison group is used, a detailed description with citations for standard care should be included in the intervention section. g) Detailed results of all treatments should be presented; adherence to interventions and co-interventions should be reported for each group. h) Whenever possible, the most relevant subgroup analyses and analyses of patient characteristics that predict a better outcome should be published together with primary results. Detailed subgroup analysis and/or de-identified patient level data can be provided as online files. # Discussion This is the first EGD for clinical research involving a complex and multi-component medical system, providing detailed advice for the design of CER in the field of Chinese medicine for single as well as multi-component treatments. This EGD has been derived from a systematic development process, with active involvement of different stakeholders from the West and China, and aims to inform researchers inside and outside China when designing their trials. The involvement of China-based stakeholders reflects both the geographic roots of CM and a growing interest in CER studies in China. During the development process, stakeholder groups uncovered a broader understanding of the complexity of a multi-component treatment, the cultural differences in CM practice and research between China and other countries, and the resulting challenges for the study design. The heterogeneity of CM as practiced in different countries made it necessary to develop recommendations that account for these variances of style and context. China has a strong research focus on herbal medicine, however this is less common in other countries due to regulatory requirements. Herbal medicine trials have unique challenges and within this consensus process we were only able to discuss the most prominent ones. For CM herbal medicine trials, it is recommended that the guidelines for randomized controlled trials investigating Chinese herbal medicine be utilized [bib_ref] Guidelines for randomised controlled trials investigating Chinese herbal medicine, Flower [/bib_ref]. A limitation of consensus procedures is that not all aspects of the study design can be addressed. For example, no recommendations for the study sites were discussed. There was discussion about the adequacy of comparison groups, but because of the broad range of optional research questions and the multifold combination of interventions, no detailed recommendations were made. However, there was consensus that the comparison group(s) should have the option for best practice and should be based on guidelines or broad expert consensus as recommended under point 7. Within the process, several methodological aspects unique to CM were identified that need further research and clarification. For example, the CM diagnosis classification system and the heterogeneity of its application need research to ensure overall validity and reliability. Another example is that the CM treatment benefits should also be measurable in CM terms. This goal may be complicated by aspects of CM's explanatory model that aims to restoring balance or increasing resilience, for which suitable outcome measures are not yet developed. # Conclusion Although CONSORT statements provide guidelines for reporting studies, EGDs provide recommendations for the design of future studies and can contribute to a more strategic use of limited research resources as well as greater consistency in trial design. In particular, the present EGD provides the first set of systematic methodological guidance for future CER on CM. ## Competing interests The workshop was funded by The Institute for Integrative Health (TIIH), Baltimore MD, USA, a non-profit organization. Brian Berman is the president of TIIH, which supported Claudia Witt with a travel grant for the submitted work. Authors' contributions CMW: designed the study, coordinated the consensus process, participated in the workshop and Delphi rounds, collected and analyzed the data, wrote the first draft of the work, revised the manuscript and approved the final version. MA: participated in the workshop and Delphi rounds, revised the work critically for important intellectual content and approved the final version, DC, CC, CE, AF, RH, JL, LL, SP, CR, RS, PW, BZ and BB: participated in the workshop and Delphi rounds, revised the work critically for important intellectual content and approved the final version, LR and JY: participated in the workshop and Delphi rounds and approved the final version, SW: participated in the coordination and data collection and the workshop, revised the work critically for important intellectual content and approved the final version, CMW and BB are guarantors for the paper and accept full responsibility for the work and controlled the decision to publish. [table] Table 1: Relevant guidelines for design and reporting [/table]	None	https://trialsjournal.biomedcentral.com/counter/pdf/10.1186/1745-6215-15-169	None
e047d3c7ae17e646eefc5b0c43d5e9d8cb6f8b24	pubmed	Clinical practice guidelines for multigene assays in patients with early-stage breast cancer: Chinese Society of Breast Surgery (CSBrS) practice guidelines 2021	Clinical practice guidelines for multigene assays in patients with early-stage breast cancer: Chinese Society of Breast Surgery (CSBrS) practice guidelines 2021 [bib_ref] Use of biomarkers to guide decisions on adjuvant systemic therapy for women..., Krop [/bib_ref] ## 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 There were 81 voting committee members for these guidelines: 70 from breast surgery departments (86.4%), 2 from medical oncology departments (2.5%), 4 from medical imaging departments (4.9%), 2 from a pathology department (2.5%), 2 from a radiotherapy department (2.5%), and 1 epidemiologist (1.2%). ## Target audience Clinicians specializing in breast diseases in China. I [bib_ref] Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive..., Paik [/bib_ref] B * Oncotype Dx ® Recurrence Score. ## Recommendations # Discussion In recent years, the US Food and Drug Administration (FDA) and numerous international bodies have approved and recommended the 70-gene (MammaPrint ® ) and 21gene (Oncotype Dx ® ) assays for clinical practice with highlevel evidence. [bib_ref] Use of biomarkers to guide decisions on adjuvant systemic therapy for women..., Krop [/bib_ref] [bib_ref] Breast cancer, version 3.2020, nccn clinical practice guidelines in oncology, Gradishar [/bib_ref] The expert panel agreed that multigene assays are of great value in adjuvant treatment decisionmaking, with 97% of experts voting for a strong recommendation for the 70-gene assay and 73% for a weaker recommendation for the 21-gene assay. Several points need to be noted for this study. First, T3-T4 patients only accounted for 1.2% of the enrolled patients, the expert panel recommended that chemotherapy is appropriate for patients with T1-T2 disease. Second, majority of patients were node-negative (79%), while node-positive patients with 1-3 nodes accounted for 14.1%, 4.5%, and 2.3%, respectively, suggesting that this study is mainly applicable to 0-3 nodes-positive patients. Up to 88.4% of patients were HR-positive, and up to 90.3% were HER2-negative, suggesting that this study is mainly applicable to HR-positive and HER2-negative patients. Third, the clinical "risk" stratification of this study is based on the improved Adjuvant! Online tool, which includes tumor size, node stage, histological grade, HR and HER2 status, but does not include age and tumor thrombus. The so-called clinical "low-risk" or "high-risk" differs from the conventional St. Gallen expert consensus on the risk of recurrence after breast cancer surgery. [bib_ref] Progress and promise: Highlights of the international expert consensus on the primary..., Goldhirsch [/bib_ref] The 21-gene assay (Oncotype Dx ® ) is currently the most widely used multigene panel and prognosis analysis method for HR-positive breast cancer patients in the USA. The result of the TAILORx study provides high-level evidence for the clinical application of the 21-gene assay in practice (See details in the Supplementary file, http://links. lww.com/CM9/A820). In recent years, three other breast cancer assay tools, EndoPredict, [bib_ref] Prediction of chemotherapy benefit by endopredict in patients with breast cancer who..., Sestak [/bib_ref] PAM50, ® [bib_ref] Pam50 risk of recurrence score predicts 10-year distant recurrence in a comprehensive..., Laenkholm [/bib_ref] [bib_ref] Comparison of the performance of 6 prognostic signatures for estrogen receptor-positive breast..., Sestak [/bib_ref] and BCI, [bib_ref] Breast cancer index and prediction of benefit from extended endocrine therapy in..., Bartlett [/bib_ref] have also been widely recommended. These tools are not yet predictive of chemotherapy benefits and are not available in China, so they were not discussed by the expert panel. The expert panel explicitly recommended that multigene assay indications include: T1-T2 and HR-positive, HER-2negative, node-negative or limited metastasis (1-3), and high-risk patients. The expert panel emphasized that ER, PR, and HER-2 status should be determined before assay. The assays are not recommended for TNBC and HER-2positive patients nor are they recommended for patients with >3 positive nodes. Decisions for chemotherapy are also not recommended for ER/PR-positive, HER-2-negative, node-negative, and clinically low-risk patients. Extended endocrine therapy based on gene test results is not recommended. Patients who are not suitable for chemotherapy due to complications, tumor stage, risk level, and other factors and who clearly need chemotherapy do not need routine genetic testing. Multigene assays including the 70-gene and 21-gene assay have uniform and strict technology standards. The analysis and interpretation of biological data is tightly controlled, which provides an important guarantee for rigorous and credible results and lays the foundation for reasonable clinical application. The expert panel stressed that any 70-gene and 21-gene assay not labeled Mammaprint ® or Oncotype Dx ® is different from the genuine Mammaprint ® and Oncotype Dx ® assays. Clinicians should be cautious about evaluating the clinical value of these assays. www.cmj.org The expert panel suggested that the following should be clarified when recommending polygenic testing for patients. First, accurate multigene assay information is helpful for clinicians to make treatment decisions based on clinical and pathological data. Gene information acquired from clinical pathology may be inconsistent, and clinicians should combine genetic and clinical-pathological results to formulate treatment plans. Multidisciplinary consultations (MDT) should be conducted when necessary. Second, the sample used for polygenic testing should be the primary tumor of invasive cancer tissue in patients with indications. The accuracy of the test is closely related to the amount of tissue, and the representative and pathological fixation status. The specific slice requirements may vary according to different tools. It is recommended that doctors should have a detailed understanding of the methods used and the tissue section requirements of the cancer tissue sectioning before testing. Third, the consistency of the results among the different tools is controversial. [bib_ref] Molecular drivers of oncotype dx, prosigna, endopredict, and the breast cancer index:..., Buus [/bib_ref] That is, for the same patient, using different multigene assays, the results may not be the same. Fourth, it must be objectively recognized that the current multigene research is mainly based on the results of the Western population, and the research on the Chinese population is still relatively small. The expert panel recommended that, with the support of national policies, multi-center research on multigene panels should be carried out to formulate national standards suitable for China's national conditions. Fifth, the costs of gene assays are relatively expensive, and, as results between the different assays may be inconsistent, doctors need to make individualized selections according to the specific clinical conditions. List of Compiling Committee Members (in alphabetical order by surname)	None	None	The role of multigene assays in chemotherapy decisionThere were 81 voting committee members for these making in patients with early invasive breast cancer has been widely recognized. In 2017, the American Society of Clinical Oncology (ASCO) clinical guidelines for multigene profiling assays focused on increasing the intensity of recommendations for the clinical use of MammaPrint ® . The 8th edition of the American Joint Committee on Cancer (AJCC) staging system, officially launched in2018, established the concept of prognostic staging for the first time, adding the use of nonanatomical information to evaluate the prognosis. Initially, Oncotype Dx ® was recommended for suitable patients based on Level I evidence. Subsequently, five testing techniques, Oncotype Dx ® , MammaPrint ® , EndoPredict ® , PAM50 ® , and BCI, were formally incorporated into the system. To assist breast disease specialists in China in their selection of appropriate multigene profiling assays and detection methods for patients, and also to instill caution on decisionmaking with reference to multigene assays, the Chinese Society of Breast Surgery (CSBrS) has, through literature investigation and expert discussion, provided information on the key clinical problems and guidelines for the use of multigene assays, evaluating the evidence with reference to the Grades of Recommendations Assessment Development and Evaluation (GRADE) system. Combined with the availability of these assays inChina, the clinical practice guidelines for multigene assays were formulated and published. The purposeof this guideline is toprovidea reference for clinicians specializing in breast diseases in China.
8f12e3220914b11b04fa386ed52cc9e703a0a97f	pubmed	Management of rheumatoid arthritis: summary of NICE guidance	Management of rheumatoid arthritis: summary of NICE guidance This is one of a series of BMJ summaries of new guidelines, which are based on the best available evidence; they highlight important recommendations for clinical practice, especially where uncertainty or controversy exists. ## Referral, diagnosis, and investigations - Refer for specialist opinion anyone with suspected persistent synovitis of undetermined cause. Refer urgently even if blood tests show a normal acute-phase response or negative rheumatoid factor and if: -The small joints of the hands or feet are affected -More than one joint is affected, or -There has been a delay of three months or longer between symptom onset and seeking medical advice. [Based on high and moderate quality observational studies of early prognosis and identification or diagnosis] - Offer to test for rheumatoid factor in people with suspected rheumatoid arthritis who have synovitis. [Based on high and moderate quality early identification observational studies] - Consider measuring anticyclic citrullinated peptide antibodies in people with suspected rheumatoid arthritis if: -They are negative for rheumatoid factor, and -Combination therapy is being considered (see section on disease modifying antirheumatic drugs). [Based on data from case series] - X ray the hands and feet early in people with persistent synovitis in these joints.[Based on high and moderate quality early identification studies] ## Communication and education - Offer verbal and written information to people with rheumatoid arthritis to: -Improve their understanding of the condition and its management, and -Counter any misconceptions they may have. - For those wishing to know more, offer participation in existing educational activities, including self management programmes. [Both recommendations are based on high and moderate quality meta-analyses, randomised controlled trials, and the GDG's opinion] The multidisciplinary team ## Non-steroidal anti-inflammatory drugs - When offering an oral NSAID or COX 2 inhibitor, the first choice should be either a standard NSAID or a COX 2 inhibitor (other than etoricoxib 60 mg) at the lowest effective dose for the shortest possible time. In either case, coprescribe a proton pump inhibitor with the lowest acquisition cost. - All oral NSAIDs and COX 2 inhibitors have analgesic effects of a similar magnitude but vary in their potential gastrointestinal, liver, and cardiorenal toxicity; therefore, when choosing the agent and dose, consider the individual's risk factors, including age. When prescribing these drugs, consider appropriate assessment and/or monitoring of these risk factors. - If a person with rheumatoid arthritis needs to take low dose aspirin, consider other analgesics before substituting or adding an NSAID or COX 2 inhibitor (with a proton pump inhibitor) if pain relief is ineffective or insufficient. - If NSAIDs or COX 2 inhibitors are not providing satisfactory symptom control, review the regimen for disease modifying or biological drugs. [ For people with established disease (longer than two years) - If disease is stable, cautiously reduce dosages of disease modifying or biological drugs; return promptly to disease controlling doses at the first sign of a flare-up. - When introducing new drugs to improve disease control, consider decreasing or stopping an individual's pre-existing rheumatological drugs once the disease is controlled. - If doses of disease modifying or biological drugs are being decreased, or the drugs are being stopped, arrange for prompt review. [ the patient with the knowledge, skills, and resources to minimise the effects of the disease. ## Further information on the guidance A wealth of guidance is now available on the diagnosis, investigations, and treatment of rheumatoid arthritis. Treatment aims to control pain and inflammation and to reduce joint damage, disability, and loss of function, thereby improving quality of life. This latest NICE guideline includes a combination of pharmacological and non-pharmacological interventions but also highlights the importance of early diagnosis and intervention. It draws on the most up to date evidence and pulls together areas covered in existing guidance [bib_ref] British Society for Rheumatology and British Health Professionals in Rheumatology guideline for..., Luqmani [/bib_ref] and in the NICE technology appraisals. 9-13 Its aim is to improve the quality of life of patients and to reduce variation in practice, such as drug sequencing, choice and combination of disease modifying antirheumatic drugs, and access to, and interventions provided by, the multidisciplinary team. # Methods The guideline was developed using current NICE guideline methodology,which involved systematic literature searches and critical appraisal and summarising of evidence. A Guideline Development Group (GDG) discussed the evidence and formulated the clinical recommendations. The GDG comprised people with rheumatoid arthritis as well as healthcare professionals representing a typical multidisciplinary team, both in primary and secondary care, and invited experts when additional expertise was required. The supporting technical team included those with specific expertise in literature search techniques, systematic evidence review, health economics, and project management. The GDG accepted a clinical diagnosis of rheumatoid arthritis as being more important than the 1987 American Rheumatism Association's classification criteria for rheumatoid arthritis. [bib_ref] The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid..., Arnett [/bib_ref] This is because an early persistent synovitis in which other disease has been ruled out needs to be treated as if it is rheumatoid arthritis to try to prevent damage to joints. International committees are currently examining the diagnostic criteria for early rheumatoid arthritis. The GDG categorised rheumatoid arthritis into two categories: recent onset (disease duration of up to two years) and "established" (disease duration of longer than two years). Within recent onset disease, categories of suspected persistent synovitis or suspected rheumatoid arthritis refer to patients in whom a diagnosis is not yet clear but in whom referral to specialist care or further investigation is required. The recommendations on NSAIDs replace the rheumatoid arthritis aspects only of NICE's 2001 technology appraisal on cyclo-oxygenase-2 (COX 2) selective inhibitors.All the recommendations (except the last one) in the latest guidance on rheumatoid arthritis are taken from NICE's 2008 osteoarthritis guideline,which updated the guidance on COX 2 selective inhibitors and NSAIDs. This was done because the GDG believed that the results of the extensive cost effectiveness modelling for the osteoarthritis guideline were unlikely to differ for rheumatoid arthritis. Health economic evidence was reviewed to evaluate whether guideline recommendations would be a cost effective use of healthcare resources. The evidence comprised published economic analyses, which compare costs and benefits (in terms of quality adjusted life years) between two or more interventions. Where health economic evidence was limited, the guideline process allowed the health economist from the GDG to develop a new economic evaluation-for example, in evaluating the use of combinations of disease modifying antirheumatic drugs and steroids in patients with early disease. The model is described in detail in the full NICE guideline. 2 The guideline was subject to a web based, external consultation from stakeholders. This drew 415 submitted comments, each of which was considered by the GDG for its validity and usefulness, and where deemed appropriate the guideline was modified in the light of these. NICE has produced four different versions of the guideline: a full version; a quick reference guide; a version known as the "NICE guideline" that summarises the recommendations; and a version for patients and carers. All these versions are available from the NICE website (www.nice.org.uk/ CG79). ## Additional recommendations: biological drugs It was part of the remit of the GDG to re-evaluate the information outlined in NICE's technical appraisal on anakinra [bib_ref] The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid..., Arnett [/bib_ref] and incorporate updated information in the new guideline, but after reviewing the evidence on anakinra, the GDG made no changes to the recommendations. The GDG also had a remit to incorporate the information on other biological drugs outlined in the NICE technical appraisals. 9-13 - On the balance of its clinical benefits and cost effectiveness, anakinra is not recommended as a treatment for rheumatoid arthritis, except in the context of a controlled, long term clinical study. If patients are already receiving anakinra, continue this until they and their consultant consider it is appropriate to stop. [Based on a NICE technical appraisal- Do not offer the combination of tumour necrosis factor-α inhibitor therapy and anakinra. [Based on high and moderate quality meta-analyses and randomised controlled trials] # Future research The exercise of developing guidelines on managing rheumatoid arthritis drew attention to enormous gaps in the knowledge of the GDG. Several areas not covered by the literature remain to be evaluated. Recognising early synovitis is not always straightforward, and clinical skills alone are not always reliable. Thus the cost effectiveness of more objective tests such as magnetic resonance imaging, ultrasonography, and testing for anticyclic citrullinated peptide antibodies needs to be examined in establishing the diagnosis and prognosis of small joint synovitis. Although the treatment of early active disease has to be aggressive, the role of disease modifying antirheumatic drugs (and the effect of symptom duration on patient outcomes) in the treatment of mild rheumatoid arthritis should be assessed. The cost effectiveness of early management with biological drugs (before the failure of two conventional disease modifying antirheumatic drugs) should be assessed to determine if this could be a cost effective strategy in subgroups of patients with rheumatoid arthritis. As more patients are exposed to biological therapies, research needs to determine the most appropriate treatment strategy if a first tumour necrosis factor-α inhibitor fails. For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe	None	None	Rheumatoid arthritis is a chronic, progressive autoimmune disease associated with inflammation principally in synovial joints and affecting over 400 000 people in the United Kingdom.1 In recent years it has become clear that pain and disability can be avoided if the disease is recognised early and treated promptly and appropriately. It is therefore crucial that all health professionals have knowledge of the recognition, management, and appropriate referral of patients with rheumatoid arthritis. This article summarises the recommendations in the guideline from the National Institute for Health and Clinical Excellence (NICE) on the management of rheumatoid arthritis, from early identification to managing chronic and severe disease.2 NICE recommendations are based on systematic reviews of best available evidence. When minimal evidence is available, recommendations are based on the opinion of the Guideline Development Group (GDG) of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets. ### Referral, diagnosis, and investigations [ Based on high and moderate quality observational studies of early prognosis and identification or diagnosis ] [ Based on data from case series ]
d40904c5904e35e934def1c3af8f14ce40874623	pubmed	Cardiovascular Manifestations of Tuberous Sclerosis Complex and Summary of the Revised Diagnostic Criteria and Surveillance and Management Recommendations From the International Tuberous Sclerosis Consensus Group	Cardiovascular Manifestations of Tuberous Sclerosis Complex and Summary of the Revised Diagnostic Criteria and Surveillance and Management Recommendations From the International Tuberous Sclerosis Consensus Group [bib_ref] Scerose tuberereuse des circonvultions cerebrales: idiotie et epilepsie hemiplegique, Bourneville [/bib_ref] [bib_ref] Zue pathologie und pathologishcen anatomie der verschiedenen idiotieform, Vogt [/bib_ref] [bib_ref] Criteria for diagnosis, Gomez [/bib_ref] [bib_ref] Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria, Roach [/bib_ref] [bib_ref] International Tuberous Sclerosis Complex Consensus Group, Northrup [/bib_ref] ## The revised diagnostic criteria include clinical genetic testing Significant changes have been implemented in the revised diagnostic criteria. [bib_ref] International Tuberous Sclerosis Complex Consensus Group, Northrup [/bib_ref] For example, clinical genetic testing has been added as an independent criterion, sufficient to make the diagnosis of TSC. Since TSC1 and TSC2, the genes that encode hamartin and tuberlin, were identified as the cause of TSC,substantial strides have been made in defining the pathogenesis of TSC. Mutations in the genes TSC1 and TSC2 cause 75% to 90% of cases . Given the increasing appreciation for disease variability and an assortment of mild disease phenotypes that may be on the TSC spectrum, the inclusion of a molecular test represents an important change in the approach to diagnosis. While approximately one-third of cases have a positive family history, this has not been included as diagnostic criteria but remains informative given the various challenges with performing genetic testing. Importantly, the designation of a definite, probable, or possible clinical diagnosis has been simplified to either "definite" or "possible." Additional changes were made in several of the clinical criteria [fig_ref] Table 1: Revised Diagnostic Criteria for TSC [/fig_ref] , and changes regarding cardiovascular features are considered next in detail. ## Overall recommendations have shifted to careful surveillance and early intervention Guidelines for the management and surveillance of TSC patients were comprehensively addressed in a companion article to the revised diagnostic criteria. [bib_ref] International Tuberous Sclerosis Complex Consensus Group, Krueger [/bib_ref] Given the successful clinical trials establishing mammalian target of rapamycin (mTOR) inhibition as a new pharmacologic treatment strategy, a variety of surveillance issues have been considered [fig_ref] Table 2: Surveillance and Management Recommendations for Newly Diagnosed or Suspected TSC Summary Table... [/fig_ref]. The addition of genetic testing to the diagnostic criteria has implications for screening that were addressed as well. These recommendations affect cardiologists directly with respect to surveillance and potentially in rare circumstances with respect to medical therapy. There is an increasing appreciation for latent cardiovascular phenotypes, indicating a need for continued surveillance of these patients. As the natural history of disease in the cardiovascular system is better understood, continued care in adulthood needs to be defined, underscoring efforts to transition care from pediatric to adult cardiology and to maintain surveillance vigilance in adulthood. ## The natural history and diagnosis of tsc The Natural History of Cardiac Rhabdomyomas Cardiac tumors are rare, and ascertaining incidence is difficult. [bib_ref] Cardiac tumors, Marx [/bib_ref] [bib_ref] Cardiac tumors, Marx [/bib_ref] Based on clinical studies and autopsy series, primary cardiac tumors occur in 0.2% of children. 14 Cardiac rhabdomyomas are by far the most common primary cardiac tumor in childhood. [bib_ref] Cardiac tumors in tuberous sclerosis: their incidence and course, Jozwiak [/bib_ref] [bib_ref] Natural history of cardiac rhabdomyomas in infancy and childhood, Smythe [/bib_ref] After the advent of echocardiography, but before clinical genetic testing was available, studies estimated that up to 70% to 90% of children with rhabdomyomas have TSC, [bib_ref] Incidence of tuberous sclerosis in patients with cardiac rhabdomyoma, Harding [/bib_ref] [bib_ref] Diagnosis and management of fetal cardiac tumors: a multicenter experience and review..., Holley [/bib_ref] [bib_ref] Pediatric primary benign cardiac tumors: a 15-year review, Beghetti [/bib_ref] and at least 50% of children with TSC have rhabdomyomas, [bib_ref] Diagnosis and management of fetal cardiac tumors: a multicenter experience and review..., Holley [/bib_ref] representing a significant increase in the proportion of cardiac rhabdomyomas attributed to TSC compared with historic clinical data. [bib_ref] Cardiac rhabdomyomata in tuberous sclerosis: their course and diagnostic value, Smith [/bib_ref] were rhabdomyomas. [bib_ref] Prospective diagnosis of 1006 consecutive cases of congenital heart disease in the..., Allan [/bib_ref] Tumors are diagnosed more frequently in fetal series than in postnatal series, resulting in an increased sensitivity when examining fetal echocardiograms. [bib_ref] Diagnosis and management of fetal cardiac tumors: a multicenter experience and review..., Holley [/bib_ref] [bib_ref] Pediatric primary benign cardiac tumors: a 15-year review, Beghetti [/bib_ref] Cardiac rhabdomyomas tend to appear at 20 to 30 weeks' gestation, with the earliest diagnosis having been made at 15 weeks at the current technical limits of ultrasonography, [bib_ref] Association between cardiac tumors and tuberous sclerosis in the fetus and neonate, Tworetzky [/bib_ref] suggesting rhabdomyomas may be present earlier in development. The frequency of fetal detection is increasing dramatically; therefore, it is reasonable to anticipate that the rate of fetal diagnosis will increase significantly. Fetal cardiac tumors may present in utero as a mass on ultrasonography, irregular heart rhythm, hydrops fetalis, or pericardial effusion. Cardiac rhabdomyomas can increase in size during the second half of gestation, and this has been attributed to maternal hormonal changes associated with pregnancy. When larger tumors result in hemodynamic compromise in utero, intrauterine fetal demise may occur. Fetal loss has been reported to be %11% in 1 small series of 44 cases. [bib_ref] Prospective diagnosis of 1006 consecutive cases of congenital heart disease in the..., Allan [/bib_ref] Cardiac rhabdomyomas do not cause symptoms or hemodynamic compromise in the vast majority of patients but may become symptomatic shortly after birth or in the first year of life. Tumors may obstruct inflow or outflow, which can cause ventricular dysfunction and heart failure, as well as redirection of flow across the foramen ovale. [bib_ref] Pediatric primary benign cardiac tumors: a 15-year review, Beghetti [/bib_ref] [bib_ref] Primary cardiac tumors in infants and children: immediate and long-term operative results, Takach [/bib_ref] [bib_ref] Cardiac rhabdomyomas and obstructive left heart disease: histologically but not functionally benign, Black [/bib_ref] Nearly 100% of fetuses with multiple rhabdomyomas have TSC, underscoring the practical importance of identifying additional tumors at the time of fetal assessment for diagnosis and prognosis. [bib_ref] Incidence of tuberous sclerosis in patients with cardiac rhabdomyoma, Harding [/bib_ref] [bib_ref] Cardiac tumours in intrauterine life, Groves [/bib_ref] In light of emerging human genetic and molecular knowledge, it is a possibility that the underlying pathogenesis of all rhabdomyomas is a result of a spectrum of TSC disease. Cardiac rhabdomyomas are typically well circumscribed and nonencapsulated (FigureB). Micropathologic examination demonstrates abnormal myocyte architecture, including vacuolization and pathognomonic "spider cells" (FigureC). The individual cardiac rhabdomyomas range in size from a few millimeters to several centimeters and are multiple in number in 90% of cases. There is an equal predilection for left, right. and septal ventricular myocardium. [bib_ref] Cardiac rhabdomyomas and obstructive left heart disease: histologically but not functionally benign, Black [/bib_ref] Tumors are typically located in the ventricles, where they can compromise ventricular function and on occasion interfere with valve function or result in outflow obstruction. Tumors may be located in the atria, where they can compress the coronary arteries, leading to myocardial ischemia. [bib_ref] Van Praagh R. Cardiac rhabdomyoma. Rare cause of fetal death, Geva [/bib_ref] ## Diagnosis of cardiac rhabdomyoma Echocardiography is the imaging modality of choice for assessing cardiac involvement in TSC. Cardiac rhabdomyomas can be detected prenatally or postnatally. In prenatal life, ultrasound detection of multiple cardiac tumors is often the first sign of TSC. [bib_ref] Clinical presentation and diagnosis of tuberous sclerosis complex in infancy, Datta [/bib_ref] Typically, cardiac rhabdomyomas are visible as multiple, echogenic, nodular masses embedded in the ventricular myocardium, sometimes protruding into the involved chamber (FigureD). They are homogeneous and hyperechoic compared with normal myocardium. Diagnosis of cardiac rhabdomyomas is made easily when these typical features are present, but differentiation from other cardiac tumors may be difficult when there is a large solitary tumor or when tumors are located in an atypical location, such as the atria. Doppler echocardiography is also useful in assessing the presence of obstruction to ventricular inflow or outflow. The identification of either a TSC1 or TSC2 pathogenic mutation in DNA from normal tissue is sufficient to make a definite diagnosis of TSC. A pathogenic mutation is defined as a mutation that clearly inactivates the function of the TSC1 or TSC2 proteins (eg, out of frame indel or nonsense mutation), prevents protein synthesis (eg, large genomic deletion), or is a missense mutation whose effect on protein function has been established by functional assessment (www.lovd.nl/TSC1, www.lovd.nl/TSC2, [bib_ref] Functional assessment of TSC1 missense variants identified in individuals with tuberous sclerosis..., Hoogeveen-Westerveld [/bib_ref] [bib_ref] Functional assessment of TSC2 variants identified in individuals with tuberous sclerosis complex, Hoogeveen-Westerveld [/bib_ref] Echocardiography is also used to assess ventricular function, which may be impaired by multiple confluent tumors. Cardiac rhabdomyomas are seen readily in fetal life after 20 weeks of gestation and are seen in a majority of infants with TSC. Rhabdomyomas can enlarge significantly in size during gestation and may be seen later in gestation when they are not visible prior to 20 weeks. Cardiac rhabdomyomas regress spontaneously in a large majority of patients during the first year of life and as a result are seen with decreasing frequency in patients with TSC after 2 years of age. [bib_ref] Usefulness of diagnostic criteria of tuberous sclerosis complex in pediatric patients, Jozwiak [/bib_ref] There is some suggestion that the incidence of identifiable cardiac rhabdomyomas in TSC increases during adolescence, 31 but this observation has not been validated in additional studies. ## Sensitivity and specificity of echocardiography to identify cardiac rhabdomyomas This varies with patient age, related to the previous discussion. In fetal life, of patients diagnosed with cardiac rhabdomyomas by echocardiography, 75% to 80% are found to satisfy criteria for TSC postnatally. [bib_ref] Association between cardiac tumors and tuberous sclerosis in the fetus and neonate, Tworetzky [/bib_ref] [bib_ref] Fetal rhabdomyoma: Prenatal diagnosis, clinical outcome, and incidence of associated tuberous sclerosis..., Bader [/bib_ref] [bib_ref] Considerations for prenatal counselling of patients with cardiac rhabdomyomas based on their..., Degueldre [/bib_ref] The presence of multiple ventricular tumors seems to be the finding best associated with TSC. [bib_ref] Association between cardiac tumors and tuberous sclerosis in the fetus and neonate, Tworetzky [/bib_ref] The presence of a family history of TSC also increases the likelihood of TSC. [bib_ref] Outcome of antenatally diagnosed cardiac rhabdomyoma: case series and a meta-analysis, Chao [/bib_ref] In fetuses with a single ventricular tumor, only 30% satisfy criteria for TSC postnatally. [bib_ref] Association between cardiac tumors and tuberous sclerosis in the fetus and neonate, Tworetzky [/bib_ref] Because a diagnosis of TSC during fetal life is often prompted by the presence of cardiac rhabdomyomas, the negative predictive value of fetal echocardiography is not established. In early infancy, the predictive value of echocardiography is similar to that in fetal life, with %80% of infants with cardiac rhabdomyomas eventually satisfying a diagnosis of TSC. Conversely, 80% to 85% of children with confirmed TSC have identifiable rhabdomyomas when younger than 2 years. [bib_ref] Usefulness of diagnostic criteria of tuberous sclerosis complex in pediatric patients, Jozwiak [/bib_ref] Beyond 2 years of age, the incidence of identifiable rhabdomyomas is significantly lower (%20% to 25%), although if they are readily seen on echocardiography, the ## Genetics Offer genetic testing and family counseling, if not done previously, in individuals of reproductive age or newly considering having children ## Brain Obtain MRI of the brain every 1 to 3 years in asymptomatic TSC patients under the age of 25 years to monitor for new occurrence of SEGA. Patients with large or growing SEGA, or with SEGA causing ventricular enlargement but still asymptomatic, should undergo MRI more frequently and the patients and their families should be educated regarding the potential of new symptoms. Patients with asymptomatic SEGA in childhood should continue to be imaged periodically as adults to ensure there is no growth. Surgical resection should be performed for acutely symptomatic SEGA. Cerebrospinal fluid diversion (shunt) may also be necessary. Either surgical resection or medical treatment with mTOR inhibitors may be used for growing but otherwise asymptomatic SEGA. In determining the best treatment option, discussion of the complication risks, adverse effects, cost, length of treatment, and potential impact on TSC-associated comorbidities should be included in the decision-making process Perform screening for TAND features at least annually at each clinical visit. Perform comprehensive formal evaluation for TAND at key developmental timepoints: infancy (0 to 3 years), preschool (3 to 6 years), pre-middle school (6 to 9 years), adolescence (12 to 16 years), early adulthood (18 to 25 years), and as needed thereafter. Management strategies should be based on the TAND profile of each patient and should be based on evidence-based good practice guidelines/practice parameters for individual disorders (eg, autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety disorder, etc). Always consider the need for an individual educational program (IEP). Sudden change in behavior should prompt medical/ clinical evaluation to look at potential medical causes (eg, SEGA, seizures, renal disease, etc.) Obtain routine EEG in individuals with known or suspected seizure activity. The frequency of routine EEG should be determined by clinical need rather than a specific defined interval. Prolonged video EEG, 24 hours or longer, is appropriate when seizure occurrence is unclear or when unexplained sleep, behavioral changes, or other alteration in cognitive or neurological function is present Vigabatrin is the recommended first-line therapy for infantile spasms. ACTH can be used if treatment with vigabatrin is unsuccessful. Anticonvulsant therapy of other seizure types in TSC should generally follow that of other epilepsies. Epilepsy surgery should be considered for medically refractory TSC patients, but special consideration should be given to children at younger ages experiencing neurologic regression and is best if performed at epilepsy centers with experience and expertise in TSC ## Kidney Obtain MRI of the abdomen to assess for the progression of angiomyolipoma and renal cystic disease every 1 to 3 years throughout the lifetime of the patient Assess renal function (including determination of GFR) and blood pressure at least annually Embolization followed by corticosteroids is first-line therapy for angiomyolipoma presenting with acute hemorrhage. Nephrectomy is to be avoided. For asymptomatic, growing angiomyolipoma measuring >3 cm in diameter, treatment with an mTOR inhibitor is the recommended first-line therapy. Selective embolization or kidney-sparing resection is acceptable second-line therapy for asymptomatic angiomyolipoma Lung Perform clinical screening for LAM symptoms, including exertional dyspnea and shortness of breath, at each clinic visit. Counseling regarding smoking risk and estrogen use should be reviewed at each clinic visit for individuals at risk of LAM Obtain HRCT every 5 to 10 years in asymptomatic individuals at risk of LAM if there is no evidence of lung cysts on their baseline HRCT. Individuals with lung cysts detected on HRCT should have annual pulmonary function testing (PFT and 6-minute walk) and HRCT interval reduced to every 2 to 3 years mTOR inhibitors may be used to treat LAM patients with moderate to severe lung disease or rapid progression. TSC patients with LAM are candidates for lung transplantation, but TSC comorbidities may affect transplant suitability Skin Perform a detailed clinical dermatologic inspection/examination annually Rapidly changing, disfiguring, or symptomatic TSC-associated skin lesions should be treated as appropriate for the lesion and clinical context, using approaches such as surgical excision, laser(s), or possibly topical mTOR inhibitor Teeth Perform a detailed clinical dental inspection/examination at minimum every 6 months and panoramic radiographs by age 7 years, if not performed previously Symptomatic or deforming dental lesions, oral fibromas, and bony jaw lesions should be treated with surgical excision or curettage when present Continued likelihood of TSC likely remains high. In late childhood and adolescence (9 to 14 years of age), the incidence of cardiac rhabdomyomas in patients with confirmed TSC seems to increase again (%40%) in small series. [bib_ref] Usefulness of diagnostic criteria of tuberous sclerosis complex in pediatric patients, Jozwiak [/bib_ref] It has been speculated that this may be related to hormonal changes. ## Alternative imaging modalities for cardiac rhabdomyomas Cardiac magnetic resonance imaging (MRI) can also be used to detect cardiac rhabdomyomas; however, its strength lies in more specific tissue characterization. [bib_ref] Characterization of cardiac tumors in children by cardiovascular magnetic resonance imaging: a..., Beroukhim [/bib_ref] It can be a useful adjunct to echocardiography in situations where it is unclear whether a cardiac tumor represents a rhabdomyoma (eg, in patients with a large solitary tumor). In addition, MRI is more accurate than echocardiography in delineating the proximity of cardiac tumors to normal myocardium and the great vessels [bib_ref] The contribution of magnetic resonance imaging to the evaluation of intracardiac tumors..., Freedberg [/bib_ref] [bib_ref] MRI in the evaluation and management of a newborn infant with cardiac..., Berkenblit [/bib_ref] and therefore may be a useful adjunct to surgical planning once a decision to operate has been made. It can also provide a more reliable and reproducible estimate of ventricular systolic function. Cardiac MRI in infants and young children (<8 years of age) requires general anesthesia or sedation and, hence, its use should be limited by necessity. ## Cardiac arrhythmia is a significant problem in tsc While arrhythmia is relatively common in individuals with TSC, the range of arrhythmic substrates is wide and not sufficiently specific to form a specific diagnostic criterion. Reported cases of arrhythmia associated with TSC from slow to irregular to fast heart rhythms. Bradycardia mechanisms have been associated with both sinus and atrioventricular (AV) nodal dysfunction. Tachycardia mechanisms have been related to atrial, accessory AV connection reentrant, and ventricular tachycardia. [bib_ref] Ventricular tachycardia in a neonate with prenatally diagnosed cardiac tumors: a case..., Hirakubo [/bib_ref] [bib_ref] cardiac rhabdomyomata and fetal hydrops in a premature infant with tuberous sclerosis, Scurry [/bib_ref] [bib_ref] Incessant ventricular tachycardia due to multiple cardiac rhabdomyomas in an infant with..., Kathare [/bib_ref] [bib_ref] Neonatal tuberous sclerosis with cardiac rhabdomyomas presenting as fetal supraventricular tachycardia, Wu [/bib_ref] [bib_ref] Ventricular tachycardia caused by cardiac rhabdomyoma in a young adult with tuberous..., Enbergs [/bib_ref] Ventricular preexcitation associated with abnormal AV connections has also been commonly reported and has been noted to participate in rapid potentially lifethreatening anomalous AV conduction during atrial fibrillation. [bib_ref] Pre-excitation syndrome secondary to cardiac rhabdomyomas in tuberous sclerosis, Mas [/bib_ref] [bib_ref] Tuberous sclerosis complex and Wolff-Parkinson-White syndrome, O'callaghan [/bib_ref] [bib_ref] Rhabdomyoma and ventricular preexcitation syndrome. A report of two cases and review..., Mehta [/bib_ref] The mechanisms of arrhythmia have often been directly linked to the location of specific cardiac rhabdomyomas. [bib_ref] Right atrial rhabdomyoma acting as the substrate for Wolff-Parkinson-White syndrome in a..., Venugopalan [/bib_ref] Indeed, abnormal AV connections associated with TSC have been shown histologically to be directly related to rhabdomyomas tumor tissue connecting the atrium to the ventricle, rather than a "typical" accessory pathway. In addition to the wide range of mechanisms of arrhythmia in these individuals, the effects of the arrhythmias can be extremely varied. Isolated atrial or ventricular ectopy may remain without symptoms for a lifetime. Bradycardia, depending on its severity, may also remain without symptoms but may result in fatigue or syncope. Differentiation of fatigue related to bradycardia from other organ system dysfunction associated with tuberous sclerosis may be challenging. [bib_ref] Sinus node dysfunction in tuberous sclerosis, Cowley [/bib_ref] Syncope may also have similar presentation to "drop attacks" and other neurologic events seen with TSC. Sustained tachyarrhythmia may result in palpitations or, in some instances, in syncope or cardiac arrest and sudden death. [bib_ref] Mechanisms of unexpected death in tuberous sclerosis, Byard [/bib_ref] Developmentally delayed individuals may not report symptomatic palpitations associated with hemodynamically stable sustained tachyarrhythmia and may present with signs and symptoms of heart failure due to tachycardia-mediated cardiomyopathy. Recurrent syncope may be mistaken for seizures or "drop attacks," and thus the warning signs of impending cardiac arrest may not be attended. The presence of a diagnosis of TSC does not alter treatment recommendations for any arrhythmia. Observation and treatment of episodes of tachycardia as they occur, antiarrhythmic medications, catheter and surgical ablation, and implanted pacemakers and defibrillators remain options for treatment as they do in all individuals. Catheter ablation appears to have less frequent success than in those without TSC, probably due to the size of the tumor and possible participation of the entire tumor in the arrhythmia mechanism. ## Cardiology changes to the diagnostic criteria The presence of cardiac rhabdomyomas remains a major criterion [fig_ref] Table 4: New Cardiology-Specific Recommendations for Tuberous Sclerosis Complex [/fig_ref]. There is no longer a need to specify 1 versus >1 rhabdomyoma. Importantly, because cardiac rhabdomyomas are often the presenting manifestation of TSC, it is important to emphasize the need for pediatric cardiologists to initiate and facilitate the TSC evaluation. Specifically, the pediatric cardiologist making a new diagnosis of rhabdomyomas should obtain clinical genetic testing and make the appropriate subspecialty referrals; typically human genetics and neurology, depending on available local resources. Genetic testing practices may vary by center, prompting a need to be familiar with local processes and the closest tertiary center with specialized care for patients with TSC. Clinical genetic testing should be obtained in all multiple cardiac rhabdomyomas and most isolated or possible rhabdomyomas. Because there is benefit to early diagnosis and potential added morbidity to late diagnosis, a proactive approach is warranted. ## The management of cardiac manifestations of tsc medical treatment for heart failure Cardiac rhabdomyomas can lead to hemodynamic compromise and congestive heart failure, and while this occurrence is rare, it remains one of the most frequent causes of death among TSC children <10 years old. [bib_ref] Causes of death in patients with tuberous sclerosis, Shepherd [/bib_ref] Heart failure occurs in 2% to 5% of infants and children with TSC-associated rhabdomyomas. [bib_ref] Tuberous sclerosis and cardiac rhabdomyoma, Nir [/bib_ref] [bib_ref] Clinical and genotype studies of cardiac tumors in 154 patients with tuberous..., J O Zwiak [/bib_ref] Pharmacology-based therapy for congestive heart failure due to TSC-associated rhabdomyomas is typically not needed; however, on occasion, medical management for CHF, including digitalis, angiotensin-converting enzyme inhibition, and diuresis, may be indicated. When the cause of heart failure is arrhythmia, then the appropriate antiarrhythmic treatment is indicated and effective. [bib_ref] Neonatal emergencies associated with cardiac rhabdomyomas: an 8-year experience, Rosa [/bib_ref] However, when the cause of heart failure is inflow or outflow obstruction, typically "watchful waiting" is used with the anticipation that most cardiac rhabdomyomas will spontaneously regress over a period of months. If the heart failure is refractory, then surgery is indicated. When there is hemodynamic compromise in the neonate, prostaglandin E may be initiated to stabilize the critically ill newborn. A critically ill neonate with hemodynamic compromise due to cardiac rhabdomyomas at the time of diagnosis should be transferred to a tertiary center with cardiac intensive care infrastructure and the ability to perform surgery if needed. ## New treatment modalities may have a role in cardiology management mTOR inhibitors have been successfully used for TSC-associated tumors in different organ systems, [bib_ref] Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with..., Franz [/bib_ref] [bib_ref] Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma, Krueger [/bib_ref] [bib_ref] Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis, Bissler [/bib_ref] and limited observations to date suggest they may also be efficacious in reducing the size of cardiac rhabdomyomas. [bib_ref] Regression of a cardiac rhabdomyoma in a patient receiving everolimus, Tiberio [/bib_ref] [bib_ref] Prenatal diagnosis of a gigantic cardiac rhabdomyoma in tuberous sclerosis complex-a new..., Mlczoch [/bib_ref] Because mTOR inhibitors are not benign drugs and rhabdomyomas tend to regress, therapy should be considered only in situations of hemodynamic compromise where there is the potential to avoid surgery with their use. Given the low frequency of surgical resection for cardiac rhabdomyomas, it will be challenging to study in a controlled manner. However, there may be opportunities to use mTOR inhibitors, such as sirolimus (rapamycin) or everolimus, to induce tumor regression. Based on limited observations, there do not appear to be significant cardiovascular side effects associated with mTOR inhibitors. In general, side effects are considered manageable in adults, but because mTOR inhibitors affect the immune system and cells' ability to grow and proliferate, there may be an increased risk for infections and malignant tumors over the long term. Case reports using sirolimus [bib_ref] Regression of a cardiac rhabdomyoma in a patient receiving everolimus, Tiberio [/bib_ref] in the context of an infant with cardiac rhabdomyomas and refractory heart failure and everolimus 57 in the context of hemodynamic instability demonstrate benefit and avoided surgery, suggesting that application in cases of malignant arrhythmia may also be therapeutic and avoid the need for invasive intervention. More studies are needed to define the role of mTOR inhibitors in this situation, as well as for arrhythmias, aneurysms, and latent left ventricular dysfunction. ## Surgical intervention for complete or partial cardiac rhabdomyoma resection is indicated in rare circumstances Because most cardiac rhabdomyomas are asymptomatic and the natural history is spontaneous regression, surgical resection is not required for the vast majority of infants with TSC. Among the 2% to 5% of cases that do present with heart failure and/or hemodynamic instability, only a small proportion require surgery. [bib_ref] Cardiac rhabdomyoma in the neonate: surgical management, Foster [/bib_ref] Surgical series have reported a rate as high as 20%, but this is likely a reflection of referral bias. [bib_ref] Cardiac rhabdomyomas and obstructive left heart disease: histologically but not functionally benign, Black [/bib_ref] [bib_ref] Surgical treatment for cardiac rhabdomyomas in children, Jacobs [/bib_ref] Because the infant with heart failure requiring surgery may be critically ill, these patients are relatively high-risk surgical candidates. However, partial resection is typically adequate if complete excision would sacrifice vital structures or myocardial mass. Orthotopic heart transplantation can be considered in extreme cases, such as in the rare event that tumor replaces myocardium; however, the necessary medical regimen is associated with significant medical risks. Specifically, the seizure threshold is lowered, and the risk of infection and malignant cancer is increased. Excellent short-and long-term results have been reported in multiple series, but cases of early death have been reported. [bib_ref] Pediatric primary benign cardiac tumors: a 15-year review, Beghetti [/bib_ref] [bib_ref] Primary cardiac tumors in infants and children: immediate and long-term operative results, Takach [/bib_ref] [bib_ref] Cardiac rhabdomyomas and obstructive left heart disease: histologically but not functionally benign, Black [/bib_ref] To date, late fetal surgical resection has not been reported, but ex utero intrapartum treatment technology suggests this may be feasible in select situations. ## Recommedations expand surveillance efforts cardiology changes to surveillance recommendations Due to the rise of diagnosis on fetal echocardiography, serial imaging during gestation is now indicated to monitor disease severity and postnatal imaging is indicated to confirm anatomy and determine the status of disease after birth. Surveillance is now recommended until regression is demonstrated [fig_ref] Table 4: New Cardiology-Specific Recommendations for Tuberous Sclerosis Complex [/fig_ref]. Because cardiac rhabdomyomas are often the presenting manifestation of TSC, it is important to emphasize the need for pediatric cardiologists to make the appropriate subspecialty referrals, typically human genetics and neurology, depending on available local resources. Given the increasing appreciation for cardiology issues later in life, including arrhythmias, ECGs are now recommended every 3 to 5 years. A lower index of suspicion is required during adolescent ages. Importantly, increasing efforts are required to facilitate transition from pediatric to adult care. 60 ## Recommendations for imaging surveillance In fetal life, echocardiography is recommended if there is a positive family history of TSC in a first-degree relative or if there is suspicion for TSC based on other criteria. If cardiac rhabdomyomas are identified, evaluation should include assessment for inflow or outflow obstruction that may lead to hemodynamic compromise postnatally, evaluation for arrhythmias and ventricular dysfunction, and evidence of hydrops fetalis. The presence of a complicating factor requires close follow-up during the pregnancy along with careful coordination and planning of prenatal and postnatal care with involvement of specialists from maternal-fetal medicine, cardiology, and cardiac surgery. Even in the absence of complicating factors, if cardiac rhabdomyomas are diagnosed or suspected on fetal echocardiography, consultation with maternal-fetal medicine and genetics is recommended to counsel the family regarding the likelihood of TSC and long-term prognosis. Because rhabdomyomas can enlarge during gestation, follow-up imaging later during gestation (30 to 35 weeks) is recommended. After birth and in the first 2 years of life, echocardiography is recommended for any child with a suspected diagnosis of TSC, because of the high correlation between the presence of cardiac rhabdomyomas and TSC in this age group. In addition, hemodynamic compromise due to outflow or inflow obstruction is most likely in this age group and can be easily assessed on echocardiography. If echocardiography is conclusive of the diagnosis of rhabdomyomas, no further imaging is recommended. In patients who are suspected but not confirmed to have TSC and have a cardiac tumor on echocardiography but the diagnosis of rhabdomyoma is uncertain, referral to a tertiary pediatric cardiac center for cardiac MRI under sedation or general anesthesia should be considered for tissue characterization. However, this decision should be made jointly by experts in cardiology, neurology, and/or genetics to consider the risk. In typical cases, and in the absence of inflow/outflow obstruction and ventricular dysfunction, follow-up echocardiography is not recommended in the first year of life but may be considered once between 1 and 3 years of age to document regression of the tumors. Once regression of tumor size has been documented, follow-up echocardiography is not recommended, unless new cardiac concerns such as arrhythmia or syncope arise, and, in these cases, should be performed in consultation with a pediatric cardiologist. Closer follow-up should be considered in atypical cases. In patients with inflow/outflow obstruction, ventricular dysfunction, or large solitary tumors, more frequent repeat echocardiography may be necessary and should be coordinated in consultation with a pediatric cardiologist. In patients suspected with TS beyond 2 years of age, echocardiography should be considered although the yield is significantly lower. Echocardiography is recommended if the physical examination is consistent with outflow tract obstruction (rare in this age group) or if there is concern for arrhythmia or syncope. ## Recommendations for electrophysiologic surveillance All individuals with tuberous sclerosis, regardless of age, should have a 12-to 15-lead ECG performed at the time of diagnosis. Subsequently, in an individual with tuberous sclerosis and no cardiac symptomatology, a repeat study every 3 to 5 years may be prudent. Evaluation of symptomatic palpitations should include cardiac event monitoring as appropriate. Episodes of "drop attacks" or "seizures" that cannot definitively exclude cardiac syncope should be evaluated with monitors with "looping" memory, either external or implanted. Particularly concerning cases of syncope or episodes in individuals with other concerning cardiac manifestations should be evaluated with invasive cardiac electrophysiology study. Sudden deaths in individuals with TSC are reported at all ages and have potentially diverse etiologies, including not only arrhythmia but also epilepsy, intratumor hemorrhage, obstructive hydrocephalus, and aneurysmal rupture. It remains unclear whether surveillance with ambulatory ECGs for occult arrhythmia will be able to predict and prevent the arrhythmic deaths. Periodic ambulatory ECGs seem prudent until the question can be answered definitively. ## Future research directions and unresolved clinical issues animal models of tsc provide potential insight into mechanisms of tumor regression Both TSC1-and TSC2-deficient mice are embryonic lethal with ventricular dysfunction potentially contributing to death. [bib_ref] A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are..., Kobayashi [/bib_ref] [bib_ref] Tsc2(+/À) mice develop tumors in multiple sites that express gelsolin and are..., Onda [/bib_ref] Heterozygous and conditional mice appear to recapitulate some of TSC phenotypes, with the Tsc2 +/À mouse demonstrating more severe overall disease. Importantly, these mice are responsive to sirolimus. [bib_ref] Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex, Zeng [/bib_ref] Meikle et al examined ventricular myocytes of mice with Tsc1 insufficiency (haploinsufficiency) conditionally restricted to the myocardium and demonstrated cardiomyopathy with cell findings reminiscent of human cardiac rhabdomyomas. [bib_ref] A mouse model of cardiac rhabdomyoma generated by loss of Tsc1 in..., Meikle [/bib_ref] However, most preclinical studies have not focused on cardiac findings, so evaluating the cardiac phenotype in these mice may provide special insight into early disease processes. For example, general mechanisms of hypertrophy may be elucidated. [bib_ref] Smooth muscle protein-22-mediated deletion of Tsc1 results in cardiac hypertrophy that is..., Malhowski [/bib_ref] In addition, because rhabdomyomas tend to regress spontaneously, mechanistic insights into regression may be elucidated, potentially identifying new therapeutic targets. The mice would also provide a mechanism to preclinically test the benefit of mTOR inhibitors controlling for regression, which may underscore limited observations in human studies. ## Unresolved issues warrant consideration for future investigation Several unresolved issues have been identified and require careful examination [fig_ref] Table 5: Cardiology-Specific Future Research Directions Why do cardiac rhabdomyomas regress and other hamartomas... [/fig_ref]. These research questions require substantial organization. Strategies that may enhance these efforts include future clinical studies examining mTOR inhibitor effects on the cardiovascular system. By adding cardiac end points to longitudinal clinical studies, we will gain insight into various natural history questions. Some of these issues may be addressed by using the TSC Alliance Clinical Registry, which has collected comprehensive clinical data on >1000 TSC patients from 17 centers [fig_ref] Table 6: Cardiology Variables Maintained in the TSC Alliance Clinical Registry Medical history, physical... [/fig_ref]. The TSC Alliance is organized to function as a network for this purpose but requires subspecialty commitments from investigators at large centers where TSC patients are cared for (not necessarily participating already within the Alliance), highlighting the importance of coordinated multidisciplinary care and standardized approaches to care. Transitioning the patient from pediatric to adult cardiology care remains a challenging and important goal, with a need for careful monitoring and a low index of suspicion for latent manifestations of cardiovascular disease, including arrhythmias. TSC is a multisystem genetic disorder characterized by variable abnormalities, such that patients carrying mutations may not fulfill clinical criteria for diagnosis, raising questions regarding familial screening. For example, does the presence of fetal cardiac rhabdomyomas warrant a recommendation for family screening, which is not presently indicated? In mutation-positive children, parents and siblings can undergo specific mutation testing as screening, but in parents and Does treatment with mTOR inhibitors decrease the long-term risk of arrhythmia? What is the incidence of latent left ventricular hypertrophy and/or dysfunction? What is the incidence and natural history of lipidemia in TSC? mTOR indicates mammalian target of rapamycin; TSC, tuberous sclerosis complex. siblings of phenotypically diagnosed children, it may be prudent to perform ECG in parents and both ECG and echocardiography in children <3 years old. Some studies have demonstrated that cardiac rhabdomyomas are more frequent in those with TSC2 (54%) versus TSC1 (20%) mutations. [bib_ref] Causes of death in patients with tuberous sclerosis, Shepherd [/bib_ref] Currently, there is insufficient evidence of absolute risks to recommend surveillance by TSC1-and TSC2-associated cardiac disease. Variability in pathology or natural history based on presentation with TSC1 and TSC2 mutations is unclear but potentially clinically significant. Genetic testing will facilitate early identification and provide opportunities for disease stratification and early intervention. [table] Table 1: Revised Diagnostic Criteria for TSC [/table] [table] Table 2: Surveillance and Management Recommendations for Newly Diagnosed or Suspected TSC Summary Table -generation family history to assess for additional family members at risk of TSC Offer genetic testing for family counseling or when TSC diagnosis is in question but cannot be clinically confirmed educate parents to recognize infantile spasms, even if none have occurred at time of first diagnosis Obtain baseline routine electroencephalogram (EEG). If abnormal, especially if features of TAND are also present, follow up with a 24-hour video EEG to assess for subclinical seizure activity Kidney Obtain MRI of the abdomen to assess for the presence of angiomyolipoma and renal cysts Screen for hypertension by obtaining an accurate blood pressure Evaluate renal function by determination of glomerular filtration rate Lung Perform baseline pulmonary function testing (PFT and 6-minute walk test) and high-resolution chest computed tomography (HRCT), even if asymptomatic, in patients at risk of developing lymphangioleiomyomatosis (LAM), typically female patients 18 years or older. Adult male patients, if symptomatic, should also undergo testing Provide counsel on smoking risks and estrogen use in adolescent and adult female patients Skin Perform a detailed clinical dermatologic inspection/examination Teeth Perform a detailed clinical dental inspection/examination Heart Consider fetal echocardiography to detect individuals with high risk of heart failure after delivery when rhabdomyomas are identified via prenatal ultrasound Obtain an echocardiogram in pediatric patients, especially if <3 years old Obtain an ECG in all ages to assess for underlying conduction defects Eye Perform a complete ophthalmologic evaluation, including dilated fundoscopy, to assess for retinal lesions and visual field deficits [/table] [table] Table 3: Surveillance and Management Recommendations for Patients Already Diagnosed With Definite or Possible TSC Summary Table [/table] [table] Table 4: New Cardiology-Specific Recommendations for Tuberous Sclerosis Complex [/table] [table] Table 5: Cardiology-Specific Future Research Directions Why do cardiac rhabdomyomas regress and other hamartomas do not? Do cardiac rhabdomyomas completely resolve? What is the incidence of sudden death? Malignant arrhythmia? Do TSC1 and TSC2 genotypes predict cardiac phenotype or outcome? [/table] [table] Table 6: Cardiology Variables Maintained in the TSC Alliance Clinical Registry Medical history, physical examination, family history Current medications ECG, CXR, echocardiogram, MRI, CT Number, size, and location of cardiac rhabdomyomas TSC, tuberous sclerosis complex; CXR, chest radiography; MRI, magnetic resonance imaging; CT, computed tomography. [/table]	None	https://www.ahajournals.org/doi/pdf/10.1161/JAHA.114.001493	Tuberous sclerosis complex (TSC) is a genetic syndrome with a highly variable phenotype that may affect several organ systems. The central nervous system findings were the first to be described, and the classic triad of cognitive impairment, facial angiofibromas, and seizures was delineated shortly
fc7fe3514f458b9900f5b1fc65d70057612b3fdc	pubmed	OBEDIS Core Variables Project: European Expert Guidelines on a Minimal Core Set of Variables to Include in Randomized, Controlled Clinical Trials of Obesity Interventions	OBEDIS Core Variables Project: European Expert Guidelines on a Minimal Core Set of Variables to Include in Randomized, Controlled Clinical Trials of Obesity Interventions Heterogeneity of interindividual and intraindividual responses to interventions is often observed in randomized, controlled trials for obesity. To address the global epidemic of obesity and move toward more personalized treatment regimens, the global research community must come together to identify factors that may drive these heterogeneous responses to interventions. This project, called OBEDIS (OBEsity Diverse Interventions Sharing -focusing on dietary and other interventions), provides a set of European guidelines for a minimal set of variables to include in future clinical trials on obesity, regardless of the specific endpoints. Broad adoption of these guidelines will enable researchers to harmonize and merge data from multiple intervention studies, allowing stratification of patients according to precise phenotyping criteria which are measured using standardized methods. In this way, studies across Europe may be pooled for better prediction of individuals' responses to an intervention for obesity -ultimately leading to better patient care and improved obesity outcomes. # Introduction Obesity is a problem that represents a significant health and economic burden in Europe and throughout the world. The prevalence of obesity across European countries has tripled in the last several decades, making it one of the leading public health challenges. A critical part of addressing this global epidemic is to improve the evidence base for more effective treatments for obesity; however, a challenge revealed in the randomized, controlled trials (RCTs) of obesity interventions is the remarkable heterogeneity of interindividual and intraindividual responses among adult patients -whether the intervention pertains to lifestyle (dietary, physical activity [PA]), or is a pharmacological or surgical intervention aiming at weight loss. Most obesity RCTs include a heterogeneous mixture of patients that, despite meeting the inclusion criteria for the study, vary remarkably when it comes to the medical history of their disease, associated complications, and many other factors (including genetics, lifestyle, environmental, and psychosocial factors) that may drive the varying responses to the same intervention. Also, different trials take different approaches to measuring the same variable. This emphasizes the need to appropriately stratify patients according to precise phenotyping criteria, as measured using standardized methods, that might predict an individual's response to an intervention: enabling a paradigm shift in individually tailored obesity treatment, going from "one-size-fits-all" to precision medicine. One important clinically relevant question is whether, among the patients who respond poorly to a given therapy, a better response might be achieved by applying a different therapy or by administering the current therapy differently. Specific patient characteristics could theoretically provide justification for choosing an alternative treatment either as a first choice or, dependent on poor response, as a second choice, but an increased burden is thus placed on researchers to provide evidence for the benefit of choosing or switching between alternative therapies. Even for the largest and most comprehensive published clinical studies on obesity, stratification leads to subgroup analyses with reduced statistical power. Moreover, some trials do not report methods for measuring relevant obesity phenotypes in sufficient detail. Thus, it is necessary to harmonize and merge the data from multiple intervention studies -but data pooling is only possible with trials that include a common set of variables measured in the same way, including samples that are collected using consistent methods or procedures, described in enough detail. Funded by a European grant, a group of European obesity researchers convened in 2018 to create a plan for helping shape future RCTs in the field of obesity by identifying the minimal set of variables that should be included in trials of different kinds of obesity interventions, whatever the type and the endpoints of the intervention. The experts intend for this minimal core set to be adopted in future studies while acknowledging that in addition, RCTs or other trials will collect data on extra variables, depending on the specific area of focus. As such, the current initiative, called OBEDIS (OBEsity Diverse Interventions Sharing -focusing on dietary and other interventions) and funded by the Joint Programming Initiative -A Healthy Diet for a Healthy Life (JPI HDHL), was created to provide the research community with a blueprint for designing future RCTs in order to allow the sharing and merging of datasets, and to enable meaningful subgroup analyses. To achieve this, the OBEDIS experts surveyed the scientific literature, especially the published work on stratifying populations of individuals with obesity. They shared their expert opinions on a recommended minimal core set of variables to be included in all future trials of adult obesity interventions and sought to reach consensus on both these variables and the related assessment methods. # Methods ## Expert involvement and working methods The OBEDIS project coordinators, supported by the European Association for the Study of Obesity (EASO), invited leading experts to contribute to this consensus on a minimal core set of variables for RCTs of obesity interventions. These European researchers represented 13 countries and were chosen for their research record and expertise related to obesity and intervention studies in the field. The total group was comprised of 30 experts (including the 4-person coordination/management team); three scientific advisory board (SAB) members; one project manager; one funding agency (JPI HDHL) representative; and one medical writer. The OBEDIS experts were purposely selected from countries with different healthcare models and demographics. These multiple perspectives were considered necessary in the discus-sions, in order to serve the field best by choosing a minimal core set of variables that are applicable across different geographies and cultures. The experts were divided into small working groups according to their expertise. They completed reviews of published RCTs in their respective domains and held initial discussions. After this foundational preparatory group work, these experts and SAB members met for a 2-day workshop in Paris, France, in October 2018, to discuss the recommendations and come to a consensus on a core set of variables to recommend in each domain. ## Criteria for minimal core set A variable is defined as "a property with respect to which individuals in a sample differ in some ascertainable way" . The minimal core set is a set of variables recommended to be measured in all trials for obesity, regardless of the type of intervention. It is understood that over time this core set will be updated according to the scientific advances in each of the identified domains. For a variable to be included in the minimal core set, it was required to fulfill the following criteria: - It provided information that made it likely to impact treatment response, according to the relevant literature (especially studies that aimed to stratify patients) - It was feasible: Given that each clinical trial has limits on budget and time as well as research team expertise, the OBEDIS group aimed to minimize the burden of including each variable in future trials. The scientists paid considerable attention to factors that would encourage widespread adoption of these measures by the European obesity research community, especially the overall number of variables that should be systematically collected. The group preferred measures that were: − Low-cost or free to utilize/able to be collected with minimal equipment or human resources − Less invasive/quick to implement − For questionnaires: Available and/or validated in multiple languages or across cultures The group provided an estimate of the average cost of including these measures in a European trial [fig_ref] Table 1: Summary table [/fig_ref]. While inclusion of these variables will in some cases introduce additional cost to individual clinical trials, they will also extend the insights made possible by each trial -making the overall research agenda proceed more purposefully and at a lower cost. While the primary purpose of the initiative was to identify a minimal core set, additional relevant variables and/or measures were identified in some cases, and these were included in what was called the "expanded set." ## Selection of minimal core set Each group presented the variables frequently used in the studies to date, and selected them based on their experience, the scientific literature, and their projections about the future direction of the field in each domain. The group then voted on each item in the minimal core set (with the outcome determined by a simple majority). The approach to this OBEDIS project was pragmatic and guided at every turn by the existing body of evidence on interventions for obesity while taking into account the constraints of the minimal core set. The experts understand that few trials will restrict themselves to only this core set and will collect additional variables depending on their specific aims and outcomes. Trial investigators may opt to carry out more detailed measurements for a certain variable when it corresponds to the main objective of the study -and in this case, regardless, the OBEDIS group recommends collecting the overlapping measures in the minimal core set to facilitate data integration on a larger scale. ## Parallel efforts The OBEDIS work with European experts occurred in parallel with a similar United States initiative funded by the National Institutes of Health: the ADOPT (Accumulating Data to Optimally Predict obesity Treatment) core measures project [bib_ref] The Accumulating Data to Optimally Predict Obesity Treatment (ADOPT) Core Measures Project:..., Maclean [/bib_ref]. In the OBEDIS workshop, the experts noted that the existence of this parallel work highlights the need for such efforts in the field. OBEDIS scientists wish to connect ideas across these two projects and build joint efforts in the same direction, for the overall benefit of the field globally. # Results The expert guidelines detailed herein represent a practical advancement in the field of research on obesity interventions. Below, the results are described in four categories -environment and context, lifestyle, subject characteristics, and complications -with a final section looking ahead to implications for future medical practice. [fig_ref] Table 1: Summary table [/fig_ref] summarizes the variables and methods. Issues pertaining to obesity interventions are covered in a separate paper. The OBEDIS experts unanimously agreed that standard operating procedures (SOPs) are of critical importance, because only with consistent harmonized procedures can data be pooled across studies. The recommended detailed assessment methods for these measurements are detailed in the supplementary materials (for all online suppl. materials, see www. karger.com/doi/10.1159/000505342). ## Environment and context: medical history of obesity, basic background information, quality of life/handicap No living entity exists in isolation: across the biological sciences, researchers consider environmental influences as major drivers of behavioral change. Various environmental factors are considered relevant in obesity, since they may contribute to the emergence and maintenance of the condition and relevant behaviors. The context where patients live and work may also impact response to interventions, making contextual factors potentially useful for patient stratification at baseline. Medical History of Obesity Minimal core set recommended variables: - Age at onset of obesity - Maximal and minimal body weight after 18 years of age - Variation of body weight during the past 3 months - Previous attempts to lose weight and weight maintained after weight loss - Etiology: categories from Hebebrand et al.- Parental history, including history of bariatric surgery Expanded set recommended variables: - Body weight self-monitoring The medical history of obesity is a recall of weight-related events and problems experienced by the patient. In adult obesity, the medical history of the disease is important because factors in the history of a patient can not only affect the course of weight gain and loss through the lifespan but may modulate the response to a specific type of intervention. Medical history variables in three main categories are relevant to intervention responses: the development of the current obesity state and previous attempts to treat it; the disease etiology; and variables related to conception and perinatal history. Comorbid medical conditions that may influence intervention outcome, or disorders for which the treatment influences outcome, are discussed elsewhere in this paper. In considering the development of the patient's current obesity state, the OBEDIS group recommends documenting both the age of the onset of obesity, and the maximal and minimal body weight during adulthood. The age at obesity onset is important because occurrence prior to age 18 can influence the development of complications later on. Meanwhile, minimal and maximal body weight in adulthood are also relevant; in particular, using maximum body mass index (BMI; rather than using BMI at the time of study) to assess mortality risks leads to stronger associations between excess weight and mortality. Another potentially important factor is recent body weight fluctuations; the group recommended assessing weight changes over the past 3 months. Assessing body weight self-monitoring behaviors is not recommended for the minimal core set of variables but may be included in the expanded set. Previous attempts to treat obesity are also relevant: for instance, in some studies a greater number of previous weight loss attempts predicted greater weight lossand some evidence suggests weight cycling may increase the likelihood of future weight gain. Data for the minimal core set should include: the number of attempts, whether the patient has undertaken individual/group behavioral interventions (pertaining to nutrition/PA/psychology), whether treatment included obesity drugs or bariatric surgery, and the maximal weight loss and weight regain as a result of these attempts. The etiology of the patient's obesity may affect response to intervention. In most individuals with obesity, the disease is multifactorial -that is, resulting from the complex interaction of many genetic/epigenetic and environmental factors. However, in cases where a defined etiological factor can be identified (a genetic mutation, for example), the OBEDIS group recommends using the categories outlined in Hebebrand et al.. Trained medical staff should be able to identify syndromic obesity to either avoid the inclusion of these patients if the trial is not specific to genetic obesity or include these patients as a separate subgroup. Factors related to periconceptional and perinatal history of the patient may also affect response to obesity interventions [bib_ref] Maternal obesity and the early origins of childhood obesity: weighing up the..., Zhang [/bib_ref] : family disease history, maternal obesity before conception, complications and health conditions during pregnancy (including maternal gestational diabetes), magnitude of gestational weight gain, preterm or term birth, and birth weight (macrosomia). Typically, not all of this information is known to the patient, but in the minimal core set the OBEDIS group recommends assessing two particularly important factors prior to conception: parental obesityand maternal history of bariatric surgery. No standardized medical history questionnaire for obesity is in use throughout Europe. Various standardized questionnaires exist to assess some of the above items, but many are not available in different European languages. Thus, the OBEDIS group recommends assessing the above medical history variables via custom questionnaire (self-report), specified in the supplementary materials. Where available, medical records (registers or electronic medical charts) may be used to corroborate the information. The group agrees that, in the future, researchers should set about developing a standardized clinical questionnaire related to the medical history of obesity, which would be translated into different languages for use by researchers and healthcare professionals across Europe. A further endeavor -which would prove extremely valuable for research purposes -is to develop a European register of health information that included data on medical history, health status, and treatment of individuals over time. Basic Background Information Minimal core set recommended variables: - Number of years of education and country Both education and other measures of socioeconomic status, such as income, may modify intervention outcomes for certain kinds of obesity interventions. Variations across education level were observed for the outcome suicide and self-harm when comparing a dietary/lifestyle modification program and bariatric surgery [bib_ref] Risk of suicide and non-fatal selfharm after bariatric surgery: results from two..., Neovius [/bib_ref] ; a similar pattern was found for the outcome of sleep medication use. In higher-income countries, an inverse association tends to exist between educational attainment and obesity. Number of years of education is widely used for assessing patient educational attainment [bib_ref] A review of educational attainment measures for social survey research, Connelly [/bib_ref] and is recommended in this context. While this measure does not allow complete comparability of data between countries, the minimal core dataset would ideally specify the country along with the number of years of education. ## Quality of life/handicap Minimal core set recommended variables: - Quality of life (QoL): EQ-5D-5L health profile scores, overall self-rated health status, and index value QoL is a subjective factor that is defined by the World Health Organization (WHO) as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns". Health-related QoL is a broad-ranging, multidimensional assessment of one's own health; it is an outcome measure that is frequently assessed along with handicap: "a disadvantage for a given individual that limits or prevents the fulfillment of a role that is normal for that individual". Given that health is "a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity", a complete assessment of health status -especially in chronic diseases -should include both objective measures (using a biomedical framework) and subjective measures (using a psychosocial framework; e.g., QoL). In the field of obesity research, health-related QoL can be an independent outcome variable for assessing the effectiveness of therapeutic strategies for obesity, complementary to the degree of weight loss and to the improvement in complications. In addition to its outcome value, QoL can also have predictive value (i.e., prediction of biopsychosocial outcomes) and discriminative value (e.g., differentiating between patients with or without other medical conditions) . QoL is an important variable in economic evaluation of healthcare interventions, as it is used to calculate quality-adjusted life years, the most commonly used effect measure in cost-effectiveness analyses. QoL, as a patient-reported outcome, is assessed using self-administered questionnaires. Many questionnaires have been validated in the field of obesity [for reviews see. The OBEDIS group used several criteria (consistent with the general criteria above) to choose the most suitable QoL questionnaire: type of concept assessed (i.e., assessment of QoL, but not symptoms/functional status or handicap), brevity, convergent validity, cross-cultural validation (particularly important in this European work), and copyright (including no or limited fees for use). The European group agrees that the EQ-5D-5L satisfies the greatest number of criteria for suitability of widespread use -especially cross-cultural validation, minimal number of items, and free copyright. This tool, designed in 1990 by The EuroQol Group (comprised of international multidisciplinary researchers devoted to measuring health status), was revised in 2005 and validated in 2011. The questionnaire includes five dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression, and an overall visual analog scale. Importantly, it has been validated in patients with obesity and who have undergone obesity surgery, and is sensitive to change [bib_ref] The Effect of Bariatric Surgery on Mobility, Health-Related Quality of Life, Healthcare..., Tarride [/bib_ref] [bib_ref] Wordsworth S; By-Band-Sleeve Study Management Group. The EQ-5D-5L is a valid approach..., Fermont [/bib_ref]. In cases where the main goal of the study is related to QoL, however, an additional obesity-specific measure may be useful to assess this parameter in more depth. ## Lifestyle and behavior: dietary intake, pa and sedentary behavior, sleep, stress and other psychological variables While human behaviors vary substantially and occur in a complex interplay with an individual's social and physical environments, characterization of specific behavior patterns is useful for predicting clinical outcomes. Discussed in this section are behaviors and lifestyle factors that affect energy balance, weight loss, and/or weight maintenance. Eating behavior, defined as an individual's food and beverage consumption and habitual eating patterns, is a complex and important modifiable behavior that directly affects weight and nutritional status through the lifespan. In obesity, assessment of eating behavior is necessary given the dual burden of disease and potential undernutrition. Obesity interventions that target eating behavior mostly aim to decrease energy intake to induce negative energy balance -a necessary condition for weight loss. Modification of dietary intake is a well-known requirement for successful treatment of adult obesity [bib_ref] Position of the Academy of Nutrition and Dietetics: Interventions for the Treatment..., Raynor [/bib_ref]. The benefits of dietary interventions for obesity go beyond weight loss, since a body of evidence shows that changes in dietary quality per se may decrease the risk of various comorbid health conditions and even reduce all-cause mortality [bib_ref] Effects of weight loss interventions for adults who are obese on mortality,..., Ma [/bib_ref] [bib_ref] Prevention of the metabolic syndrome in IGT subjects in a lifestyle intervention:..., Boer [/bib_ref]. Dietary intake constitutes a critical factor that interfaces with genetic heterogeneity and metabolic phenotypes, resulting in different health outcomes; for example, dietary fat intake can interact with genotype and/or phenotype to affect the risk of obesity. In addition, dietary fatty acid exposure can also interact with sex and genes together to predict the development of the metabolic syndrome. Many dietitians and nutrition scientists recognize the need to move from populationbased nutrition to personalized subgroup-based nutrition. Obesity is highly heterogeneous, so personalized or targeted interventions are warranted [bib_ref] Personalised nutrition and health, Ordovas [/bib_ref] but a major challenge is to determine which diet-related variables stratify individuals into groups that will respond to a given intervention. For all adult trials on obesity interventions, regardless of whether they focus on diet, the OBEDIS group recommends assessing both dietary intake and overall diet quality. The OBEDIS group acknowledges, however, the particular difficulty of identifying dietary assessment tools applicable to the broad range of cultural and geographic groups across Europe. While obtaining data on energy, and macronutrient and micronutrient intake is a major objective, the various assessment tools that exist are each appropriate for a specific country or region. Dietary intake is a detailed account of which foods and beverages are consumed, and in what quantities, during a set period of time. Initiatives exist (beyond the scope of these guidelines) that propose the most appropriate dietary assessment method in order to collect good quality dietary data, depending on the study objectives. The group recommends assessing this parameter in the minimal core set using a food frequency questionnaire (FFQ); the experts put forth the EPIC-Norfolk FFQ for consideration [bib_ref] EPIC-Norfolk FFQ Study. A new tool for converting food frequency questionnaire data..., Mulligan [/bib_ref] , while noting that the FFQ used in each trial should be validated according to the country in which it is being used. A 3-day weighed food record is appropriate for detailed studies where greater insights and links to biological readouts are required; such an assessment may capture short-term changes as a result of intervention. In the expanded set of variables (or depending on the study question) the experts recommend the use of a 3-day weighed food record, which is more suitable for detecting the effects of an intervention. Reviews like Dao et al.can help researchers select and implement the most appropriate dietary assessment method(s) to collect highquality dietary data. The group also recommends in the minimal core set an assessment of dietary quality, while acknowledging that the healthy eating indices applicable in Europe are linked with country-specific dietary guidelines and guidelines for PA. The Dutch Healthy Diet index was cited as a useful tool; however, the experts emphasize that the index used in a given trial must be adapted according to local guidelines and habits. The group also notes that in some contexts, it is important to use additional measures for tracking specific components of diet: for example, fiber intake or sugar-sweetened beverage consumption or the consumption of processed food. The group agrees the nutrition community should invest in the design and validation of assessment tools for dietary intake (included validated smartphone apps) that improve upon the ones currently available. Dietary intake assessment is highly challenged by the lack of accurate biomarkers, particularly in relation to energy intake and macronutrient intake, whilst micronutrient status may be more feasible. Biomarkers of dietary compliance were discussed by the OBEDIS experts. Such biomarkers are required to provide subjective insight in relation to habitual diet, as well as compliance to dietary interventions. However, those currently available have inherent limitations; for example, serum fatty acids only provide a short-term and limited assessment/reflection of dietary fatty acid intake. These biomarkers are not recommended for the minimal core set, but the experts note the critical importance for trials with free-living interventions of having an objective measure of compliance to identify nonresponse due to either noncompliance or lack of biological response. When faced with stress, individuals exhibit differences in eating patterns: approximately 40% increase and 40% decrease their energy intake, while around 20% do not change. Regardless of whether overall energy intake is increased, however, stress begets a shift toward choosing foods higher in sugar and fat. Hyper-palatable foods may act as a distress coping mechanism, particularly in those who have previously associated intake with relief. Dieting constitutes a risk factor for emotional eating, since stress and negative affect can be consequences of energy restriction, and paradoxically, may lead to food-related coping strategies. There may also be a biological basis for emotional eating, as individuals who exhibit this pattern demonstrate a blunted hypothalamic-pituitary-adrenal axis response to cortisol that leads to increased food intake. Emotional eating is associated with current and prospective weight, and interacts with perceived stress, negative life events, and short sleep duration. Greater weight loss success has been associated with decreased emotional eating score during a behavioral weight loss program. Eating in response to distress may also influence the timing of meal consumption -and because recent studies have indicated that meal timing in relation to sleep phase is an important factor for weight regulation, clinical trials should capture individuals' tendency toward emotional eating. The recommended tool for assessing these behaviors in the OBEDIS minimal core set is the Emotional PA is any bodily movement produced by the contraction of skeletal muscles that results in energy expenditure (EE) above resting levels, while exercise is a subtype of PA: one that is planned, structured, repetitive, and designed to improve or maintain physical fitness, physical performance, or health. PA helps adjust energy balance in those with obesity. Yet when diet is held constant, individuals in different BMI categories may experience different effects of PA on weight. Overall, studies report inconsistent results on how increased PA (including exercise training) affects weight loss; however, an inverse association has been shown between PA and longterm weight gain, although it is recognized that relatively high levels of PA might be required. There is general agreement that a major benefit of PA in subjects with obesity is prevention of weight regain after weight loss [bib_ref] Appropriate Physical Activity Intervention Strategies for Weight Loss and Prevention of Weight..., Donnelly [/bib_ref]. Studies show PA attenuates many health risks that are associated with overweight or obesity, and importantly, numerous health benefits result from increased PA even with no weight loss or only modest weight loss. Current evidence indicates that PA, at levels that are feasible to perform in subjects with overweight or obesity, only results in modest weight loss. SB is defined as any waking behavior characterized by an EE equal to or lower than 1.5 metabolic equivalent tasks (or MET, with 1 MET representing EE by a subject at rest, sitting); this includes behaviors carried out while sitting, reclining, or lying. Independent of PA levels, SB is associated with a higher risk of cardiometabolic disease and other complications. Decreasing SB is promoted in parallel with interventions that aim to increase habitual PA. The OBEDIS group agrees on the importance of including both objective and subjective measures of PA and SB in each clinical trial. Objective data on both of these can be gathered most commonly using an accelerometer -a type of movement sensor that is feasibly used in large-scale studies to quantify PA intensity and duration as well as SB duration, including breaks in sedentary time, with minimal inconvenience to the participant. The group recommends this method while noting several limitations: when worn on the hip, accelerometers typically miss upper body movement; neither do they provide data on body posture nor data in cycling or aquatic activities. The required accelerometer data comprises PA level as well as week day time in SB and weekend day time in SB. A subjective measure of PA and SB is also needed to add important information, such as the specific types of activities performed, the perceived level of exertion during exercise, and additional information about the context (place, time) of the PA. For these purposes, the group put forward a short questionnaire called the Paffenbarger Physical Activity Questionnaire. This widely used instrument is available in multiple languages and has ten questions that focus on moderate-to-vigorous PA, ranging from common activities such as stair climbing and walking to specific leisure activities. In addition to PA and SB, physical fitness is an important patient characteristic that may also relate to outcomes of the intervention(s). Physical fitness is a physiological attribute determining a person's ability to perform muscle-powered work, and it has been defined as "the ability to carry out daily tasks with vigor and alertness, without undue fatigue, and with ample energy to enjoy leisure-time pursuits and respond to emergencies". One major component of physical fitness is CRF. High CRF is associated with greater longevity and reduced cardiovascular risk in all BMI categories. While the usual measure of CRF is maximal oxygen uptake (VO 2 max, or maximal aerobic power) during an exercise test, requirements for specialized equipment and expertise render it impractical for the minimal core set. The OBEDIS experts instead recommend the use of the 6-min walk test, a field submaximal exercise test for assessment of physical function that requires a 30-m hallway and no specialized training or equipment. The test measures the distance an individual can quickly walk on a flat, hard surface over a period of 6 min, and it can be used to predict VO 2 max. The expanded set, however, may include the Chester step test as a measure of CRF: in this validated assessment of aerobic capacity, the participant is asked to step on and off an elevated platform in time with an audible metronome beat [bib_ref] The Chester step test-a simple yet effective tool for the prediction of..., Sykes [/bib_ref]. Another important component of physical fitness is muscular fitness. A measure of muscle strength, as an important component of muscular fitness, is therefore also recommended for the minimal core set, since the evidence in aggregate shows that muscle strength is associated with reduced mortality in all BMI categories and that resistance training (designed to increase muscle strength), even without weight loss, improves health risk [bib_ref] Appropriate Physical Activity Intervention Strategies for Weight Loss and Prevention of Weight..., Donnelly [/bib_ref]. More importantly, weight loss treatments may be associated with decreases in muscle strength, especially if the treatment does not include exercise. The Southampton grip-strength measurement is chosen for this purpose. Given these recommendations, the group notes an added value of the assessment methods in the minimal core set: some of the chosen methods are useful for assessing several variables. This is the case for the use of accelerometers to assess both PA and sleep behaviors; grip strength to measure both muscular fitness and (in the expanded set) sarcopenia; and the 6-min walk test to predict CRF. Habitual PA, SB, and physical fitness all must be measured at baseline (before any exercise training or intervention occurs) and at the end of an intervention; in trials longer than 6 months, these variables should be measured every 6 months. ## Sleep Minimal core set recommended variables: - Sleep duration and timing - Presence of sleep apnea: STOP-BANG Expanded set recommended variables: - Sleep duration and timing: accelerometry Sleep is influenced by the circadian clock -a self-sustained molecular oscillator, which aligns endogenous rhythms with daily exogenous signals to coordinate metabolism and behavior. Ample data show mistimed sleep contributes to "chronodisruption"or "circadian-phase misalignment"and promotes weight-related pathologies [bib_ref] Role of sleep and circadian disruption on energy expenditure and in metabolic..., Mchill [/bib_ref]. Commonly, sleep disruption occurs because of atypical work schedules: night shift work patterns are associated with the risk of overweight/obesity -especially abdominal obesity -and permanent night shifts appear to confer a higher risk than rotating night shifts. A lesser degree of chronodisruption called "social jetlag," however, can result from social activities and has been associated with an increased BMI [bib_ref] Social jetlag and obesity, Roenneberg [/bib_ref]. Given these data, the OBEDIS group recommends systematically recording whether individuals work on atypical schedules (specifically: the presence of night shift work and permanent night work), and whether they experience social jetlag. Although the Munich Chronotype Questionnaire (MCTQ) is sometimes used for these purposes, the OBEDIS group recommends a shorter custom assessment (see supplementary material) for patients to self-administer. Quantitative sleep data acquired from an accelerometer may be used (as part of the expanded set) in trials where resources allow. Prolonged wakefulness and sleep deprivation are hallmarks of modern lifestyles. Across cross-sectional and longitudinal studies, individuals' sleep duration shows a somewhat in consistent pattern of association with obesity. Experimental data suggest that sleep restriction increases food intake and alters EE. The OBEDIS group advocates for a basic assessment of sleep duration in the minimal core set. Specific questionnaires exist that capture various dimensions of sleep, including sleep duration, but many are subject to copyright restrictions and/or lack validated translations into different languages. For assessing sleep duration, the OBEDIS group recommends a custom, self-administered questionnaire (shown below). In individuals with obesity, disordered breathing during sleep is prevalent. Well-documented is the idea that obstructive sleep apnea (OSA) overlaps with obesity-related risksand impacts metabolic risk. Use of the OSA therapy continuous positive airway pressure (CPAP) may also change energy balance or metabolism, with potentially positive effects on glycemic control. The presence of OSA and the use of CPAP should therefore be assessed. While the gold-standard objective measure of OSA is the apnea-hypopnea index with nocturnal polysomnography, the OBEDIS group recommends subjective assessment using a brief questionnaire called the STOP-BANG. This questionnaire, which is freely available, was created to screen for symptoms of OSA in surgical patients and in all individuals. It can be completed in approximatively 1 min and has good predictive ability for mild, moderate, and severe OSA [bib_ref] Diagnostic accuracy of the Berlin questionnaire, STOP-BANG, STOP, and Epworth sleepiness scale..., Chiu [/bib_ref]. CPAP use may be assessed using a custom questionnaire item. ## Stress and other psychological variables Minimal core set recommended variables: - Perceived stress: Perceived Stress Scale (PSS) Previous research has indicated the necessity for simultaneous assessment of sleep and stress in trials on obesity. Poor sleep and emotional stress are predictors of incident obesity and may have an additive role. Not only does perceived stress associate with BMI, waist circumference, and serum triglyceride level [bib_ref] Perceived stress correlates with visceral obesity and lipid parameters of the metabolic..., Tenk [/bib_ref] , but also, those with poor sleep and incident obesity appear to have the greatest emotional stress and the shortest subjective sleep duration. Perceived stress is the degree to which situations in life are appraised as stressful by the individual. The expert group recommends subjective assessment of individuals' stress levels via the PSS. As the most widely used psychological instrument for measuring the perception of stress, the scale includes direct queries about a patient's current levels of experienced stress. The items on the questionnaire are general, easy to grasp, and require a total of 2 min for completion. An additional advantage of the tool is the availability of validated versions in many languages. ## Subject characteristics: anthropometry, body composition, ee, and hormonal status All trials involving individuals with obesity include measures of participants' characteristics, including anthropometric measures, body composition, and/or EE. Aspects of hormonal status are also important characteristics to consider in trials, as detailed below. Anthropometry, Body Composition, and EE Minimal core set recommended variables: - Weight and BMI - Anthropometry (waist, hip, neck circumference) - Fat mass and fat-free mass: dual energy X-ray absorptiometry (DXA) Expanded set recommended variables: [formula] - EE: open-circuit indirect calorimetry [/formula] The WHO defines obesity as "a condition of abnormal or excessive fat accumulation in adipose tissue, to the extent that health may be impaired". In clinical trials on obesity, researchers must quantify this increased adiposity in a way that allows comparisons between Alligier et al.: OBEDIS Core Variables Project www.karger.com/ofa subjects, and over time in the same subject. Patient-reported data are not adequate for these purposes. The OBEDIS experts acknowledge that the study of body composition assessment methods is rapidly moving forward, far beyond basic calculations of BMI, and this may present an important opportunity for identifying precise body composition subgroups that may respond predictably to an intervention. BMI -calculated from measures of a subject's height and weight -is the simplest and most frequent way of classifying an individual as underweight, normal weight, overweight, or obese, and is therefore recommended for inclusion in the minimal core set. Although the relationship between BMI and all-cause mortality has been confirmed, BMI as a "surrogate measure" of obesity does not directly capture large interindividual variation in excess adipose tissue. This makes BMI misleading for individuals who exhibit differences in proportions of lean body mass and fat mass (for instance, elite athletes and those with sarcopenia). Indeed, going beyond a patient's BMI adds valuable additional information about health [bib_ref] Body adiposity and type 2 diabetes: increased risk with a high body..., Gómez-Ambrosi [/bib_ref]. Recent work shows it is the excess fat that constitutes a risk factor for a range of comorbid diseases: type 2 diabetes (T2D), ischemic heart disease, hyperlipidemia, sleep apnea, certain forms of cancer, and others. Further anthropometric measures -waist, hip, and neck circumferences -are recommended in all clinical trials focusing on obesity, as ways to assess subjects' fat distribution. Ample evidence shows increased central or android fat distribution (assessed via waist-toheight ratio) is associated with greater risk to health [bib_ref] Waist-to-height ratio as an indicator of 'early health risk': simpler and more..., Ashwell [/bib_ref] compared to more peripheral or gynoid fat distribution. Adding waist circumference to other anthropometric measures is valuable for predicting metabolic phenotypesand a rationale even exists for how variables that include waist circumference directly affect intervention response. Waist-tohip ratio predicts cardiovascular morbidity and mortality in those with obesity and T2D. In addition, neck circumference has been shown valuable for identifying excess body weightand associates with the presence or severity of different comorbidities [bib_ref] Different impacts of neck circumference and visceral obesity on the severity of..., Kawaguchi [/bib_ref] [bib_ref] Neck Circumference, along with Other Anthropometric Indices, Has an Independent and Additional..., Huang [/bib_ref]. Many options exist for more precise measurements of body composition. Available methods, each with their pros and cons, include bioelectrical impedance analysis (BIA), magnetic resonance imaging, computerized tomography scan, air displacement plethysmography (BOD POD), underwater weighing, and DXA. Body weight, BMI, or variables derived from weight alone are unable to distinguish between fat-free mass and fat mass, yet these components have specific medical relevance: increased fat-free mass may be found in athletes, who are not obese despite a high body weight/BMI; decreased fat-free mass is characteristic of a pathological condition called sarcopenia (or sarcopenic obesity), which needs to be detected; and fat-free mass is a determinant of EE (see below). Meanwhile, the visceral component of total body fat has unique physiological characteristics, which influence diseaserelated processes in the body. Increased visceral adipose tissue in those with obesity is associated with an increased risk of metabolic (glucose intolerance, T2D) and cardiovascular disease (CVD). The OBEDIS group agrees that precisely capturing the amount and distribution of body fat is required for the minimal core set of variables. At present, however, no easy methods exist for assessment. BOD POD and BIA are two-compartment models (capturing fat mass and fat-free mass), while DXA is a three-compartment method (dividing the body into fat mass, lean body mass, and bone mineral content). This relatively accurate, noninvasive method enables rapid measurement of percent body fat, although it remains dependent on several assumptions (namely, the constancy of fat-free mass composition) and exposes participants to a small dose of ionizing radiation. But because DXA is validated for those with obesity, it is the OBEDIS group's recommendation. The use of DXA, a method that requires specialized equipment, is an exception to the general principle of simplicity in the OBEDIS minimal core set, but the group agrees that the potential predictive value of DXA-generated data is sufficiently great to enable rapid progress in the field. In cases where trial limitations in budget, equipment, or expertise render it impossible to incorporate DXA, the group recommends BIA or plethysmography as an alternative to measuring fat mass and fat-free mass. Overall, the expert group concurs that the field needs more research and development on easy and inexpensive tools for precise measurements of body composition. Energy balance in obesity may be important for prediction of intervention outcomes [bib_ref] Accumulating Data to Optimally Predict Obesity Treatment (ADOPT): Recommendations from the Biological..., Rosenbaum [/bib_ref]. EE is one component of energy balance, and hence, highly relevant for evaluating body weight changes. A subject's EE is likely to change in the course of an intervention, as it can vary with changes in body weightor fat-free mass; changes in the composition of body weight gained or lost; adaptive thermogenesis (thyroid hormones, sympathetic nervous system, brown adipose tissue); and pharmacologic agents. Twenty-four-hour EE is the sum of basal metabolic rate (BMR), adaptive thermogenesis (food, thermoregulation, etc.), and PA/exercise thermogenesis; it can be measured in freeliving individuals with doubly labelled water, but this method is expensive and restricted to a few specialized centers. Resting EE can be measured by indirect calorimetry -but again, this method is not feasible in all centers, and accurate measurements require very strict conditions (overnight fast; no PA prior to measurement, requiring that measurement is done on inpatients; thermoneutrality, etc.). BMR varies according to body composition (mainly fat-free mass), and hormonal status (thyroid hormones, sympathetic nervous system/catecholamines, brown adipose tissue). BMR can be predicted with equations based on body weight or body composition: BMR = a - body weight + b (where a and b are different for males and females); or BMR = a - fat-free mass + b (where a and b are identical for both males and females). Expressing results as kcal expended per kg body weight or per kg fat-free mass invariably underestimates values in overweight/obese individuals and should not be used. Results should instead be expressed as percentages of predicted value based on validated equations (Mifflin Jeor or others; see supplementary materials). EE is an essential feature for metabolic phenotyping, but direct measurement of EE should be included in the OBEDIS expanded set rather than in the minimal core set. The energy requirements of individuals included in a study can instead be predicted based on the BMR prediction equations above, multiplied by a PA level of 1.1-1.9 for PA level. Measurement of EE may nonetheless be highly relevant in some mechanistic studies, since variations in BMR may occur during interventions due to changes in body weight/fat-free mass (body composition-dependent changes) and changes in tissue (fat-free mass) metabolic activity. Such measurements are best done by open-circuit indirect calorimetry using standardized procedures. Simultaneous measurement of body composition is strongly recommended for data interpretation. Endocrine and gynecological system alterations can occur in obese individuals, and many different measurements give insights into these complications; these include markers of thyroid status, that can be related to regulation of energy balance, and markers of gonadal axis in both sexes [bib_ref] Menopause and diabetes: EMAS clinical guide, Slopien [/bib_ref]. Among these hormones, the group recommends the measurement of TSH to assess thyroid function; FSH and LH may be used in the expanded set to confirm, when necessary, menopausal status in women. In both males and females, androgens might provide valuable additional information; however, should their measurement be included, it should be mandatorily accomplished by mass spectrometry-based assays. A panel of peptides and cytokines is usually characterized in studies focusing on obesity, including leptin, as a marker of body fat; adiponectin, as a predictor of metabolic dysregulation; tumor necrosis factor alpha and interleukin-6, as markers of inflammation; ghrelin, as a hunger signal; glucagon-like peptide-1 and peptide YY as a measure of satiation signal function. Consequently, measurement of each of these hormones may be included in clinical trials for obesity, according to the specific research question. However, preanalytical and analytical issues related to the measurement of most of these substances dramatically affect the consistency of the results. Assay standardization and harmonization among labs are urgently needed to generate normative values. In addition, mass spectrometry-based assays for the quantitative and qualitative (isoforms, posttranslational modifications, etc.) assessment of peptide hormones are regarded as promising for their thorough characterization; however, the introduction of such techniques into routine clinical labs does not appear feasible in the near future. ## Complications: t2d, cardiovascular risk, liver disease, and other long-term obesity complications The many complications of obesity are of interest because of their associations with poorer overall health and with more complex clinical management. These comorbid conditions, and the medications taken to ameliorate them, may affect response to intervention. The major comorbid conditions in obesity are addressed in this section. Type 2 Diabetes Minimal core set recommended variables: - Fasting glycemia (two measurements) - Hemoglobin A1c: HPLC-CE or HPLC-MS - Fasting insulin and insulin-derived insulin sensitivity indices - Family history of diabetes Expanded set recommended variables: - Hyperinsulinemic-euglycemic clamp Obesity is associated with alterations in normal endocrine and metabolic functions, leading to a number of pathological conditions: among these, T2D -affecting around 30-40% of obese individuals [bib_ref] A Consensus Report by the American Diabetes Association (ADA) and the European..., Davies [/bib_ref]. Although metabolically healthy obese individuals exist, epidemiological evidence shows a high incidence of metabolic syndrome in those with obesity. In patients with both obesity and T2D, interventions that lead to successful weight management substantially improve outcomes related to metabolic control. Response to interventions may also be modified by the use of various antidiabetic medications, which might affect weight either positively or negatively [bib_ref] A Consensus Report by the American Diabetes Association (ADA) and the European..., Davies [/bib_ref]. The OBEDIS group recommends including several T2D-related variables in all clinical trials on obesity interventions: two measurements of fasting plasma glucose for assessing T2D, hemoglobin A1c (HbA1c) for screening and monitoring of glycemic control, and fasting insulin as a surrogate marker for insulin resistance as well as indicating the secretory capacity of the beta cells. HbA1c measurement is recommended both for assessing blood glucose control in people with diagnosed T2D, and for diagnosing the disease or its early stages ("prediabetes"). The group agrees that C-peptide could take the place of fasting insulin as a marker of remaining insulin secretion. Further, insulin-derived insulin sensitivity indices should be calculated: Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) represents the presence and extent of insulin resistance; whereas HOMA-beta reflects beta cell function. Both calculations are mainly used in clinical studies. Several additional factors related to T2D are important to know -the individual's family history of T2D (to indicate possible genetic risk), as well as current medication and dosages. Recommendations on specific methods for each of these parameters are detailed in [fig_ref] Table 1: Summary table [/fig_ref]. There are more invasive measures of insulin secretion and sensitivity (hyperinsulinemic-euglycemic clamp, intravenous glucose tolerance test, etc.) and more comprehensive measures of key aspects of metabolic flexibility, but these tests are not feasible for all large-scale clinical interventions. ## Cardiovascular risk Minimal core set recommended variables: - Smoking habits - Blood pressure and heart rate: automatic blood pressure device - Total cholesterol, high-density lipoprotein cholesterol, triglyceride - Inflammation: C-reactive protein (CRP) - Heart electrical activity: 1-to 5-min electrocardiography (ECG) - CRF: 6-min walk test Individuals with obesity often exhibit disordered vascular and heart function, and an elevated risk of CVD. Intervention strategies may be modified by the presence of CVD or its various risk factors. Most CVD risk is driven by age plus three other major CVD risk factors in addition to diabetes; namely, high cholesterol, high blood pressure, and smoking, together accounting for about 80% of population-attributable risk. Cardiovascular risk algorithms exist [bib_ref] An independent external validation and evaluation of QRISK cardiovascular risk prediction: a..., Collins [/bib_ref] , but due to the imprecise estimates they provide and the factors that are included in these algorithms, they may not prove useful in the context of short-term interventions for obesity. While risk scores were not included in the minimal core set, the OBEDIS group proposes measuring smoking status as well as several parameters related to vascular and cardiac function, which may help, now and in the future, to stratify individuals in order to optimize intervention outcomes. Assessment of current smoking habits in the minimal core set is achieved using two custom questions: number of cigarettes per day and duration of smoking. Related to vasculature (atherosclerosis), the group recommended obtaining data on selected serum biomarkers: total cholesterol, high-density lipoprotein cholesterol, triglycerides, and high-sensitivity CRP (hsCRP). Fasting hsCRP is included as a surrogate marker of inflammation, and CRP appears to be one of the best-established CVD risk markers [bib_ref] Clinical usefulness of very high and very low levels of C-reactive protein..., Ridker [/bib_ref] while having the advantage of being analyzed in a standardized and relatively inexpensive way. Additional measures relevant to CVD, including blood glucose and insulin concentrations, which capture insulin resistance and beta-cell function, are covered in the T2D section. The adipokine interleukin-6 also seems promising, and is recommended for the expanded set, with the recommendations about its measurement proposed in the supplementary materials. Among the variables related to cardiac function that could potentially modulate response to interventions for obesity, the following are recommended by the OBEDIS group for assessment: blood pressure, cardiopulmonary function, and electrical activity of the heart as measured by ECG. It is well-established that blood pressure may be modified by certain interventions, with weight loss causing important decreases in blood pressure. Despite somewhat limited reproducibility for automatic blood pressure devices, the group recommends using these in order to reduce human error. As an indirect but validated way to assess CRF, the group identifies the 6-min walk testrather than the determination of maximal aerobic capacity (VO 2 max), which is expensive and has a poor association with fat mass and the loss thereof [bib_ref] Is low VO2max/kg in obese heart failure patients indicative of cardiac dysfunction?, Hothi [/bib_ref]. Finally, the group recommends performing a 1-to 5-min ECG as detailed in [fig_ref] Table 1: Summary table [/fig_ref]. Although not fully validated for hard endpoints, 1-to 5-min ECG is often used in small intervention clinical trialsand predicts cardiovascular death; thus, it may be used as a noninvasive means of risk stratification. Assessing the presence of OSA is also essential, since OSA is associated with hypertension and an increased risk for CVD and T2D. These measures are detailed in the section on sleep behaviors. ## Liver disease Minimal core set recommended variables: - Nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) and fibrosis-4 index (FIB-4): ALT, AST, GGT, platelet count, and albumin from blood - Alcohol intake: WHO AUDIT questionnaire Obesity comes with an increased risk of different forms of NAFLD: steatohepatitis (increased liver triglycerides), possibly progressing to fibrosis (irreversible scarring of the liver) [bib_ref] Obesity-Associated Liver Disease, Marchesini [/bib_ref]. Tracking the occurrence of these liver conditions is deemed important for the minimal core set, as these conditions may affect a subject's response to intervention. To detect fibrosis noninvasively, most guidelines [bib_ref] The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance From..., Chalasani [/bib_ref] recommend using the FIB-4 or the NFS, both of which are low cost and straightforward. Given the relationship of alcohol intake to liver disease, the OBEDIS group also recommends a brief assessment of alcohol intake using the WHO's AUDIT questionnaire. Other Long-Term Obesity Complications: Osteoarthritis and Cancer Minimal core set recommended variables: - QoL: EQ-5D-5L Expanded set recommended variables: - Pain-related physical functioning: WOMAC VA 3.0 Over the long term, besides the significantly increased risk of CVD and T2D, obesity confers an increased risk for several other conditions: major medical complications (cancer), and functional complications (arthrosis). Data on these conditions are part of a comprehensive assessment of the obesity phenotype. Obesity increases the risk for osteoarthritis, a degenerative condition of joint pain and dysfunction. The presence of this condition is normally assessed through specific selfadministered validated osteoarthritis questionnaires. But (pain-related) physical functioning is the most important factor related to osteoarthritis that may change with an intervention, and the OBEDIS group decided this factor is adequately assessed by an overall QoL questionnaire. The addition of a specific osteoarthritis questionnaire to the QoL questionnaire recommended above would provide marginal improvement in predictive ability. In the expanded set of variables, however, investigators may want to include the Western Ontario and McMaster Universities (WOMAC VA 3.0) osteoarthritis index, a self-report questionnaire covering hip and knee osteoarthritis. Those with obesity experience cancer at a higher rate than the general populationand a patient's history of cancer may be relevant to the exclusion criteria in a clinical trial. Once a patient is enrolled in a trial, however, investigators may want to track cancer occurrence. The OBEDIS group decided that including cancer data in the minimal core set was not necessary; because of the long delay before cancer occurrence, the following data need only be collected in cohorts with more than 5 or 10 years of follow-up: date of diagnosis and cancer type (according to the International Classification of Diseases). The data should be obtained from medical records where possible and validated by independent medical experts. ## Future medical practice Several areas of analysis have the potential to advance precision medicine within the field of obesity: tissue phenotyping, as well as genetics, and omics. It is already known that researchers may gain insights into the molecular underpinnings of variability in weight loss by precisely analyzing different body tissues in individuals with obesity: apart from components of blood, urine, and stool, this may include biopsies and/or assessments of white adipose tissue, skeletal muscle, and the liver. Precise phenotyping of patients by tissue analysis is a promising area within the field of obesity; some studies have successfully used this approach to identify subgroups of participants that have increased susceptibility to obesity or that will predictably respond to a treatment. However, the complexity of these methods rules them out for the minimal core set at present. In the future, patients may be stratified based on the presence of specific genetic markers. Data from family, twin, and adoption studies show that both body weight (40-70%) and body fat distribution are highly heritable. Heritability also seems to play a role in the nature, magnitude, and/or timing of response to obesity interventions [bib_ref] Polygenic Prediction of Weight and Obesity Trajectories from Birth to Adulthood, Khera [/bib_ref] : studies have shown genetic influences on dietary interventionsand heritability of response to bariatric surgery (Roux-en-Y). Obesity-related gene expression may be attenuated by PA. This field is expected to advance rapidly over the next few years and zero in on very specific genetic markers for patient stratification. Beyond human genes, advances in high-throughput technologies for analysis of biologic molecules have created the potential for defining the biological characteristics of those with obesity with great precision. New omics technologies enable examination, not only of a patient's genome, but also of complete sets of transcripts, proteins, and metabolites. Analyses that fall under the category of omics are those that provide "a comprehensive, or global, assessment of a set of molecules": genomics, epigenomics (reversible modifications of DNA or DNA-associated proteins across the genome), proteomics, metabolomics (small molecule types), microbiomics, lipidomics, transcriptomics, and others. Already, findings from omics studies have identified important avenues of research in obesity: for instance, epigenomic studies have mechanistically linked aspects of the environment before conception with the probability of becoming obese later in life [bib_ref] Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring, Ng [/bib_ref] , while weight loss induced by gastric bypass surgery affects a patient's DNA methylation and gene expression profile. The analyses mentioned above are key components of certain obesity intervention studies, depending on their aims. The OBEDIS group considered the pros and cons of including genetic and omics data, as well as tissue analyses, in the minimal core set for all obesityfocused clinical trials; the group concludes that at present, the ability of these tests to explain variability in weight loss is not great enough to justify the added costs. The group strongly suspects, however, that as costs fall and evidence increases, researchers will soon have adequate justification for including such analyses in all trials. In anticipation of the probability that certain blood measurements may yield new insights in the near-term future, biobanking is highly recommended by the group -whole blood where possible, but at a minimum, samples of whole blood dried on paper. Dried blood spots are suitable for many potential future measurements, and also have the advantages of easy and low-cost collection and storage. The OBEDIS group agrees that consent is another important issue to address for this field: a challenge is to develop SOPs around consent, which will allow sharing and reuse of omics and other data over the long term and as new discoveries are made. The group envisions a set of consent-related SOPs implemented across Europe, adapted to local circumstances. # Conclusion The expert consensus detailed herein represents a practical advancement in the field of obesity research -with the group members supporting the adoption of these variables in future clinical trials, collected systematically either before or both before and after intervention. The group fully expects to add further variables to this minimal core set as more data become available in each of the identified domains or remove variables if they do not impact differential treatment response. Basic and preclinical research should, of course, continue in tandem, building a larger context for informing better intervention strategies and identifying the appropriate adult patient groups for each specific intervention. The translational potential of the work begun here is therefore of high value: over time, this project should enable more efficient convergence of evidence to support better care for those with obesity. The OBEDIS group sees the ability to pool datasets and compare very large numbers of trial participants as key to the advancement of "precision" or "personalized" medicine. In the future, when a clinician encounters a newly referred adult patient with obesity, he or she will be able to group the patient according to baseline characteristics and suggest a tailored intervention plan, backed by robust data. The OBEDIS workshop and the resulting guidelines, achieved only through the support of EASO, represent an historic collaboration in the field of obesity in Europe. The experts welcome feedback that will help these measures to be widely adopted throughout the field. # Disclosure statement K. Clément is a consultant for Danone Research and LNC therapeutics for work unassociated with the present study. M. Neovius has received advisory board fees from Itrim and Ethicon Johnson & Johnson. L. Tappy received a research grant from Soremartec Italy srl and speaker's fees from Soremartec Italy srl and Nestlé AG, Switzerland. No other authors have conflicts of interest to declare. # Funding sources This initiative was funded by the Joint Programming Initiative Heathy Diet for Healthy Life. # Author contributions All authors contributed to the guidelines described in this paper. M. Alligier and M. Laville led the initiative with J. Bouwman, K. Clément, and D. Langin. K. Campbell prepared the manuscript. [table] Table 1: Summary table [/table]	None	https://www.karger.com/Article/Pdf/505342	Heterogeneity of interindividual and intraindividual responses to interventions is often observed in randomized, controlled trials for obesity. To address the global epidemic of obesity and move toward more personalized treatment regimens, the global research community must come together to identify factors that may drive these heterogeneous responses to interventions. This project, called OBEDIS (OBEsity Diverse Interventions Sharing – focusing on dietary and other interventions), provides a set of European guidelines for a minimal set of variables to include in future clinical trials on obesity, regardless of the specific endpoints. Broad adoption of these guidelines will enable researchers to harmonize and merge data from multiple intervention studies, allowing stratification of patients according to precise phenotyping criteria which are measured using standardized methods. In this way, studies across Europe may be pooled for better prediction of individuals’ responses to an intervention for obesity – ultimately leading to better patient care and improved obesity outcomes.
be190792c857ef1239e0229de81d5d671a692134	pubmed	The requirements of a specialist breast centre	The requirements of a specialist breast centre The Breast 51 (2020) 65e84Produced by EUSOMA and endorsed by ECCO as part of Essential Requirements for Quality Cancer Care (ERQCC) programme, and ESMO.The centrepiece of this article is the requirements section, comprising definitions; multidisciplinary structure; minimum case, procedure and staffing volumes; and detailed descriptions of the skills of, and resources needed by, members and specialisms in the multidisciplinary team in a breast centre. These requirements are positioned within narrative on European breast cancer epidemiology, the standard of care, challenges to delivering this standard, and supporting evidence, to enable a broad audience to appreciate the importance of establishing these requirements in specialist breast centres. ## A b s t r a c t This article is an update of the requirements of a specialist breast centre, produced by EUSOMA and endorsed by ECCO as part of Essential Requirements for Quality Cancer Care (ERQCC) programme, and ESMO. To meet aspirations for comprehensive cancer control, healthcare organisations must consider the requirements in this article, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis, to treatment, to survivorship. ## Introduction: the need for quality frameworks There has been a growing emphasis on driving up quality in cancer organisations in order to optimise patients outcomes. The European Cancer Concord (ECC), a partnership of patients, advocates and cancer professionals, has recognised major disparities in the quality of cancer management and in the degree of funding in Europe, and has launched a European Cancer Patient's Bill of Rights, a patient charter that underpins equitable access to optimal cancer control, cancer care and research for Europe's citizens [bib_ref] The European cancer patient's Bill of rights, update and implementation, Højgaard [/bib_ref]. It follows an assessment of the quality of cancer care in Europe as part of the first EU Joint Action on Cancer, the European Partnership for Action Against Cancer (EPAAC, http://www.epaac.eu), which reported in 2014 that there are important variations in service delivery between and within countries, with repercussions in quality of care. Factors such as waiting times and provision of optimal treatment can explain about a third of the differences in cancer survival, while lack of cancer plans, for example a national cancer plan that promotes clinical guidelines, professional training and quality control measures, may be responsible for a quarter of the survival differences. The EU Joint Action on Cancer Control (CANCON), which replaced EPAAC from 2014, also focused on quality of cancer care and in 2017 published the European Guide on Quality Improvement in Comprehensive Cancer Control.This recognised that many cancer patients are treated in general hospitals and not in comprehensive cancer centres (CCCs) and explores a model of 'comprehensive cancer care networks' that can integrate expertise under a single governance structure. Research also shows that care provided by multidisciplinary teams (MDTs) result in better clinical and organisational outcomes for patients [bib_ref] Is it worth re-organising cancer services on the basis of multidisciplinary teams..., Prades [/bib_ref]. Countries have been concentrating expertise for certain tumour types in such networks and in dedicated centres, or units, such as for childhood and rare cancers, and all CCCs have teams for the main cancer types. For common adult tumours, however, at the European level there has been widespread effort to establish universal, dedicated units only for breast cancer, following several European declarations that set a target of the year 2016 for care of all women and men with breast cancer to be delivered in specialist multidisciplinary centres. While this target was not met, as detailed in a European Breast Cancer Council manifesto calling for universal breast unitsa , the view of the ERQCC expert group is that healthcare systems must strive to adopt the principles of such dedicated care for all types of cancer. ## Breast cancer There is a 20-year history in Europe of calling for, and developing, specialist breast cancer units. In the year 2000, the European Society of Breast Cancer Specialists (EUSOMA) published a position paper, 'The requirements of a specialist breast unit', which was the first to set out standards for establishing high-quality breast cancer centres or units across Europe. The paper followed a consensus statement drawn up at the first European Breast Cancer Conference in Florence in 1998 that demanded that, 'Those responsible for organising and funding breast cancer care ensure that all women have access to fully equipped multidisciplinary and multiprofessional breast clinics based on population numbers of around 250,000.' [bib_ref] Florence statement on breast cancer: forging the way ahead for more research..., Cataliotti [/bib_ref] The statement was based on a growing body of evidence that optimal care for breast cancer patients can only be obtained by an MDT, preferably based at one location. In the following years, European Parliament resolutions and declarations have called for universal breast cancer units or centres in Europe, while a number of papers and documents have developed quality standards and EUSOMA has refined the requirements [bib_ref] The requirements of a specialist breast centre, Wilson [/bib_ref] , which were also included in the European Guidelines for Quality Assurance in Breast Cancer Screening and Diagnosis. This paper is an update of the EUSOMA requirements paper, endorsed by the European CanCer Organisation (ECCO) as part of its Essential Requirements for Quality Cancer Care (ERQCC) programme, and by the European Society of Medical Oncology (ESMO). This update has a wider quality context, adding narrative on epidemiology, challenges in breast cancer care, and quality and audit processes and examples, in addition to the components of a breast centre. It is based on the changes in organisation and care over the past 5 years as detailed by representatives of the disciplines working in breast cancer care. The definition of the breast centre (or unit) that applies throughout this paper is: The place where breast cancer is diagnosed and treated; it has to provide all the services necessary, from genetics and prevention, through the treatment of the primary tumour, to care of advanced disease, supportive and palliative care and survivorship, and psychosocial support. ## . epidemiology Breast cancer is the most common cancer in women in the European Union and a rare cancer in men. It comprises a wide range of histopathological subtypes, the most common being invasive carcinoma of no special type (NST), previously named invasive ductal carcinoma, and invasive lobular carcinoma. Much less common are all the other histological subtypes. Ductal carcinoma in situ (DCIS), where cancer cells are only in the glandular tree, is a pre-malignant condition that may lead to invasive breast cancer. Nowadays, breast cancer is also classified into molecular subtypes, namely luminal A and B, HER2-positive and basal. Due to logistical and financial reasons, surrogate subtypes are mainly used in clinical practice e hormone receptor and HER2 receptor status, and a proliferation measure (usually Ki67). Oestrogen-positive (ERþ)/HER2-negative breast cancer is the most common subtype, comprising about 70% of cases. Breast cancer incidence varies across European countries but overall the lifetime risk is about 1 in 10 for women. Breast cancer is a substantial health burden on society, and has been estimated to cost about 13% of the total cancer healthcare costs in the EU, the highest of any cancer, and second in overall economic burden after lung cancer [bib_ref] Economic burden of cancer across the European Union: a population-based cost analysis, Luengo-Fernandez [/bib_ref]. The estimated incidence of breast cancer in 2018 in Europe (EU 28 þ European Free Trade Association (EFTA) countries) was about 416,000 with a European age standardised rate of 145/100,000). Estimated incidence was highest in Belgium (204/100,000), Luxembourg and the Netherlands, the lowest in Romania (90/100,000) and Poland; generally, incidence is lower in Southern and Eastern Europe, but data from these countries might be incomplete due to issues with cancer registries. Estimated mortality in 2018 was about 100,000, with the highest European age standardised rates in Croatia (43/100,000), Iceland and Ireland, and the lowest in Spain (23/100,000), Finland and Norway (see [fig_ref] Figure 1: European breast cancer mortality and incidence Source [/fig_ref]. There are high survival rates for breast cancer in Europe. The EUROCARE-5 study, the latest in the series, reports the 5-year relative survival rate in 2000e2007 at 82%, ranging from 74% (Eastern Europe) to 85% (Northern Europe), and survival increased during the study period [bib_ref] Survival of women with cancers of breast and genital organs in Europe..., Sant [/bib_ref]. Survival was uniformly higher for women in countries with population breast cancer screening. The 5-year relative survival was highest in the 45e54 and 55e64 year age groups and declined in older patients. Breast cancer mortality rates have declined in the European Union and are predicted to fall further, with the largest falls in young women (20e49 years, À22% between 2002 and 2012) [bib_ref] Trends and predictions to 2020 in breast cancer mortality in Europe, Carioli [/bib_ref]. The fall in mortality is said to be mainly due to improvements in the management and treatment of breast cancer, although early diagnosis and screening are also important. ## Improving breast cancer management in central and eastern Europe is a particular priority [bib_ref] Trends and predictions to 2020 in breast cancer mortality in Europe, Carioli [/bib_ref]. It is important to note that there has been little progress in extending the median survival of patients with advanced or metastatic (stage 4) breast cancer, which remains at about 3 years, although longer survival may be seen particularly in the HER2-positive subtype [16e18]. ## Risk factors Risk factors for breast cancer in women include older age, family history, previous benign breast disease, and a previous breast cancer diagnosis. In addition, several hormonal factors, particularly those that expose women to more menstrual cycles, play a role in increasing risk, including early menstrual periods, late menopause, less (and later) childbirths and less breast feeding. Pathological germline variants in the BRCA1/2 genes can greatly increase risk; other gene variants can also add variable risk. Women with dense breasts are more likely to be diagnosed with breast cancer. Preventable risk factors include overweight/obesity, lack of physical activity, smoking and alcohol consumption. Hormonal replacement therapy increases risk. Women who have had radiation therapy to the chest or breast as treatment for other cancers (i.e. lymphoma) are also at increased risk. Risk factors for breast cancer in men include older age, family history, BRCA1/2 variants (especially in BRCA2), gynecomastia, heavy alcohol intake, liver disease, obesity and radiation exposure. ## Diagnosis and treatment Note key ESMO and ESO-ESMO guideline references for diagnosis, treatment and care of early breast cancer [bib_ref] Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Cardoso [/bib_ref] and advanced breast cancer.. Breast cancer is one of only three cancers where there is robust evidence for the benefit of population screening (cervical and colorectal are the other two) and most European countries have introduced mammographic screening programmes, most commonly screening women between the ages of 50 and 70 at 2 year intervals to primarily detect small tumours that cause no symptoms. However, about an equivalent number of breast cancers are detected by self-examination for breast lumps and other symptoms including a change in the size or shape of a breast, dimpling of skin, inverted nipple, nipple rash and discharge, and a swelling or lump in the armpit. Ductal carcinoma in situ (DCIS), which is a non-invasive pre-malignant condition, may be asymptomatic or associated with a lump and is detected by mammography (usually through the presence of abnormal microcalcifications). Diagnosis should be made by a 'triple assessment', comprising clinical assessment (patient history and physical examination), mammography and/or ultrasound imaging, and a biopsy (a core needle biopsy is necessary; a fine-needle aspiration (FNA) is insufficient and should not be performed in the breast, since it has a high rate of false results and does not allow for adequate biomarker characterisation). Ultrasound is also used to image the axilla (armpit area) for affected lymph nodes, as a common site of spread are ipsilateral axillary nodes, and a biopsy/FNA taken if involvement is suspected; if not suspected, to rule out spread to the nodes, sentinel lymph node biopsy (SLNB) is a surgical procedure that has become the standard of care to identify the first node(s) that could be involved in early breast cancer. Breast cancer is commonly staged according to the TNM system and graded for cell differentiation (nuclear atypia and proliferation) and tubule formation. All invasive breast cancer should be assessed for ER, progesterone (PgR) and HER2 receptor status. The distinction between low and high-grade DCIS and invasive cancer is also important. Genetic testing for the BRCA 1/2 mutations is recommended in certain cases as it has implications for clinical management [bib_ref] Prevention and screening in BRCA mutation carriers and other breast/ ovarian hereditary..., Paluch-Shimon [/bib_ref]. Early invasive and locally advanced breast cancer are treated with curative intent. Local treatments include surgery (breastconserving surgery (BCS) or mastectomy with sentinel lymph node biopsy or axillary dissection) and radiation therapy. Systemic therapy options include chemotherapy, endocrine therapy, HER2 targeted therapy and bisphosphonates, according to risk of relapse and receptor status, and can be offered before (primary systemic therapy, also known as neoadjuvant or preoperative) and/or after surgery (adjuvant therapy). Primary systemic therapy is being used increasingly in higher risk biological subtypes (e.g. triple negative and HER2-positive) even in cases where BCS would be possible upfront, since this strategy enables personalisation of therapy based on response and facilitates prediction of prognosis for individuals based on pathological response. Primary systemic therapy is the recommended strategy for locally advanced breast cancer and inflammatory breast cancer. For locally advanced disease, surgical treatment varies depending on characteristics at diagnosis and response to therapy, while for inflammatory breast cancer, mastectomy and axillary dissection, followed by radiation therapy, is usually necessary even in the presence of a good response to primary systemic therapy. Tamoxifen and aromatase inhibitors are approved endocrine agents for ER þ early breast cancer. Ovarian ablation (removal of the ovaries) or suppression of oestrogen with drugs may also be offered to some premenopausal women with ER þ cancer. BCS followed by breast irradiation (plus endocrine therapy in some cases) is the preferred treatment for most DCIS patients, though widespread DCIS may well require treatment by mastectomy. Radiotherapy may be avoided in selected cases, i.e. low grade DCIS. Mastectomy or BCS with sentinel lymph node biopsy or axillary dissection and a similar range of medical and radiation therapy options are used for male breast cancer. Aromatase inhibitors alone should not be used for early breast cancer in male patients [bib_ref] Multidisciplinary meeting on male breast cancer: summary and research recommendations, Korde [/bib_ref]. Systemic therapy with endocrine therapy, chemotherapy and targeted therapy is the strategy of choice in advanced/metastatic breast cancer. The choice of systemic therapy depends on many factors, including the biology of the tumour, the burden of metastatic disease, symptoms, performance status, comorbidities, socioeconomic factors and patient preferences. Early and continuous appropriate supportive, palliative and psychosocial support are indispensable throughout the management of advanced/metastatic disease. Surgery, radiation therapy and interventional radiology are important to treat certain conditions, such as brain or bone metastases, to prevent bone fractures and relieve pain. In highly selected de novo (i.e. diagnosed already as stage 4) metastatic cases, locoregional therapy of the primary tumour, with surgery and/or radiation therapy, may also be performed. ## Challenges in breast cancer care ## Screening and detection Mammography screening services are often separate from breast treatment centres, missing opportunities for multiprofessional working in assessment and diagnosis. There has been wide publicity given to controversy about the benefits and harms of population-based mammography screening, which is one of the flagship health screening programmes in many countries. Women must be given information that allows them to make informed choices about participation in these programmes. Education on breast health awareness is often lacking in countries and should target girls at school as well as adult women. In view of exponential increase in cancer incidence, primary care physicians must be involved in many steps of the cancer journey, starting with screening and early diagnosis [bib_ref] ECCO essential requirements for quality cancer care: primary care, Banks [/bib_ref]. It is essential to promote close collaboration between these specialists and breast centres for a fast referral. ## Staging and grading There are concerns about the quality of breast cancer pathology services in Europe: e They can vary to a considerable extent in the accuracy of assessing parameters important for treatment decisionmaking; few countries are monitoring and assessing this variability e Most pathology departments are general and may lack pathologists experienced in the increasingly complex area of breast pathology and may also lack sufficient volume of cases to develop and maintain expertise e In many countries there is a shortage of pathologists. e Availability of intra-operative pathology assessment is crucial to substantially decrease the rate of re-interventions. A manifesto by the European Breast Cancer Council addressed these concerns [bib_ref] Optimal breast cancer pathology manifesto, Tot [/bib_ref]. ## Early breast cancer e treatment and support A wide range of shortcomings and challenges in care result from a lack of multidisciplinary breast centres: e Overtreatment in all areas (surgery, radiation and medical therapies), often related to outdated reimbursement rules e Underuse of treatments such as primary systemic therapy e Lack of surgical expertise and experience has led to too many mastectomies, too many axillary dissections and too many reinterventions e Lack of expertise and experience in breast radiation and medical therapies e Lack of oncoplastic/reconstructive expertise. Choosing the right treatment among an increasingly complex range of options has become a major challenge for patients and it is important that balanced advice is given by all breast specialists. There is a lack of dedicated breast nurses and patient navigators who can help guide patients through this complex care pathway. Breast care nurses are in place in only a few European countries at present. Developing breast care nursing is important to offer optimised care for patients [bib_ref] The breast care nurse: the care specialist in breast centres, Voigt [/bib_ref] and studies have shown that specialist nurses improve patient outcomes [bib_ref] Training breast care nurses throughout Europe: the EONS postbasic curriculum for breast..., Eicher [/bib_ref] [bib_ref] The role of the breast care nurse in patient and family care, Luck [/bib_ref]. They are essential members of the core MDT. There is a lack of adequate supportive and psychological support. About one third of breast cancer patients experience high levels of emotional distress [29e31], and about half report increased levels of depression and anxiety in the year after diagnosis [bib_ref] Depression and anxiety in women with early breast cancer: five year observational..., Burgess [/bib_ref]. Side-effects from treatments are often not adequately managed. There is a lack of data on treatment of older patients and very young patients. Although about 20% of breast cancer occurs in patients 75 years old or older, there is a lack of data on management of older patients, especially those who are frail and vulnerable. Chronological age alone must not be used to withhold effective therapies [bib_ref] Management of elderly patients with breast cancer: updated recommendations of the international..., Biganzoli [/bib_ref]. ## Advanced breast cancer (includes inoperable locally advanced and metastatic breast cancer) e treatment and support In Europe, most advanced breast cancer patients are still treated outside of MDTs, by medical oncologists alone. Treating advanced disease in specialised breast units/centres increases access to treatment according to international guidelines, locoregional management of certain types of metastases, correct management of symptoms and side-effects of therapies, inclusion in clinical trials, and early links to psychosocial supportive and palliative care, all of which are associated with higher quality of care and improved outcomes. Treatment is complex, can be costly, and often involves multiple lines of therapy with periods of good quality of life between treatment spells, with several agents approved in recent years. Issues of accessibility to optimal treatment options (e.g. cancer medicines, radiation therapy) are crucial and access is highly uneven between countries and within each country (see 2.2.7 Inequalities, below). Management of advanced disease in breast centres can centralise and optimise access in a cost-effective manner. ## Support services and survivorship Many breast cancer patients are of working age or have dependants or children and may suffer financial loss as a result of treatment related incapacity. Social support to aid in financial and other difficulties may be required but hard to obtain. Services are often also required to help manage secondary effects from treatments that affect quality of life, such as physiotherapy and occupational therapy (rehabilitation), nutritional counselling and psycho-oncology, but there may be gaps in provision, particularly when these services are best delivered in the community in partnership with breast centres. As more patients are being diagnosed at a fertile age, and before they have completed their families, fertility preservation is crucial and should be part of the breast centre's services. Advanced breast cancer patients face a range of survivorship issues such as isolation, lack of information and financial hardship. ## Genetic testing There are well-established protocols for testing women at high risk of breast cancer, such as Ashkenazi Jews or those with many affected family members for variants of the BRCA1/2 genes, but there is rapidly developing research on lesser risk genes and also in the most common genetic variants, SNPs [bib_ref] Prevention and screening in BRCA mutation carriers and other breast/ ovarian hereditary..., Paluch-Shimon [/bib_ref]. The rapid rise in commercial tests and in research on genetic breast cancer risk is placing pressure on clinical genetics services and on the knowledge base of other health professionals. In particular, there is a major challenge in uncontrolled and substandard tests that can raise anxiety and raise demand for counselling, and even lead to unnecessary treatment, as set out in the 2018 European Breast Cancer Council manifesto [bib_ref] European Breast Cancer Council manifesto 2018: genetic risk prediction testing in breast..., Rutgers [/bib_ref]. ## Inequalities Women with higher socioeconomic status in Europe have a higher breast cancer incidence but lower mortality than women in lower status groups [bib_ref] Socioeconomic inequalities in breast cancer incidence and mortality in Europe e a..., Lundqvist [/bib_ref]. While higher incidence is linked to reproductive factors, hormonal replacement therapy and higher use of opportunistic screening, lower fatality seems to be explained by earlier stage of diagnosis, and access to optimal treatment. A report from England also shows that socioeconomically advantaged women are more likely to be diagnosed with breast cancer, and finds that there are geographical variations, as women living in disadvantaged areas are more likely to be diagnosed at a later stage with a lower chance of survival. The same report from England also found inequalities related to black and ethnic minority status, which are also likely to be seen in other parts of Europe. There is evidence than many older women (over 70) are not offered the same standard of care as younger patients despite being eligible for treatment (see for example the National Audit for Breast Cancer in Older Patients (NABCOP) on services in England and Wales e (https://www.nabcop.org.uk). They are also more likely to be diagnosed at a later stage. There is also evidence that quality of care for male patients with breast cancer is lower than for their female counterparts [bib_ref] Characterization of male breast cancer: results of the EORTC 10085/TBCRC/BIG/NABCG international male..., Cardoso [/bib_ref]. There are substantial inequalities in access to treatment among and within European countries. Some Eastern European countries, especially, have shortcomings in radiation therapy and drug availability, including inexpensive breast cancer drugs such as tamoxifen as well as expensive new therapies, some of which are listed by WHO as essential medicines, although lack of access could be due to organisational and not only financial constraints. The use of international guidelines (which recommend cost-effective therapies) and new tools to objectively evaluate benefit and prioritise effective therapies (such as the ESMO Magnitude of Clinical Benefit Scale) [bib_ref] ESMO-magnitude of clinical benefit Scale version 1.1, Cherny [/bib_ref] are potential solutions. The shortage of cancer medicines was highlighted in a report from the Economist Intelligence Unit in collaboration with ESMO, and needs to be urgently tackled. ## Research Conducting research, in particular clinical research, is associated with better outcomes for patients and should be included in the services provided by the breast centre. Currently, clinical research in some European countries is oriented towards industry sponsored studies, especially those funded by pharmaceutical companies, and academic research must be supported by independent sources of funding, as called for by the Clinical Academic Cancer Research Forum [bib_ref] Safeguarding the future of independent, academic clinical cancer research in Europe for..., Negrouk [/bib_ref]. Evidence suggests that clinical research in Europe is not oriented towards investigation of antineoplastic drugs effect on endpoints that are most important to patients (i.e. improvements in quality of life, reduction of risk of recurrence for the early stages of the disease, and life prolongation for advanced disease) [bib_ref] Availability of evidence of benefits on overall survival and quality of life..., Davis [/bib_ref]. Therefore, a cornerstone of research should be to investigate the impact of intervention on endpoints that are patient oriented. In addition, clinical research should provide evidence of interventions' efficacy and safety from real life data, to confirm/question results from clinical trials. Important research topics in breast cancer include [bib_ref] Research needs in breast cancer, Cardoso [/bib_ref]. e Earlier diagnosis, apart from screening e Novel methodology with adaptive trial designs within platforms and validation of novel biomarkers of early response e Predictive factors and therapy individualisation e Escalation and de-escalation of therapy in early breast cancer e Identification of treatment strategies that optimise patients' quality of life without loss of quantity. There is an urgent need to increase research in patient groups that are under-represented and under-researched in breast cancer studies, particularly older and young women, and men. There is a pressing need for the development and incorporation of patient reported outcomes/measures (PROs/PROMs), and research on quality of life and survivorship. Patient advocacy groups are valuable partners in all aspects of breast cancer research, from epidemiology to treatments to survivorship, and should be involved in all stages of research. ## Cancer registration and data availability Cancer registration practice, coverage and quality are highly unequal across Europe [bib_ref] Cancer registries in Europe e going forward is the only option, Forsea [/bib_ref]. Consequently, basic epidemiological data on incidence, mortality and survival are not uniformly available for all countries. Also, only a minority of cancer registries can provide sufficient data for the calculation of parameters necessary for the assessment of outcomes and quality of care [bib_ref] Uses of cancer registries for public health and clinical research in Europe:..., Siesling [/bib_ref]. A particular shortcoming in breast cancer is that few cancer registries collect data on recurrences, including distant, which means that there are only estimates of the number of patients living with incurable disease. This makes it hard for healthcare services and wider society to allocate resources for one of the largest populations of advanced cancer patients. There is a need to find ways of improving quality of nationally/ internationally collected routine data so it can be embedded within clinical trials as outcome data. Cancer registries in Europe should be compatible with each other to analyse data collectively. Registries and/or other forms of real-world data should include data on the effects on treatment outcomes of the use of OTC (over the counter) medicines or CAM (complementary alternative medicines), which are commonly used by cancer patients [bib_ref] Complementary medicine, refusal of conventional cancer therapy, and survival among patients with..., Johnson [/bib_ref]. In addition, registries and/or other forms of real-world data should allow for the assessment of the true benefit of cancer therapies, evaluating whether results from clinical trials are translated into the real-life setting for efficacy and safety. This could also benefit the evaluation of efficacy and safety profile of the population unrepresented in randomised clinical trials. ## Breast centre: definitions Breast centre: The place where breast cancer is diagnosed and treated. It has to provide all the services necessary, from genetics and prevention, through the treatment of the primary tumour, to care of advanced disease, supportive and palliative care, survivorship and psychosocial support. The breast centre comprises a group of dedicated breast cancer specialists working together as a multidisciplinary team (MDT) with access to all the facilities required to deliver high-quality care throughout the breast cancer pathway. Preferably, all services should be in the same facility, limiting to a minimum the need for the patient to travel between locations. Therefore breast centres are encouraged to be organised in one location. However, when for organisational reasons this is not possible, some services may be based at different locations but must be in the same geographical area, and protocols must be in place for the optimal integration of care, guaranteeing multidisciplinary work and timely access, and all sites must share the same database for quality assurance and research. Protocols: Official procedures or systems of rules, including local organisational aspects, for the diagnosis and management of breast cancer at all stages, including surveillance and long-term follow-up. Breast data audit: Evaluation of quality indicators to identify corrective actions through multidisciplinary discussion. Formal internal review meeting: Evaluation of performance on quality indicators, organisational and clinical aspects, audit results, identification and implementation of corrective actions. Breast multidisciplinary meeting (MDM): Where the core MDT meets to evaluate and plan patient care at any step of the diagnostic and treatment process. Breast clinic: A session at which a number of breast patients are seen for clinical examination and/or investigations, counselling, etc. Breast specialist: A person certified in her/his own discipline and fully trained in management of breast cancer. Breast core MDT members: Breast specialists who are essential for diagnosis and care of breast cancer, who spend the majority of their working time in breast cancer and who must participate in MDM (except for radiographers, who are part of core team but are not requested to attend the MDM). These specialisms are detailed in the essential requirements in section 5: Breast radiologist: board-certified specialist in imaging with expertise in breast cancer diagnosis (including diagnostic interventional procedures), further assessment and follow-up Breast radiographer: technician specialised in breast imaging examination Breast pathologist: board-certified pathologist with expertise in breast disease Breast surgeon: board-certified surgeon with expertise in breast surgery including oncoplastic procedures. In some centres this role may be shared by a breast cancer surgeon and a reconstructive surgeon working together. Breast medical oncologist: board-certified medical oncologist with expertise in breast cancer. In some countries (e.g. Germany), systemic therapy for breast cancer patients is currently delivered by organ specialists such as gynaecologists, but the goal is that, in the near future, systemic therapy is only delivered by medical oncologists. It is crucial that any specialist who now delivers systemic therapy has training defined by the ESMO-ASCO Global Curriculum for Medical Oncology. Breast radiation oncologist: board-certified radiation oncologist with expertise in breast cancer or Breast clinical oncologist: in some countries (such as the Nordics and the UK) clinical oncologists are professionals who are board-certified in both radiation and medical treatments, but must be dedicated to breast cancer. Breast care nurse: a nurse with specialist training in breast care nursing Breast data manager: person responsible for breast cancer data management (detailed in section 4.10). Extended MTD members: Specialists who are consulted during breast cancer care and treatment, but are not routinely involved in breast cancer care for every patient. These specialisms are detailed in the essential requirements in section 6: Psycho-oncologist: professional who identifies distress and psychological morbidity and provides psychological interventions to breast cancer patients and their families Geriatric oncologist/geriatrician: geriatrician with cancer expertise who applies geriatric assessment for appropriate treatment Oncology pharmacist: pharmacist with expertise in cancer medicines Nuclear medicine physician: board-certified nuclear medicine specialist with expertise in the management of breast cancer patients, including sentinel lymph-node technique, molecular imaging and theranostics Physiotherapist: professional who provides physical support of patients after breast cancer therapies (breast surgery and radiotherapy) Plastic surgeon: board-certified plastic surgeon with expertise in breast reconstruction techniques Interventional radiologist: board certified specialist who carries out interventional radiology techniques, such as biopsies of metastatic lesions and local management of some types of breast cancer metastases such as bone metastases Self-image professional: a specialist in breast or hair prosthesis Palliative care specialist: specialist who provides physical, psychosocial and spiritual care to patients who have, or may soon have, severe symptoms and distress from advanced disease Clinical geneticist: medical specialist concerned with the assessment of genetic risk and counselling for individuals and families with increased risk of breast cancer Primary prevention professionals: specialists with expertise in physical exercise, diet and lifestyle counselling. All members of the breast centre should have knowledge and skills to provide basic psychological care and screen for distress. Qualified care providers other than nurses (e.g. radiation technologists) also provide links between patients and the breast team. To guarantee the availability of other specialists who may be needed for consultations during a breast cancer patient's care pathway, such as nutritionists, fertility preservation experts, cardiologists, gynaecologists, neuro-surgeons, orthopaedic surgeons etc., the breast centre must have established working arrangements which allow immediate and effective consultation. ## Breast centre requirements ## Breast centre There must be a formal document (that complies with any national regulations) which describes organisation of the breast centre and which could include its relationship within the wider cancer infrastructure such as the cancer centre and regional cancer network (see [fig_ref] Figure 2: Breast cancer centre schematic [/fig_ref]. ## Critical mass A breast centre must be of sufficient size to manage at least 150 [48e50] newly diagnosed cases of early breast cancer (all ages, based on surgery) coming under its care each year [bib_ref] Florence statement on breast cancer: forging the way ahead for more research..., Cataliotti [/bib_ref]. The breast centre must also treat at least 50 cases of metastatic breast cancer a year, independently from the line of treatment. The minimum number is necessary to ensure a caseload sufficient to maintain expertise for each team member and to ensure cost-effective working of the breast centre [50e52]. There is good quality data that shows that breast cancer survival is related to the number of cases treated per annum (see also supporting evidence in Appendix 1, section 1. ## Screening Where a population-based breast cancer screening programme exists, the breast centre and the screening programme should coordinate the assessment of screen-positive cases to ensure quality and continuity of care and optimisation of resources. It is recommended that diagnostic assessment of screendetected imaging findings is done in the breast centre. The breast centre should contribute to improving protocols and professional expertise at screening centres. ## Patient pathway and protocol The breast centre must develop a patient pathway that ensures continuity of care and describes the steps and their timing from diagnosis (or screening) to follow-up including advanced disease, palliative care and end of life. This pathway must be backed up by evidence-based protocols between care providers which guarantee the continuity of care. The breast centre must identify the guidelines (national and/or international) from which to develop the patient pathway and internal protocols must be formally reviewed at least on an annual basis at the formal internal review meeting. The patient pathway must be agreed at least by the core MDT members but preferably also by extended team members. ## Mdt meeting (mdm) The breast centre must hold at least weekly a multidisciplinary case management meeting (MDM) to discuss diagnostic preoperative and postoperative cases, as well as any other issues related to breast cancer patients that requires multidisciplinary discussion. Advanced breast cancer cases must also be discussed. At least 95% of all early and locally advanced breast cancer cases and at least 50% of metastatic cases must be discussed at the meeting (but in future the goal is that all cases, early and metastatic, are discussed at the MDM). At pre-operative stage, the MDM must consider patient-related factors, tumour-related factors, and treatment options. Team members who must be present: e Discussion of pre-operative breast cancer cases: radiologist, pathologist, medical oncologist, surgeon, radiation oncologist, breast nurse and breast data manager e Discussion of post-operative cases: pathologist, surgeon, medical oncologist, radiation oncologist, breast nurse and breast data manager e Discussion of metastatic breast cancer cases: medical oncologist, radiation oncologist, breast nurse, radiologist, pathologist, nuclear medicine physician (mandatory if the breast centre performs and uses positron emission tomographycomputed tomography (PET-CT) and recommended if the nuclear medicine service is not inside the hospital), palliative care specialist and breast data manager. Other team members must be encouraged to attend and must be available for consultation. Other specialists must be involved if necessary to discuss the clinical situation of patients. Radiological images must be available at the MDM. A photograph of the breast should be available to decide the best surgical strategy. Macroscopic pictures or the histology of special cases preferably from slides (video microscope or scanned slide) should be shown to support understanding of difficult histopathological reports. Evidence on decisions taken for each patient at the meeting must be formally recorded. The name of all team members participating in each meeting must be formally recorded. As the patient is usually not present at the MDM and patient preferences must always be taken into account, and because the available clinical documents could miss key information, an MDM decision might, in some cases, be modified at the time of communication with the patient. For this reason, it is important that the breast care nurse present knows the patient's wishes and expectations to ensure they can be shared at the MDM. The clinician who informs and discusses with the patient must have the competence to understand why the patient wants a change of the recommendation. The reason for change must be documented in the patient chart and the MDM must be informed. ## Breast centre coordinator The breast centre must have a nominated breast centre coordinator, who can be a healthcare professional from any specialty within the core team, responsible for the multidisciplinary approach and the full involvement of breast experts from the core disciplines and their regular participation in the MDM. The coordinator must ensure there is training and continuing medical education of MDT members; ensure the centre has certain breast related research; and ensure the centre's performance is based on high quality data collection and indicators. ## Communication of diagnosis, treatment plan and waiting times A diagnosis must be given to the patient in a face to face meeting as soon as possible and must not be given by letter or on the telephone, unless there are exceptional circumstances. A preliminary communication on the diagnosis can be given to the patient by each specialist according to their competence. The MDT recommendation for the treatment plan should be communicated and discussed with the patient by the clinician who has initially seen the patient and/or the clinician who will take primary responsibility for providing the first treatment modality. This discussion with the patient is crucial to arrive at a shared decision which includes the patient's wishes. Healthcare professionals who deal with cancer patients and their families are recommended to have training in and knowledge about communication skills. A breast care nurse must be available to discuss and give any additional information to the patient regarding treatment and to give emotional support. A private room should be available. A psycho-oncologist should also be available to provide more advanced support, when needed, to the patient and family. Each patient must be fully informed about each step in the diagnostic and therapeutic pathway and must be given adequate time to consider the options and make an informed decision. Patients must be allowed to ask for a second opinion [bib_ref] Results of the Lynn Sage Second-Opinion Program for local therapy in patients..., Clauson [/bib_ref] , without being penalised in any way. Patients must start primary treatment within a maximum of 4e6 weeks from the first diagnostic examination in the breast centre [bib_ref] Quality indicators in breast cancer care: an update from the EUSOMA working..., Biganzoli [/bib_ref] or first consultation at the breast centre if diagnosed elsewhere. Follow-up should be done within the breast centre according to the local organisation and patient preference. The breast centre should offer to plan imaging investigation procedures at the same visit. The breast centre must give advice and support to the patient with symptoms and complaints due to hormonal therapy (osteoporosis, gynaecological problems, etc.), referring the patient to the appropriate specialist. If the patient does not attend the breast centre for follow-up, the centre should collect follow-up information from elsewhere at least yearly for its database. ## Patient information Patients must be offered clear verbal and written information (leaflets) that describe the diagnostic and treatment options. Leaflets should be personalised for the breast centre in all the main languages spoken by the population served. The leaflets should inform patients about diagnostic and treatment options not offered by the breast centre if they are covered in current guidelines. The centre should provide information on local support groups and national advocacy organisations and the availability of group and/or individual psychological support in the centre. Patients should be provided with a copy of their rights as outlined in the breast cancer resolution of the European Parliament. ## Advocacy group/patient volunteer group It is recommended that the breast centre collaborates with a local/national advocacy group or patient volunteer group. This group should collaborate with the centre to offer activities and projects dedicated to breast centre patients. ## Quality control The breast centre must have a database to collect data on all primary and advanced breast cancer patients it treats. Data collection is essential to monitor compliance with national and/or international quality indicators, standards and guidelines, and it is also a basis for scientific research at the breast centre. The breast centre must achieve the minimum standard for EUSOMA's mandatory quality indicators (as described in EUSOMA's quality indicators in breast cancer care, 2017, and future updates) [bib_ref] Quality indicators in breast cancer care: an update from the EUSOMA working..., Biganzoli [/bib_ref]. If a minimum standard is not achieved the breast centre must put in place corrective actions and reevaluate measures at an agreed date. Data must include source of referral, clinical and pathological diagnosis, treatment, follow-up and clinical outcomes. The breast centre must also collect in the database, or in a separate register, data on all surgical operations performed on benign disease (with the exclusion of inflammatory disease, operations for cosmetic reasons or prophylactic surgery). The breast centre must have a data manager who works in the core team under the supervision of a medical doctor designated by the clinical coordinator. The data manager is responsible for data collection and analysis and for the organisation of audit meetings. Data should preferably be collected during the patient management process. The data manager must inform the breast centre team about performance quality according to indicators and about any emerging criticality. The breast centre should participate in external benchmarking activities (comparison of results with those of other centres). Breast centres should yearly monitor their outcomes at least on the following items: local recurrence rate, distant recurrence rate, sequelae (surgical, radiation and systemic therapy) aesthetic outcomes, functional outcomes. Breast centres are strongly advised to collect and analyse validated patient reported outcomes (PROs) using validated measurements (patient reported outcome measures, PROMs). The centre must have a formal internal review meeting at least once a year to discuss all performance aspects, i.e. audit results, continuity of care, organisational and clinical aspects, critical issues, results of corrective actions, new projects, etc. Core team members must participate in this meeting, and extended members should participate. Minutes of the meeting and the list of participants must be kept. ## Education The breast centre should provide teaching on a local, national or international basis. Some breast centres may have expertise in teaching certain subjects, such as reconstruction, screening, pathology/molecular biology, systemic therapies, radiation oncology, etc. The breast centre should organise at least one teaching course per year at local, regional, national or international level. ## Research Research is an essential part of training specialists and underpins every aspect of clinical practice, and breast centres should be involved in both clinical (i.e. clinical trials) and translational research. The breast centre should record the numbers of patients participating in clinical trials and collect details of any other research activities, such as evaluation of newly introduced techniques. The breast centre should aim to include at least of 5% of patients in clinical trials each year. ## Core mdt members All core MDT members should comply with EUSOMA's guidelines on standards for training specialised health professionals who deal with breast cancer [bib_ref] Guidelines on the standards for the training of specialised health professionals dealing..., Cataliotti [/bib_ref]. All specialists must work according to protocols and national/international guidelines. All specialists working in the core team must comply with all specialist related requirements indicated in the sections below. ## Breast radiology Breast radiologists. The breast centre must have at least 2 dedicated breast radiologists. To be considered a breast specialist, a radiologist must spend at least 50% of their working time on breast imaging. Breast radiologists must be involved in the full assessment of breast patients, including invasive procedures (core biopsy, ultrasound guided, stereotactic vacuum assisted biopsy, etc.). Breast radiologists should participate in national or regional radiology quality assurance schemes. Where possible, radiologists involved in the assessment of breast patients should participate in both breast screening and symptomatic breast imaging. Breast radiologists must read a minimum of 1000 mammography cases per year and conduct and read a minimum of 200 breast ultrasound studies (targeted, diagnostic or screening) per year, and a minimum of 50 breast MRI studies per year. Breast radiologists participating in a centralised screening programme must have a workload of at least 5000 cases per year. Breast radiologists must attend at least one diagnostic clinic per week for symptomatic patients or further assessment of breast screening recall. Each breast radiologist must perform a minimum of 50 breast guided interventions per year. Double reading of mammograms is encouraged both for screening and symptomatic mammography when the breast centre workload is less than 3000 per year; double reading of breast MRI studies is encouraged when the MRI workload is less than 200 per year. All imaging studies taken outside the centre must be reviewed by breast centre radiologists. Examinations. The breast radiology team must perform: ◊ Clinical examination ◊ Mammography ◊ Ultrasound and Doppler ultrasound of the breast and axilla ◊ Breast MRI ◊ Core biopsy e free-hand, ultrasound guided, mammography guided ◊ Vacuum-assisted biopsy under mammographic or breast MRI guidance. If this is not available within the breast centre, there must be a formal agreement with a local diagnostic service ◊ Lesion localisation and bracketing under ultrasound, mammography, and MRI guidance. If this is not available within the breast centre, there must be a formal agreement with a local diagnostic service ◊ Multidisciplinary working should allow all standard investigations for triple assessment (clinical examination, mammography and/or ultrasound and biopsy) to be completed in one visit (but respecting patient's preferences) and maximum within 5 working days Non-surgical diagnosis by needle biopsy of both benign and malignant disease is the required standard. Palpable lesions must be examined via ultrasound and where there is an ultrasound correlate, needle biopsy must be done under ultrasound guidance. Needle biopsy must be image-guided for all non-palpable lesions. Image-guided biopsy of non-palpable lesions must be done under the guidance of an appropriate imaging method; usually, the same imaging method that was used to establish the diagnosis should be used to guide biopsy. MRI-guided and mammography guided biopsy can be replaced by ultrasound guided biopsy; however, in these cases, the radiologist must ensure that the target identified on ultrasound corresponds to the target seen on the other imaging method. Primary diagnosis using open surgical biopsy is not recommended and only acceptable in exceptional cases. Core or vacuum assisted biopsy is the preferred technique for sampling the breast. Core biopsy is also considered the preferred technique for sampling axillary lymph nodes. Fine needle aspiration cytology (FNAC) may also be used but requires the availability of a pathologist who is experienced in interpreting cytology of FNAC specimens. The breast centre must use a single formal imaging risk classification (e.g. BI-RADS or the European classification). The breast centre must collaborate with board certified imaging experts who carry out interventional radiology techniques, such as biopsy of metastatic lesions in breast cancer patients. Imaging equipment. The breast centre must have: Digital mammography Stereotactic biopsy attachment and/or dedicated prone biopsy table Methods for mammography guided stereotactic lesion localisation and bracketing (wire or clip) Ultrasound equipped with a small parts probe !12 MHz and including Doppler function Methods for ultrasound guided core biopsy Methods for ultrasound guided lesion localisation and bracketing procedures Breast MRI with !1.5 T, dedicated bilateral breast coil; dedicated equipment for breast immobilisation is strongly encouraged Access to MRI-guided vacuum-assisted biopsy and MRI-guided lesion localisation or bracketing, either in-house or by formal agreement with an affiliated diagnostic service Digital storage of all images (mammograms, ultrasound documentation, MRI studies) Equipment no older than 10 years, unless carefully maintained and complying with national and/or international standards Routine quality control of all equipment used for breast imaging, according to national protocols and/or European guidelines. If the centre follows a national protocol, this must include essential points such as assessment of image quality of the monitors and estimate of the maximum average of glandular dose. Breast radiographers. Radiographers must have training in breast diagnosis to perform mammography. The breast centre must have at least 2 breast radiographers, each performing at least 1000 mammograms a year. Radiographers should also attend refresher courses at least every 3 years. The breast centre must have protocols on the periodical review of the technical performance of radiographers. Radiographers should participate in regular audit of their technical performance. Breast centres must have protocols on quality control on a daily basis and must follow guidelines on equipment quality control as detailed in European guidelines. ## Breast pathology Breast pathologists. The breast centre must have at least 2 dedicated breast pathologists (1 of whom should be nominated as the breast pathology lead for the MDT). A pathologist at the breast centre must spend at least 50% of their working time on breast disease. A breast centre pathologist must report on at least 50 early breast cancer resections per year and should report on at least 100 pre-operative samples (with a mandatory minimum of 50) and 25 metastatic breast surgical specimens per year. Breast pathologists must take part in regional, national and/or European breast cancer quality assurance schemes. Breast pathologists must be familiar with their national and/or European quality standards and guidelines. ## Procedures. Breast pathology reports must include histological type (according to the WHO Classification of Tumours of the Breast), grading (according to WHO and EU guidelines: Elston and Ellis modified Bloom-Richardson grading system), immunohistochemistry (IHC) for diagnosis and for oestrogen, progesterone and HER2 receptors status. In situ hybridisation (ISH) analyses of HER2 must be obtained from reference laboratories. Reports should also include evaluation of proliferation. Ki67 is the preferred marker to assess proliferation [bib_ref] De-escalating and escalating treatments for early-stage breast cancer: the St, Curigliano [/bib_ref] but is not mandatory. Caution is needed about the reproducibility of IHC for Ki67. If used, the St Gallen International Breast Cancer Conference has suggested calibrating a common scoring method to achieve high inter-laboratory reproducibility in Ki67 on centrally stained tissue microarray slides [bib_ref] De-escalating and escalating treatments for early-stage breast cancer: the St, Curigliano [/bib_ref]. For reporting core biopsies, breast pathologists must use the B1-5 classification as described in European guidelines. Reporting by 2 pathologists of core biopsies is encouraged. When the patient is treated in an institution different from that performing the pathological diagnosis, the tumour blocks and slides must be requested for revision by the breast pathologist. Breast tissue samples must be kept as long as possible because the patient can relapse more than 20 years after the first diagnosis. At least 1e2 FFPE blocks most representative of the lesion must be stored in perfect conditions (controlled temperature, humidity and parasites) and kept for at least 20 years or according to the national law, whichever is longer. An archive of digital slides should be considered. ## Equipment. The pathology laboratory must be equipped with microscopes, cryocut, histoprocessors, microtome staining machines and immunostainers, and a system for obtaining surgical sample and slide pictures. The equipment must be replaced every 10 years unless carefully maintained and complying with national and/or international standards. ## Breast surgery Breast surgeons. The breast centre must have at least 2 dedicated breast surgeons with training in breast surgery. Breast surgeons must spend at least 50% of their working time on breast disease. Any breast surgeon at the breast centre must carry out primary surgery as first operator on at least 50 newly diagnosed breast cancers a year. If the centre has surgeons in training, those responsible for supervising trainees might perform fewer than 50 primary cases as first operator. In this case documentation on their role as second operator supervising trainees must be available. Breast surgeons must be able to perform sentinel lymph node biopsy in all settings (adjuvant, neoadjuvant, recurrence), all types of mastectomy (nipple sparing, skin sparing, simple) and guided surgery for non-palpable tumours, and breast conserving surgery. Breast surgeons must be able to perform risk-reducing techniques for high-risk patients. Breast surgeons should advise and where necessary treat women with benign disease, e.g. cysts, fibroadenoma, mastalgia, inflammatory conditions. The breast surgical team should be able to offer level I and II oncoplastic techniques; breast surgeons should have additional training in oncoplastic procedures to offer the patient surgical options. ## Breast medical oncology Breast medical oncologists. The breast centre must have at least 2 breast medical oncologists dedicated to breast cancer. Any breast medical oncologist at the breast centre must spend 50% of their working time on breast cancer. Breast medical oncologists must treat a minimum of 50 early and 25 metastatic breast cancer patients per year. Breast medical oncologists must supervise systemic therapy and all decision-making processes for its use. Follow-up information on all patients treated with systemic therapy must be collected, even if patients are treated outside the breast centre. ## Breast radiation oncology Breast radiation oncologists. The breast centre must have at least 2 radiation oncologists dedicated to breast cancer. Any breast radiation oncologist at the breast centre must spend at least 50% of their working time on breast cancer. Breast radiation oncologists must treat a minimum of 50 early breast cancer patients per year. They must also have experience with palliative treatments. Breast radiation oncologists must be competent to determine the need for techniques such as intensity modulated radiotherapy (IMRT), image guided radiotherapy (IGRT), cardiacsparing radiotherapy, brachytherapy, stereotactic body radiotherapy (SBRT) and stereotactic radiosurgery. Radiation oncologists must be adequately trained in breast cancer contouring, including regional nodes, and use international guidelines such as those developed by the European Society for Radiotherapy and Oncology (ESTRO). Radiation oncology units must develop and work to an evidence-based breast radiation therapy clinical protocol that is reviewed and updated regularly: this should include dose objectives and constraints for each breast radiation technique. It is recommended that all radiation oncology units have a dedicated breast radiation planning and treatment MDT with radiation oncologists, radiotherapy physicists, dosimetrists and therapy radiographers to review and manage challenging cases including those who cannot be treated within the standard clinical protocols. If the radiation oncology unit is not available within the hospital, the breast centre must have an agreement with a radiation oncology unit and breast radiation oncologists must attend the MDM at the breast centre. In all situations, breast radiation oncologists must have full access to all patient data regarding diagnosis and treatment and must be involved in the patient management plan. Follow-up information on all patients treated with radiation therapy must be collected, even if patients are treated and/or followed-up outside the breast centre. ## Breast radiation technicians. It is strongly recommended that the breast centre has dedicated radiotherapy physicists, dosimetrists and therapy radiographers. At least 1 medical physicist and 2 radiation therapists/ dosimetrists should have breast cancer as a main interest. ## Equipment and techniques. The staffing and technical platform should fulfil the requirements described by the EORTC Radiation Oncology Group [bib_ref] Profile of European radiotherapy departments contributing to the EORTC Radiation Oncology Group..., Budiharto [/bib_ref]. Therefore, the minimum equipment in a radiation oncology unit must include at least 2 megavoltage units, a CT scanner dedicated to treatment preparation, and a 3D treatment planning system. Treatment machines must be equipped with IGRT tools to verify accurateness of treatment delivery. Equipment must be no older than 12 years, unless carefully maintained, upgraded and complying with national and/or international standards. Radiation therapy planning must be carried out according to optimised (3D) procedures based on anatomically defined volumes, with treatments individualised to 3D target volume definitions and contouring. Field-based treatments must be abandoned. The evaluation must be done using tools such as dose volume histograms, taking into account predefined objectives for the dose distribution for the target volumes and dose constraints for organs at risk (including as a minimum the heart and lungs). Respiratory control should be available and used according to predefined indications including patient risk factors and doses to heart and lungs. Experience is essential especially in techniques aimed at optimising the homogeneity of dose distribution, including IMRT and IGRT, partial breast irradiation, and cardiac sparing techniques such as breath-hold. Access to 3D brachytherapy is highly recommended. SBRT and radiosurgery must be available for treatment of oligometastases and brain metastases. The breast centre must have a quality assurance programme for the entire radiation oncology process, including for the machines/infrastructure. If specific equipment or working procedures are in place for treating breast cancer patients, they must be included in the quality assurance programme. Sufficient ongoing education for all healthcare professionals is essential. Clinical and translational radiation therapy research is encouraged. ## Breast cancer nursing Breast care nurses. The breast centre must have at least 2 breast care nurses dedicating all their working time to breast cancer. Breast care nurses must see a minimum of 50 early and 25 metastatic breast cancer patients per year. Breast care nurses must be available: ◊ Throughout the patient pathway from diagnosis through treatment and follow-up, to offer practical advice, emotional support, explanation of the treatment plan and information on side-eff ects [bib_ref] Training breast care nurses throughout Europe: the EONS postbasic curriculum for breast..., Eicher [/bib_ref]. Breast care nurses must also: ◊ Help to develop protocols, patient pathways, information and implementation of nursing research [bib_ref] Training breast care nurses throughout Europe: the EONS postbasic curriculum for breast..., Eicher [/bib_ref]. ◊ Document their meetings with patients. Record keeping is an essential part of nursing care [bib_ref] Issues in nursing documentation and record-keeping practice, Prideaux [/bib_ref] and promotes high quality, effective and safe care [bib_ref] Standardized nursing documentation supports evidence-based nursing management, Mykk€ Anen [/bib_ref] as the information can be important for use by other professionals in the MDT [bib_ref] Evaluating nursing documentation e research designs and methods: systematic review, Saranto [/bib_ref]. ## Extended mdt and other services ## Psychological support/psycho-oncology Basic psychological counselling and emotional support must be provided by a breast nurse or another professional trained in the psychological aspects of breast cancer care. If psychological morbidity cannot be dealt with effectively by them, patients must be referred to a psycho-oncologist or psychiatrist. Distress must be recognised, monitored, documented and treated promptly at all stages of disease. It must be assessed in all patients using a tool such as a distress thermometer. A psycho-oncologist must be available throughout the disease continuum to patients and their families at the breast centre to help patients deal with common psychological issues in breast cancer such as fear of recurrence, body image disruption, sexual dysfunction, treatment-related anxieties, intrusive thoughts about illness, marital/partner communication, feelings of vulnerability, existential concerns regarding mortality, fertility, work-related issues, depression, and, in particular for advanced breast cancer patients, fear of dying, coping with an incurable disease and continuous treatment, and feelings of isolation and guilt. A psychiatrist must also be available to patients. ## Geriatric oncology The breast centre must have access to geriatricians with oncology experience. The role of the geriatric oncologist is to coordinate recommendations to other specialists about the need for personalised interventions for older patients with increased vulnerability to stressors. All older patients (70þ) and patients who appear frail or have severe comorbidity must be screened with a quick, simplified frailty screening tool, such as the adapted Geriatric-8 (G8) screening tool [bib_ref] Mathoulin-P elissier S. Detection of frailty in elderly cancer patients: improvement of..., Petit-Mon Eger [/bib_ref] [bib_ref] Diagnostic test accuracy of simple instruments for identifying frailty in community-dwelling older..., Clegg [/bib_ref]. Frail patients as suggested by the screening tool should undergo a full geriatric assessment [bib_ref] International Society of Geriatric Oncology consensus on geriatric assessment in older patients..., Wildiers [/bib_ref]. The assessment can be based on self-report combined with objective assessments that can be performed by the breast nurse in collaboration with a physician (geriatrician/internist/medical oncologist). Cognitive impairment affects all aspects of treatment e ability to consent, compliance with treatment, and risk of delirium e and screening using tools such as Mini-Cog [bib_ref] The Mini-Cog as a screen for dementia: validation in a population-based sample, Borson [/bib_ref] is advised. A geriatrician, geriatric psychiatrist or neurologist should preferably be involved with impaired patients. For frail patients, the geriatrician should be present in the MDT meeting, or easily available for consultation, to discuss treatment options aligned with the patient's goals for care. ## Oncology pharmacy Oncology pharmacists must have experience with antineoplastic treatments and supportive care; interactions between drugs; drug dose adjustments based on age, liver and kidney function, and toxicity profile; utilisation and monitoring of pharmacotherapy; patient counselling and pharmacovigilance; and knowledge of complementary and alternative medicines. Oncology pharmacists must liaise with medical oncologists to discuss cancer treatments, including interactions with other treatments. Oncology pharmacists must be involved in the clinical trials research of the breast centre. Oncology pharmacists must use the European QuapoS guidelines (European Society of Oncology Pharmacy). Oncology drugs must be prepared in the pharmacy and dispensing must take place under the supervision of the oncology pharmacist. ## Nuclear medicine The breast centre must have access to nuclear medicine specialists for procedures relevant to breast cancer care. Sentinel node biopsy (SNB) is included in the standard of care and must be available. The nuclear medicine physician should oversee the procedure and identify the nodes in planar and single photon emission computerised tomography (SPECT) or SPECT/CT images (recommended if available), as well as marking the location on the skin, and may collaborate with the surgeon during surgery in locating the lesion with an intraoperative probe. The nuclear medicine physician must oversee all aspects of PET/ CT for patients who require this procedure either with 18 F-FDG or with other radiotracers, including indications, multidisciplinary algorithms and management protocols [68e72]. There is evidence of the efficacy of 18 F-FDG-PET/CT in selected clinical indications in breast cancer, such as staging of high-risk patients, treatment planning, response monitoring, and detection of recurrent disease [68e71] 18 F-FDG-PET/CT should not be used for surveillance for recurrent disease in asymptomatic patients. Conventional nuclear medicine such as bone scan and cardiac multigated acquisition (MUGA) should also be available. Equipment should preferably be onsite, be less than 10 years old, unless carefully maintained and complying with national and/or international standards, ready for radiation treatment planning, and have an integrated picture archiving and communication system/radiology information system (PACS/RIS) and updated workstations. The nuclear medicine department must be able to perform daily verification of protocols and to react accordingly. Qualityassurance protocols must be in place. An option for ensuring the high quality of PET/CT scanners is provided by the European Association of Nuclear Medicine (EANM) through EARL accreditation. ## Physiotherapy There must be at least 2 physiotherapists with expertise in lymphatic drainage for the treatment of lymphoedema and its related sequelae, and to ensure good shoulder mobility. Physiotherapists with expertise in rehabilitation of metastatic patients with sequelae of bone or brain metastases and their treatments must be available for breast centre patients. A rehabilitation programme for cancer patients who require assistance in the recovery of functional status after treatment must be available. Physiotherapists must collaborate with the palliative care service and with medical oncologists and breast nurses at the breast centre. ## Breast plastic surgery The role of breast plastic surgeons depends on the organisation of the breast centre. In most centres, microsurgery reconstruction techniques are performed by breast plastic surgeons as part of the breast surgical team. If necessary the breast centre must make arrangements with 1 or 2 breast plastic surgeons with a special interest in breast reconstructive and reshaping techniques. ## Interventional radiology The breast centre must have access to interventional radiologist expertise. Bone metastases carry an important risk of developing skeleton-related events that impact quality of life. Besides surgery and radiotherapy, percutaneous image-guided cementoplasties/ closed internal fixation/thermal ablation have a growing role in the treatment of these metastases. ## Self-image support There must be a breast prosthesis fitting service within the breast centre or referral to a service outside the centre. There must be counselling about hair prosthesis and referral to recommended services. ## Palliative care Palliative care, as defined by the World Health Organisation, applies not only at end of life but throughout cancer care. Palliative care means patient and family-centred care that enhances quality of life by preventing and treating physical, psychosocial and spiritual suffering early in the course of advanced disease [73e75]. Palliative care services include general palliative care provided by the oncology professionals at the breast centre who are responsible for breast cancer care and specialised palliative care provided by a multidisciplinary palliative care team [76e78]. Close collaboration between the breast centre and palliative care teams is crucial. There must be a specialist palliative care team that provides expert outpatient and inpatient care including specialist physicians and nurses, working with social workers, chaplains, physiotherapists, occupational therapists, dieticians, pain specialists and psycho-oncologists. In practice: ◊ The breast centre team, in particular medical oncologists and breast nurses, is usually responsible for basic palliative care such as symptom control and screening for disease and treatment related symptoms and suffering ◊ Patients with severe symptom burden or unmet physical, psychosocial or spiritual needs must be referred to a specialist palliative care team, irrespective of the cancerspecific treatment plan [bib_ref] Referral criteria for outpatient specialty palliative cancer care: an international consensus, Hui [/bib_ref]. The most common physical, psychosocial and spiritual symptoms/problems and functional impairments must be assessed in all patients using tools such as the Edmonton Symptom Assessment Scale (ESAS) [bib_ref] The Edmonton Symptom Assessment System 25 years later: past, present, and future..., Hui [/bib_ref] or EORTC questionnaire on quality of life in palliative cancer care patients (QOL-C15-PAL e https:// qol.eortc.org/questionnaire/qlq-c15-pal). The palliative care team must have good knowledge of cancer disease and cancer treatments including adverse effects of treatment and rehabilitation needs to be able to offer holistic care in collaboration with other professionals. Early palliative care should be provided in conjunction with cancer specific treatments for treatment-related distressing symptoms such as pain and dyspnoea, and for psychosocial and spiritual care. The palliative care team must support family members and carers, and have experience of taking care of younger patients and their families. Palliative care specialists and oncologists must aspire to meet the standard of ESMO Designated Centres of Integrated Oncology and Palliative Care (http://www.esmo.org/Patients/ Designated-Centres-of-Integrated-Oncology-and-Palliative-Care). To ensure continuity of care at home, the palliative care team must work with primary or community care providers or be able to provide direct care at home, and must provide end-of-life care. ## Clinical genetics The breast centre must have a dedicated clinical geneticist responsible for a genetics clinic, or an agreement with a hospital where this service is available. The clinical genetics service must offer: ◊ Diagnostic surveillance with protocols for high-risk women including screening MRI according to the level of risk ◊ Risk assessment counselling and testing for BRCA mutations in high-risk groups in accordance with national and/or international protocols ◊ Genetic testing for BRCA mutations; a molecular geneticist must be accessible for consultation ◊ Protocols for risk reduction surgeries and chemoprevention ◊ Psychological support to facilitate an accurate perception of risk and its acceptance, to assure adherence to surveillance plans, and to support the patient with complex decisionmaking ◊ Registration of patient data in an appropriate database and involvement in research ◊ BRCA mutation testing for metastatic breast cancer patients, in view of the potential clinical implications. At present, no other genes are recommended for testing in the metastatic setting, including with any next generation sequencing (NGS) test. ## Prevention A growing body of evidence documents the effectiveness of physical activity and a correct diet for a variety of outcomes in breast cancer survivors. There is evidence from randomised trials that physical activity in breast cancer patients has positive effects on physical functions, psychological outcomes and quality of life [bib_ref] Physical activity for cancer survivors: meta-analysis of randomised controlled trials, Fong [/bib_ref] [bib_ref] Exercise for the management of cancer related fatigue in adults, Cramp [/bib_ref]. There is evidence from well conducted observational studies and meta-analyses [bib_ref] Age and the effect of physical activity on breast cancer survival: a..., Fontein [/bib_ref] [bib_ref] Physical activity, biomarkers, and disease outcomes in cancer survivors: a systematic review, Ballard-Barbash [/bib_ref] that physical activity reduces overall and cause specific mortality in breast cancer patients [85e87]. There is preliminary evidence that physical activity produces beneficial effects on biomarkers linked to better prognosis and on local recurrence [88e90]. A World Cancer Research Fund report recommends that breast cancer survivors follow the same physical exercise and diet recommendations as for the general population. Breast centres must offer or recommend physical activity and dietary intervention programmes to their patients; compliance with such programmes should be assessed and encouraged during regular follow-up visits. Lifestyle counselling should include home-based exercise [bib_ref] Effective physical activity promotion to survivors of cancer is likely to be..., Hardcastle [/bib_ref] and is an important supportive role for the breast care nurse [bib_ref] Rationale for promoting physical activity among cancer survivors: literature review and epidemiologic..., Loprinzi [/bib_ref]. ## Appendix 1. supporting evidence and information ## Critical mass/volume requirements/mdt working The concept of the multidisciplinary breast centre e which may also treat other breast conditions as well as cancer e is now well established in several countries in Europe and North America. There are some national specifications that may complement the one set out in this paper. The evidence base is partly built on procedures by specialist breast surgeons. For example, in 1996 a study comparing survival outcomes by specialist and non-specialist breast cancer surgeons in Scotland showed that the absolute 5 year survival rate was 9% higher and the 10 year survival 8% higher for patients cared for by specialist surgeons, with a relative reduction in risk of dying of 16% [bib_ref] Survival outcome of care by specialist surgeons in breast cancer: a study..., Gillis [/bib_ref]. A later paper from the United States, in 2003, found a similar absolute benefit, of 7% at 5 years, and a relative risk reduction of 33%, of treatment by specialist surgical oncologists [bib_ref] Breast cancer: do specialists make a difference?, Skinner [/bib_ref]. Hospital and surgical volume have also been confirmed as positive factors. A systematic review of the volume-outcome relationship with breast cancer surgery found that improved survival was significantly associated with high volume providers [bib_ref] A systematic review and meta-analysis of the volumeoutcome relationship in the surgical..., Gooiker [/bib_ref]. Another study found that higher surgeon and hospital volume significantly predicted lower subsequent re-operation after breast conserving surgery and after adjustment for sociodemographic and clinical variables [bib_ref] Hospital and surgeon caseload are associated with risk of re-operation following breast-conserving..., De Camargo Cancela [/bib_ref]. A recent study from the United States reported that treatment at high volume centres is associated with improved survival for breast cancer patients regardless of stage, and that high case volume could serve as a proxy for the institutional infrastructure required to deliver complex multidisciplinary breast cancer treatment [bib_ref] The effect of hospital volume on breast cancer mortality, Greenup [/bib_ref]. Looking at multidisciplinary aspects, an observational cohort study evaluated the effects on breast cancer survival on nearly 14,000 women in Scotland, and found MDT working was associated with a 18% lower breast cancer mortality at 5 years [bib_ref] Effects of multidisciplinary team working on breast cancer survival: retrospective, comparative, interventional..., Kesson [/bib_ref]. By comparing an area where MDT working was introduced with areas that had not implemented it, the authors found that it probably improves patient outcomes by influencing various aspects of care, such as adherence to guidelines, nurse education, increased surgical volume and experience, and improved interdisciplinary working. A study in Taiwan that compared those receiving MDT treatment with those without found that MDT intervention significantly increased the breast cancer survival rate. A population study from a region in Germany suggested there may be evidence of increased mortality if breast cancer patients do not receive guideline compatible treatment [bib_ref] Effect of multidisciplinary case conferences on physician decision making: breast diagnostic rounds, Foster [/bib_ref]. There are studies that report changes in treatment plans following MDT discussion. In single institution studies in the United States and Canada, a second evaluation of patients referred to a multidisciplinary tumour board led to changes in the recommendations for surgical management in 77 of 149 of patients studied (52%) [bib_ref] Changes in surgical management resulting from case review at a breast cancer..., Newman [/bib_ref] , and management plans changed in 41% of cases presented, the majority due to new/clarified diagnostic information [bib_ref] Provision of breast cancer care and survival in Germany e results from..., Holleczek [/bib_ref]. A UK study found that MDT meetings enable cross-speciality interrogation of requests for prophylactic mastectomy, minimise unnecessary surgery and restrict mastectomy to those likely to derive maximum benefit [bib_ref] A multidisciplinary team approach minimises prophylactic mastectomy rates, Leff [/bib_ref]. A global survey, completed by principal investigators from 39 countries participating in a phase III trial, showed that mandatory MDT working for breast cancer ranged from about two-thirds of centres in Eastern/Western Europe to only a quarter in South America and a third in Asia [bib_ref] Role of the multidisciplinary team in breast cancer management: results from a..., Saini [/bib_ref]. But a review of breast cancer MDT working notes about this survey that most centres that reported having mandatory MDT care lacked national or regional guidelines regarding composition or practice of MDT work to ensure consistency of provision (only 19% reported having such guidelines) [bib_ref] Benefits of multidisciplinary teamwork in the management of breast cancer, Taylor [/bib_ref]. Among the most compelling recent evidence is a study on Germany's breast cancer services. It reports that low-volume hospitals with 30 cases/year had a statistically significant 3fold increased risk of death after breast conserving treatment and a significantly increased the likelihood of postoperative complications after both breast conserving treatment and breast ablative therapy [bib_ref] Multidisciplinary breast centres in Germany: a review and update of quality assurance..., Wallwiener [/bib_ref]. Also noted was that length of stay was shorter and non-routine discharge was lower at high-volume hospitals and that the likelihood of receiving breast conserving surgery was significantly higher at high-volume hospitals. Another study in Germany found that adherence to breast cancer surgery quality processes is higher in hospitals that treat more cases [bib_ref] Case numbers and process quality in breast surgery in Germany: a retrospective..., K€ Oster [/bib_ref]. ## Pathways Care for all cancer patients should be organised in pathways that cover the patient's journey, and pathways must correspond to current national and European evidence-based clinical practice guidelines on diagnosis, treatment and follow-up. The European Pathway Association defines a care pathway as "a complex intervention for the mutual decision making and organisation of care processes for a well-defined group of patients during a well-defined period". This broad definition covers terms such as clinical, critical, integrated and patient pathways that are also often used See http://e-p-a.org/care-pathways and also the WHO framework on integrated people-centred health services, http://www.who.int/servicedeliverysafety/areas/peoplecentred-care. There are many examples of care pathways for breast cancer given the pioneering role this cancer has played in developing multidisciplinary care. Examples are from the National Institute for Health and Care Excellence (NICE) in the UKand Cancer Council Australia. A paper from the UK also gives a good example and emphasises the role that care pathways play with the MDT as the integral part of the system [bib_ref] Care pathways for patients with breast cancer, Pittathankal [/bib_ref]. The UK was one of the first countries to establish the value of MDTs for a cancer type, and together with defined care pathways has been instrumental in addressing variations in outcomes among breast units and regions in the country. A key point reiterated is that the management of breast cancer patients is a complex undertaking, requiring coordination among specialist team members to enable high-quality individualised care. ## Patient advocacy Patient advocacy for breast cancer is the most widely available and well organised of any cancer type in the world. The principal European-wide organisation is Europa Donna, which counts more than 50 national member organisations or representatives in Europe (https://www.europadonna.org). Europa Donna has been instrumental in lobbying at European level for the adoption of declarations and resolutions on universal screening and multidisciplinary breast cancer services in the European Union. Many European countries have dedicated advocacy groups, such as Breast Cancer Care (https://www.breastcancercare.org.uk) and Breast Cancer Now (http://breastcancernow.org) in the UK, Brustkrebs in Germany (http://brustkrebsdeutschland.de), and the Dutch Breast Cancer Association (https://borstkanker.nl). There is a need to develop more advocacy and support for advanced/metastatic breast cancer patients. This can be achieved by dedicated advocacy groups, such as in the US with MetaVivor and the Metastatic Breast Cancer Network, or through the development of dedicated resources within advocacy groups. Examples of the latter are the recently launched MBC advocacy programme and website of Europa Donna (https://mbc.europadonna.org) and the MBC programmes of Komen (http://www.komen.org) and Breast Cancer Network Australia (http://www.bcna.org.au). The recently created ABC Global Alliance is a multistakeholder platform, coordinated by ESO (European School of Oncology), and is dedicated to advanced/metastatic breast cancer patients globally (http://www.abcglobalalliance.org). ## Accreditation/certification, audit and quality There is wide evidence of the benefit of external audits (i.e. certification or accreditation) for improved performance and outcomes in many fields, including medicine in general and oncology in particular. There are a variety of methods for organisational quality assessment, which can differ with respect to several characteristics, e.g. voluntary versus compulsory, and collegial (driven by professionals) versus regulatory (driven by governments). Another important difference is between assessment of organisational and quality systems aspects and those that focus on clinical aspects or specialty services [bib_ref] When science and policy collaborate for health. European Commission Initiative on Breast..., Bramesfeld [/bib_ref]. All breast centres must consider a voluntary certification process at national and/or European level. Such schemes include the following. A voluntary certification scheme (accredited by Accredia) based on the EUSOMA requirements has been developed and accredited (http://www.breastcentrescertification.com). It evaluates the patient pathway in terms of services, health professionals, equipment, organisation, and data collection. A yearly report is issued to monitor compliance with EUSOMA's quality indicators. The German Cancer Society certification system for cancer centres in Germany was launched in 2003, initially for breast cancer (https://www.krebsgesellschaft.de/gcs/german-cancersociety/certification.html). It is a voluntary initiative that has been subject to evaluation in several papers and now covers breast cancer centres in Austria, Switzerland and northern Italy, as well as Germany. The German Cancer Society's report for the audit year 2017 details the performance of certified breast cancer centres. It covered 275 clinical sites and includes provision of psycho-oncology and social services counselling. The National Accreditation Program for Breast Centres (NAPBC) is a programme run by the American college of Surgeons and made its first award in 2008 (https://www.facs.org/qualityprograms/napbc). It accepts applications from centres outside of the US. Organisation of European Cancer Institutes (OECI) accreditation is a European accreditation and quality improvement programme for cancer centres and comprehensive cancer centres which evaluates the whole quality system in cancer including research, and which can help to integrate breast centres within the wider cancer centre infrastructure (https://www.oeci.eu) [bib_ref] Quality assessments for cancer centers in the European Union, Wind [/bib_ref]. QASDG has defined the care pathway for breast cancer screening and care, the interventions and services to be considered, the quality domains to be included and how the scheme can be implemented in Europe. Importantly, QASDG is taking a modular approach to adapt to different breast service configurations in Europe. Outputs, expected in 2020, will be a quality assurance manual, a self-assessment tool and a quality indicators calculator. Other national and international quality examples and projects. NICE in the UK updated its quality standard for breast cancer services in 2016; it comprises 6 statements, and NICE considered that others previously listed are no longer priorities for improvement (such as on ultrasound evaluation of the axilla, oncoplastic breast conserving surgery, those with early invasive cancer are offered the same care regardless of age). As such the current quality standard is a guide to issues that may also be identified in other countries as priorities. org.uk). The need for the audit was based on concern that delivery of care by NHS services in the UK has found breast cancer services have a non-standard and variable approach to the management of older patients. The report says that breast cancer units should review patient and carer involvement with decision making, develop protocols to assess the health of older patients, identify patients who could benefit from specialist older person teams, and define the contributions of specialists such as nurses and palliative care doctors for care of older people, among other recommendations. In the Netherlands, the NABON Breast Cancer Audit (NBCA) started collecting data from all Dutch hospitals from 2011 with the aims of nationwide evaluation of quality parameters, evaluation of guideline adherence, and weekly feedback to participating institutions. After 4 years of auditing, patients being discussed in pre-and post-operative multidisciplinary team meetings improved (2011: 83% and 91%; 2014: 98% and 99%, respectively) [bib_ref] Clinical auditing as an instrument for quality improvement in breast cancer care..., Van Bommel [/bib_ref]. Tumour margin positivity rates after breastconserving surgery for invasive cancer requiring re-operation were consistently low, but other indicators, for example, the use of an MRI scan prior to surgery or immediate breast reconstruction following mastectomy showed considerable hospital variation. The mission of the Breast Centres Network is to promote synergy among breast units by connecting specialists and personnel working in the field, and to help breast cancer patients find the right place for care or for a second opinion (http://www. breastcentresnetwork.org). It is run by the European School of Oncology and currently lists more than 220 breast units globally. ## Education and training It is essential that each breast cancer centre provides professional clinical and scientific education on the disease and that at least one person is responsible for this programme. Healthcare professionals working in breast cancer must also receive training in psychosocial oncology, palliative care, rehabilitation and communication skills. Such training must also be incorporated into specialist postgraduate and undergraduate curriculums for physicians, nurses and other professionals. An expert group at the European Commission has endorsed a recommendation for multidisciplinary training of cancer specialists to improve the value of MDTs and patient care [bib_ref] Multidisciplinary training of cancer specialists in Europe, Benstead [/bib_ref]. Breast cancer training varies greatly among European countries and there is a need for multidisciplinary initiatives such as the Certificate of Competence in Breast Cancer from the European School of Oncology, which started in 2017 [bib_ref] How to become a breast cancer specialist in 2018: the point of..., Montagna [/bib_ref]. There is a great variability in breast cancer surgery training in Europe and it is imperative to develop quality standards for breast cancer surgery training to ensure that patients receive standardised and certified surgical management regardless of the country in which they are treated [bib_ref] Variability in breast cancer surgery training across Europe: an ESSO-EUSOMA international survey, Rubio [/bib_ref]. A curriculum for breast care nurses has been introduced by the European Oncology Nursing Society (EONS) [bib_ref] Training breast care nurses throughout Europe: the EONS postbasic curriculum for breast..., Eicher [/bib_ref]. ## Clinical research and registries Centres treating breast cancer should have clinical research programmes (either their own research or as a participant in programmes led by other centres/cooperative groups). The research portfolio should have both interventional and noninterventional projects and include academic research. The MDT must assess all new patients for eligibility to take part in academic and industry sponsored clinical trials at the centre or in research networks. Collaboration within national and/or international European academic research networks or cooperative groups is strongly recommended since high-quality clinical and translational research can no longer be performed in isolated centres. Breast cancer research is well organised worldwide, with most countries having at least one national breast cancer group and with BIG (Breast International Group, http://www. bigagainstbreastcancer.org), which is an umbrella organisation of national and international breast cancer cooperative groups. BIG has longstanding collaboration with North American breast cancer groups for large global projects. In countries where clinical trials are less available, centres treating breast cancer should engage with policymakers to investigate referring patients to other countries (as proposed with European Reference Networks) and should be prepared to participate in clinical trials from an organisational standpoint. Researchers at other centres should be considered as part of the extended MDT for at least annual discussion of clinical trial participation. Generally, pan-European action should be taken to increase participation of breast cancer patients in clinical trials (both industry-sponsored and academic), and internet access to local clinical trial databases should be developed. Older adults are currently underrepresented in cancer clinical trials despite having a disproportionate burden of disease. Strategies to increase the participation of older adults must be implemented and trials designed to take their needs into account. Other underrepresented breast cancer patients in clinical trials are male breast cancer patients and young premenopausal women. Strategies to increase their participation must be implemented. Correlative biomarker research is a crucial part of all phases of clinical studies and requires close cooperation with between basic and clinical research groups, as well as the availability of high-quality certified biobanks, at local, national or international level. Cancer control plans must include high-quality population and clinical cancer registries for breast cancer to inform both research and improve quality of care. A population example is Nordcan (http://www-dep.iarc.fr/NORDCAN), which includes breast cancer in 50 cancer types in the Nordic countries; and for screening, CANSCREEN5 (http://canscreen5.iarc.fr). Important bodies are the International Association of Cancer Registries (IACR) and the European Network of Cancer Registries (ENCR), and the European Commission's Joint Research Centre (JRC), which with ENCR is working on harmonisation of data and registration processes. [fig] Figure 1: European breast cancer mortality and incidence Source: European Cancer Information System. European age standardised rates. [/fig] [fig] Figure 2: Breast cancer centre schematic. [/fig] [fig] ◊: At the time of communication of recurrent or metastatic disease At follow-up clinics. [/fig]	None	http://www.thebreastonline.com/article/S0960977620300606/pdf	None
bee2a70a3f422ff1294bda3257025c4e7c3c8721	pubmed	American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: July 2021 update on postdischarge thromboprophylaxis	American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: July 2021 update on postdischarge thromboprophylaxis ## Summary of recommendations The ASH guideline panel suggests that outpatient anticoagulant thromboprophylaxis not be used for patients with COVID-19 who are being discharged from the hospital and do not have suspected or confirmed venous thromboembolism (VTE) or another indication for anticoagulation (conditional recommendation based on very low certainty in the evidence about effects ). ## Remarks: An individualized assessment of the patient's risk of thrombosis and bleeding and shared decision making are important when deciding on whether to use postdischarge thromboprophylaxis. Prospectively validated risk assessment models to estimate thrombotic and bleeding risk in COVID-19 patients after hospital discharge are not available. The panel acknowledged that postdischarge thromboprophylaxis may be reasonable for patients judged to be at high risk of thrombosis and low risk of bleeding. # Background Hospitalization for acute medical illness is a common risk factor for venous thromboembolism (VTE), with most such events occurring after hospital discharge. [bib_ref] Duration of venous thromboembolism risk across a continuum in medically ill hospitalized..., Amin [/bib_ref] [bib_ref] Venous thromboembolism prophylaxis and risk in the inpatient and outpatient continuum of..., Amin [/bib_ref] Meanwhile, there is a high incidence of thrombotic complications in patients hospitalized for COVID-19-related acute illness or critical illness. [bib_ref] COVID-19 and its implications for thrombosis and anticoagulation, Connors [/bib_ref] [bib_ref] Risk of venous thromboembolism in patients with COVID-19: A systematic review and..., Nopp [/bib_ref] However, there are limited reports regarding rates of VTE after discharge for patients who have been hospitalized for COVID-19. [bib_ref] Postdischarge thromboembolic outcomes and mortality of hospitalized patients with COVID-19: the CORE-19..., Giannis [/bib_ref] [bib_ref] Postdischarge thrombosis and hemorrhage in patients with COVID-19, Patell [/bib_ref] Thus, there has been much interest in establishing whether postdischarge pharmacological thromboprophylaxis in this population is warranted. These guidelines are based on systematic reviews of evidence conducted under the direction of the McMaster University GRADE (grading of recommendations, assessment, development and evaluations) Centre with international collaborators. This is an update of the previous American Society of Hematology (ASH) guideline published in February 2021 [bib_ref] American Society of Hematology 2021 guidelines on the use of anticoagulation for..., Cuker [/bib_ref] and focuses on the role of thromboprophylaxis for patients discharged from the hospital after COVID-19. The panel followed best practice for guideline development recommended by the Institute of Medicine and the Guidelines International Network (GIN). [bib_ref] Board of Trustees of the Guidelines International Network. Guidelines International Network: Principles..., Sch€ Unemann [/bib_ref] [bib_ref] Board of Trustees of the Guidelines International Network. Guidelines International Network: toward..., Qaseem [/bib_ref] The panel used the GRADE approach [bib_ref] GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and..., Alonso-Coello [/bib_ref] [bib_ref] GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and..., Alonso-Coello [/bib_ref] [bib_ref] GRADE Working Group. Systems for grading the quality of evidence and the..., Atkins [/bib_ref] [bib_ref] Oxman AD; GRADE Working Group. Letters, numbers, symbols and words: how to..., Sch€ Unemann [/bib_ref] [bib_ref] GRADE Evidence to Decision (EtD) frameworks for adoption, adaptation, and de novo..., Sch€ Unemann [/bib_ref] [bib_ref] GRADE guidelines: 2. Framing the question and deciding on important outcomes, Guyatt [/bib_ref] [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] to assess the certainty of the evidence and formulate recommendations. The recommendation is listed in [fig_ref] Table 1: Recommendations Recommendation RemarksRecommendation 3 [/fig_ref]. ## Values and preferences The guideline panel identified all-cause mortality, pulmonary embolism (PE), deep vein thrombosis (DVT), and major bleeding as critical outcomes and placed a high value on avoiding these outcomes with the interventions assessed. Panel members noted that there was possible uncertainty and variability in the relative value that patients place on avoiding major bleeding events compared with reducing thrombotic events. ## Explanations and other considerations # Introduction Aims of these guidelines and specific objectives Please refer to the original ASH guidelines on the use of thromboprophylaxis for patients with COVID-19. [bib_ref] American Society of Hematology 2021 guidelines on the use of anticoagulation for..., Cuker [/bib_ref] All recommendations and updates to these living guidelines are accessible on the ASH COVID-19 anticoagulation Web page. ## Description of the health problem The COVID-19 pandemic has had a significant public health impact. As of 21 September 2021, over 229 million cases and 4.5 million deaths have been attributed to COVID-19-related illness globally.It is estimated that 5% to 20% of infected patients require hospital admission, of whom 5% to 15% may develop critical illness requiring intensive care support. [bib_ref] Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in..., Cummings [/bib_ref] [bib_ref] Critical care utilization for the COVID-19 outbreak in Lombardy, Italy: early experience..., Grasselli [/bib_ref] Thrombosis has emerged as an important complication of patients hospitalized with COVID-19-related acute or critical illness, with VTE occurring in up to 8% and 23% of such patients, respectively. [bib_ref] Risk of venous thromboembolism in patients with COVID-19: A systematic review and..., Nopp [/bib_ref] This result aligns with the recognition that patients hospitalized for other acute medical illnesses, such as pneumonia, stroke, and heart failure, are at increased risk of VTE. Predictors of VTE in such medically ill inpatients include reduced mobility, advanced age, active cancer, and prior VTE. [bib_ref] Goldhaber SZ; PREVENT Medical Thromboprophylaxis Study Group. Randomized, placebo-controlled trial of dalteparin..., Leizorovicz [/bib_ref] [bib_ref] A risk assessment model for the identification of hospitalized medical patients at..., Barbar [/bib_ref] Previously published ASH guidelines provided focused recommendations for the prevention of VTE in hospitalized patients with COVID-19, and in non-COVID-19 medical inpatients. [bib_ref] American Society of Hematology 2021 guidelines on the use of anticoagulation for..., Cuker [/bib_ref] [bib_ref] American Society of Hematology living guidelines on the use of anticoagulation for..., Cuker [/bib_ref] [bib_ref] American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis..., Sch€ Unemann [/bib_ref] In non-COVID-19 medical inpatients, most hospitalization-related thrombotic events occur after discharge; heightened VTE risk may extend until at least 1 month after discharge. [bib_ref] Duration of venous thromboembolism risk across a continuum in medically ill hospitalized..., Amin [/bib_ref] [bib_ref] Effect of a near-universal hospitalization-based prophylaxis regimen on annual number of venous..., Heit [/bib_ref] Several risk assessment models (RAMs) in patients without COVID-19 have been developed to assess the risk of VTE after hospitalization. [bib_ref] A risk assessment model for the identification of hospitalized medical patients at..., Barbar [/bib_ref] [bib_ref] The IMPROVE-DD VTE Risk Score: Incorporation of D-Dimer into the IMPROVE Score..., Gibson [/bib_ref] [bib_ref] Modified IMPROVE VTE Risk Score and elevated D-Dimer identify a high venous..., Spyropoulos [/bib_ref] However, randomized trials of postdischarge prophylaxis in patients without COVID-19 have not shown a substantial absolute benefit in VTE reduction, and the 2018 ASH guidelines recommended against postdischarge prophylaxis in medically ill patients who did not have COVID-19, owing to a low absolute benefit offset by an increase in bleeding risk. [bib_ref] American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis..., Sch€ Unemann [/bib_ref] [bib_ref] Extended Thromboprophylaxis with Betrixaban in acutely ill medical patients, Cohen [/bib_ref] [bib_ref] Rivaroxaban for thromboprophylaxis after hospitalization for medical illness, Spyropoulos [/bib_ref] [bib_ref] ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients, Goldhaber [/bib_ref] There is a belief that patients with COVID-19 may have a higher risk of VTE after discharge than patients without COVID-19. However, available COVID-19-specific estimates do not bear this out. Although there remains considerable uncertainty, published estimates of postdischarge VTE in COVID-19 patients generally range from 0.5% to 1.5%, [bib_ref] Postdischarge thromboembolic outcomes and mortality of hospitalized patients with COVID-19: the CORE-19..., Giannis [/bib_ref] [bib_ref] Postdischarge thrombosis and hemorrhage in patients with COVID-19, Patell [/bib_ref] comparable to the baseline risk of postdischarge VTE in the non-COVID-19 population. Several clinical risk factors have been found to be independently associated with postdischarge VTE after COVID-19, including advanced age, cardiovascular disease, chronic kidney disease, and intensive care unit (ICU) admission. [bib_ref] Postdischarge thromboembolic outcomes and mortality of hospitalized patients with COVID-19: the CORE-19..., Giannis [/bib_ref] However, there are no RAMs that have been specifically derived and prospectively validated in patients with COVID-19 thus far, although non-COVID RAMs have been externally validated in hospitalized patients with COVID-19, and the COVID-thromboembolism score was derived specifically from patients with COVID-19 with concomitant malignancy. [bib_ref] COVID-19 Consortium Group. Validation of the IMPROVE-DD risk assessment model for venous..., Spyropoulos [/bib_ref] [bib_ref] External validation of the IMPROVE-DD risk assessment model for venous thromboembolism among..., Goldin [/bib_ref] [bib_ref] The CoVID-TE risk assessment model for venous thromboembolism in hospitalized patients with..., Li [/bib_ref] Moreover, although the recent CORE-19 registry demonstrated a reduction in the composite outcome of VTE, arterial thromboembolism (ATE), and all-cause mortality with postdischarge anticoagulation, there remains a paucity of high-quality prospective and randomized data. As such, the relative risks and benefits of postdischarge thromboprophylaxis remain uncertain in this population. In this living guideline update, the role of postdischarge thromboprophylaxis after hospitalization for COVID-19 is addressed. ## Description of the target populations The target population included patients discharged from the hospital after admission for COVID-19-related illness. # Methods This new guideline recommendation on the use of prophylacticintensity anticoagulation for patients being discharged after admission for COVID-19-related illness was developed in the living phase of the ASH 2021 Living Guidelines on the Use of Anticoagulation for Thromboprophylaxis for Patients with COVID-19. The ASH guideline panel added this question as a priority in January 2021 and generated recommendation 3 on 14 April 2021 before asking for public comments. We followed the same methods as published in the initial guideline, [bib_ref] American Society of Hematology 2021 guidelines on the use of anticoagulation for..., Cuker [/bib_ref] with the following important updates and differences for the recommendation reported herein: Organization, panel composition, planning, and coordination: with 1 exception, we retained the same panel members; no conflicts of interest emerged that would require exclusion of panel members. Guideline funding and management of conflicts of interest: Supplement 4 provides updated Participant Information Forms for all panel members, detailing financial and nonfinancial interests, as well as the ASH conflict of interest policies agreed to by each individual. Supplement 5 provides the updated complete Participant Information Forms of researchers on the systematic review team who contributed to these guidelines. Formulating specific clinical questions and determining outcomes of interest: this update of the guidelines focuses on 1 question: for patients with COVID-19 who are being discharged from the hospital and who do not have suspected or confirmed VTE or another indication for anticoagulation, should we use prophylactic-intensity direct oral anticoagulants, low-molecularweight heparin, unfractionated heparin, or fondaparinux vs no anticoagulation? We originally intended to include antiplatelet agents in the question, but we ultimately chose not to because of the lack of published evidence in COVID-19 patients. However, antiplatelet agents may be included in living updates. ## Evidence review and development of recommendations An evidence-to-decision framework was created for recommendation 3 (see "Recommendations"), by using the same methods as the initial guideline. [bib_ref] Postdischarge thrombosis and hemorrhage in patients with COVID-19, Patell [/bib_ref] The systematic review to identify comparative anticoagulation studies for the entire guideline was updated until 5 March 2021. The initial guideline's literature search strategy (Supplement 6) was modified to add search terms for antiplatelet agents for this guideline question. The protocol (Supplement 9) was modified to focus on inclusion of only randomized controlled trials for other previously published recommendations. Baseline risk estimates for outcomes of patients with COVID-19 who were discharged from the hospital were based on studies identified using the same overall systematic review as reported in the initial guideline, updated until 24 March 2021. ## Document review The draft recommendation was reviewed by all members of the panel and made available online from 8 to 19 July 2021 for external review by stakeholders, including allied organizations, other medical professionals, patients, and the public. As part of the public comment, there were 143 views; 2 individuals or organizations submitted responses that did not require changes to the document. On 10 August 2021, the ASH Guideline Oversight Subcommittee and the ASH Committee on Quality assured that the defined guideline development process was followed, and on 12 August 2021, the officers of the ASH Executive Committee approved submission of the updated guideline manuscript for publication under the imprimatur of ASH. The updated guideline was then subjected to peer review by Blood Advances. ## How to use these guidelines We refer readers to the description in the initial guideline publication of February 2021, 7 as well as the user guide to ASH clinical practice guidelines. 37 ## Recommendations Patients being discharged from the hospital after admission for COVID-19 Should prophylactic-intensity direct oral anticoagulants, low-molecular-weight heparin, unfractionated heparin, or fondaparinux vs no anticoagulation be used for postdischarge thromboprophylaxis for patients with COVID-19 who are discharged from the hospital and who do not have suspected or confirmed VTE or another indication for anticoagulation? ## Recommendation 3 The ASH guideline panel suggests that outpatient anticoagulant thromboprophylaxis not be used for patients with COVID-19 who are discharged from the hospital and do not have suspected or confirmed VTE or another indication for anticoagulation (conditional recommendation based on very low certainty in the evidence about effects ). ## Remarks: An individualized assessment of the patient's risk of thrombosis and bleeding and shared decision making are important when deciding on whether to use postdischarge thromboprophylaxis. Prospectively validated risk assessment models to estimate thrombotic and bleeding risk of patients with COVID-19 after hospital discharge are not available. The panel acknowledged that postdischarge thromboprophylaxis may be reasonable for patients judged to be at high risk of thrombosis and low risk of bleeding. Summary of the evidence. We rated the certainty in the evidence as low for the outcome of major bleeding in patients without COVID-19, owing to very serious indirectness, and as very low for all other outcomes, mainly owing to (very) serious risk of bias (see evidence profile and evidence to decision [EtD] framework online at https://guidelines. ash.gradepro.org/profile/uEXUjtWgVAQ). We found no systematic reviews that addressed this question. Three observational studies provided evidence related to the question. Supplement 10 presents the characteristics of the included studies. One prospective registry study reported the effect of postdischarge prophylactic-intensity anticoagulation on the outcomes of any VTE or ATE, mortality, and bleeding 5 ; 1 retrospective cohort study on the outcome of any VTE or ATE [bib_ref] Vascular thromboembolic events following COVID-19 hospital discharge: Incidence and risk factors, Eswaran [/bib_ref] ; and 1 matched case-control study on the outcome of readmission. [bib_ref] Morr as I, et al; Puerta de Hierro Hospital Admission Study Group...., Parra [/bib_ref] Benefits. The evidence was very uncertain for all of the considered outcomes leading to the following interpretation. Postdischarge prophylactic-intensity anticoagulation may reduce the risk of mortality (odds ratio [OR] 0.55; 95% confidence interval [CI], 0.37-0.83), which corresponds to 5 fewer (from 7 fewer to 2 fewer) deaths per 1000 patients; very low certainty. Postdischarge prophylacticintensity anticoagulation may reduce the risk of PE (OR, 0.76; 95% CI, 0.46-1.25), which corresponds to 1 fewer (from 3 fewer to 1 more) PEs per 1000 patients; very low certainty. Postdischarge prophylactic-intensity anticoagulation may reduce the risk of VTE (OR, 0.76; 95% CI, 0.46-1.25), which corresponds to 4 fewer (from 9 fewer to 4 more) VTEs per 1000 patients; very low certainty. Postdischarge prophylactic-intensity anticoagulation may reduce the risk of readmission (OR, 0.92; 95% CI, 0.41-2.05), which corresponds to 5 fewer (from 35 fewer to 57 more) readmissions per 1000 patients; very low certainty. No benefit or harm was observed for the outcomes of DVT, ischemic stroke, and ST-elevation myocardial infarction in terms of absolute effect, but there was very low certainty in the evidence. Harms and burden. Indirect evidence from acutely ill patients who do not have COVID-19 indicated that postdischarge prophylactic-intensity anticoagulation after hospitalization may increase the risk of major bleeding (relative risk, 2.09; 95% CI, 1.33-3.27), but the evidence is uncertain; this corresponds to 4 more (from 1 more to 9 more) major bleeding episodes per 1000 patients at lower risk of bleeding, and to 13 more (from 4 more to 27 more) major bleeding episodes per 1000 patients at higher risk of bleeding; low certainty. Direct evidence from patients acutely ill with COVID-19 indicates that postdischarge prophylactic-intensity anticoagulation may increase the risk of major bleeding but the evidence is very uncertain (OR, 1.52; 95% CI, 0.86-2.67). This result corresponds to 1 more (from 0 to 2 more) major bleeding episode per 1000 patients; very low certainty. Other EtD criteria and considerations. The guideline panel noted that there was possible uncertainty and variability in the relative value patients place on reducing thrombotic events compared with avoiding major bleeding events. The panel agreed that the use of postdischarge anticoagulant thromboprophylaxis would be acceptable to patients and health care providers. In addition, the panel acknowledged that patients who are not insured may have reduced access to postdischarge anticoagulant therapy, which could adversely affect health care equity. There would be a potential for increased costs for those paying out of pocket for postdischarge prophylaxis. Conclusions for this recommendation. The panel judged both the benefits and harms of postdischarge thromboprophylaxis to be trivial in terms of absolute effects. Although there was a trivial mortality benefit and reduction in VTE with postdischarge anticoagulant therapy, there was very low certainty in the evidence. Meanwhile, there was less uncertainty in the potential undesirable effects of anticoagulant therapy in increasing the risk of major bleeding complications. Although there was no direct high-quality evidence available for patients with COVID-19, the panel considered that there was higher quality indirect evidence for patients without COVID-19 that indicated an increase in the risk of major bleeding when postdischarge anticoagulation was used. [bib_ref] ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients, Goldhaber [/bib_ref] [bib_ref] Effect of extended-duration thromboprophylaxis on venous thromboembolism and major bleeding among acutely..., Chi [/bib_ref] [bib_ref] Post-hospital discharge venous thromboembolism prophylaxis in medically ill patients, Berkman [/bib_ref] The panel judged that the major bleeding complications outweigh the potential benefits (particularly given the relatively low baseline risk of postdischarge VTE) and that, overall, the undesirable consequences outweigh the desirable consequences. On the basis of these judgments, the panel suggests that postdischarge thromboprophylaxis not be used. [bib_ref] American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis..., Sch€ Unemann [/bib_ref] However, the panel emphasized the importance of an individualized decision for each patient based on an assessment of thrombosis and bleeding risks. ## What are others saying and what is new in these guidelines? There are multiple other guidance documents on the use of anticoagulation in patients with COVID-19. These include the 2020 CHEST COVID-19 Guidelines, Anticoagulation Forum interim clinical guidance, International Society on Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee (SSC) COVID-19 clinical guidance, National Institutes of Health (NIH) COVID-19 treatment guidelines, and American College of Cardiology (ACC) clinical guidance. [bib_ref] Subcommittee on Perioperative, Critical Care Thrombosis, Haemostasis of the Scientific, Standardization Committee..., Spyropoulos [/bib_ref] [bib_ref] Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from..., Barnes [/bib_ref] [bib_ref] Prevention, diagnosis, and treatment of VTE in patients With coronavirus disease 2019:..., Moores [/bib_ref] Major differences between the current ASH guidelines and these other documents include use in ASH guidelines of high-quality systematic reviews and ED frameworks, which increase transparency, along with the use of marker states to estimate the relative importance to patients of key outcomes of treatment. The present ASH guideline is also unique in its "living" format, though other guidance documents may also be updated. All 5 of these other guidance documents do not recommend routine use of postdischarge pharmacological thromboprophylaxis after hospitalization for COVID-19-related illness. However, given the lack of high-quality evidence, they all suggest that an individualized decision be made taking into account the patient's thrombosis risk factors and bleeding risk at the time of discharge. The CHEST guideline suggests that postdischarge thromboprophylaxis would result in net clinical benefit only if the risk of symptomatic VTE were found to be .1.8% within 35 to 42 days after release from the hospital. [bib_ref] Prevention, diagnosis, and treatment of VTE in patients With coronavirus disease 2019:..., Moores [/bib_ref] Meanwhile, the ISTH guidance document suggests that postdischarge thromboprophylaxis be considered for all patients hospitalized with COVID-19 who meet high-risk VTE criteria, including advanced age, ICU admission, cancer, prior VTE history, thrombophilia, severe immobility, elevated D-dimer, or an IMPROVE VTE score of 4 or more. [bib_ref] Subcommittee on Perioperative, Critical Care Thrombosis, Haemostasis of the Scientific, Standardization Committee..., Spyropoulos [/bib_ref] The guidance from AC Forum, NIH, and ACC all suggest that postdischarge prophylaxis be considered in light of thrombotic risk, bleeding risk, and access to medication. At the time of this writing, there have been no published randomized trials examining the efficacy and safety of postdischarge thromboprophylaxis in patients with COVID-19. However, there are several ongoing or recently completed clinical studies examining this question. [bib_ref] Recent randomized trials of antithrombotic therapy for patients with COVID-19: JACC State-of-the-Art..., Talasaz [/bib_ref] These prospective studies include the MICHELLE (registered at https://clinicaltrial.gov, as NCT04662684)and ACTIV-4c trials (NCT04650087),which examine the use of prophylactic-intensity direct oral anticoagulants. ## Limitations of these guidelines The limitations of these guidelines are inherent in the low certainty in the evidence we identified for the research questions. In addition, the use of treatments other than anticoagulants for management of COVID-19-related acute and critical illness (eg, corticosteroids, anticytokine therapies, ventilatory support), the affected patient population, as well as the emergence of different viral variants has changed over the course of the pandemic. These changes may affect the baseline risk of VTE. Evidence collected earlier in the pandemic and included in our systematic reviews may not fully reflect the baseline risk of VTE or the effect of postdischarge thromboprophylaxis in the current phase of the pandemic. ## Plans for updating these guidelines These recommendations will be updated based on a living review of evolving evidence, including data from randomized trials. See the initial guideline publication for methods of living systematic reviews and recommendations, including considerations for deciding when to reassess and update recommendations. 7 ## Updating or adapting recommendations locally Adaptation of these guidelines will be necessary in many circumstances. These adaptations should be based on the associated EtD frameworks. [bib_ref] GRADE Evidence to Decision (EtD) frameworks for adoption, adaptation, and de novo..., Sch€ Unemann [/bib_ref] ## Priorities for research On the basis of gaps in evidence identified during the guideline development process, the panel identified the following urgent research priorities in this patient population: Studies assessing baseline VTE risk after hospitalization in patients with COVID-19-related illness. Randomized controlled trials comparing antithrombotic therapy (including anticoagulants and antiplatelet agents) for thromboprophylaxis after hospitalization. Identification of predictors of thrombosis and bleeding in patients discharged after COVID-19-related illness. Development and validation of risk assessment models for thrombosis and bleeding risk in patients discharged after COVID-19-related illness. Studies examining the impact of nonanticoagulant interventions (eg, anticomplement therapy, corticosteroids, antiviral therapies, anticytokine therapies, antiplatelet therapies, monoclonal antibody therapy, convalescent plasma) on risk of thrombosis after hospital discharge. Studies examining the impact of anticoagulant therapy on thrombosis and bleeding outcomes after hospitalization in patients of different racial and ethnic backgrounds. Conflict-of-interest disclosure: All authors were members of the guideline panel or members of the systematic review team or both. As such, they completed a disclosure of interest form, which was reviewed by ASH and is available as Supplements 4 and 5. [fig] Authorship: Contribution: E.K.T., R.N., A.C., R.A.M., and H.J.S. wrote the manuscript; all other authors contributed to critical revisions of the manuscript and approved the content; members of the knowledge synthesis team, R.N., R.N.A.J., Y.N.A.J., A.M.B., A.B., I.B.A., M.B., R.B.-P., R.C., M.C., L.E.C.-L., K.D., A.J.D., H.H., S.G.K., P.K., R.M., G.P.M., R.Z.M., G.M.-S., M.K.N., A.N., B.A.P., T.P., Y.Q., Y.R.B., F.S., A.S., K.S., and W.W. searched the literature, extracted data from eligible studies, analyzed the data, and prepared evidence summaries and evidence-to-decision tables; panel members A.C., E.K.T., P.A., C.B., K.D., J.D., M.T.D., D.D., D.O.G., S.R.K., F.A.K., A.I.L., I.N., A.evidence, voted and made judgments within the evidence-todecision framework, and discussed and issued the recommendations; the methods leadership team, R.N., R.B.-P., K.D., A.S., K.S., A.C., E.A.A., W.W., R.A.M., and H.J.S. developed the methods and provided guidance to the knowledge synthesis team and guideline panel; and A.C., R.A.M., and H.J.S. were the cochairs of the panel and led the panel meetings. [/fig] [table] Table 1: Recommendations Recommendation RemarksRecommendation 3. The ASH guideline panel suggests that outpatient anticoagulant thromboprophylaxis not be used in patients with COVID-19 who are being discharged from the hospital and who do not have suspected or confirmed VTE or another indication for anticoagulation (conditional recommendation based on low certainty in the evidence about effects ). individualized assessment of the patient's risk of thrombosis and bleeding and shared decision making are important when deciding whether to use postdischarge thromboprophylaxis. Prospectively validated risk assessment models to estimate thrombotic and bleeding risk in patients with COVID-19 after hospital discharge are not available. The panel acknowledged that postdischarge thromboprophylaxis may be reasonable in patients judged to be at high risk of thrombosis and low risk of bleeding. [/table]	None	https://ashpublications.org/bloodadvances/article-pdf/6/2/664/1891268/advancesadv2021005945c.pdf	Background: COVID-19 related acute illness is associated with an increased risk of venous thromboembolism (VTE). Objective:These evidence-based guidelinesof the American Society of Hematology (ASH) are intended to support patients, clinicians and other health care professionalsin decisions aboutthe use of anticoagulation for thromboprophylaxis in patients with COVID-19 who do not have confirmed or suspected VTE. Methods:ASH formed a multidisciplinary guideline panel, including three patient representatives,and applied strategies to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including performing systematic evidence reviews(up to March 2021).The panel prioritized clinical questionsand outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approachto assess evidence and make recommendations, which were subject to public comment. Results:The panel agreed on one additional recommendation. The panel issued a conditional recommendation against the use of outpatient anticoagulant prophylaxis in patients with COVID-19 being discharged from the hospital who do not have suspected or confirmed VTE or another indication for anticoagulation. Conclusions: This recommendation was based on very low certainty in the evidence, underscoring the need for high-quality, randomized controlled trials assessing the role of post-discharge thromboprophylaxis. Other key research priorities include better evidence on assessing risk of thrombosis and bleeding outcomesin patients with COVID-19 after hospital discharge.
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c376bcae504b6411c8a00e776dd93302e38497d1	pubmed	Transfusion strategies in bleeding critically ill adults: a clinical practice guideline from the European Society of Intensive Care Medicine	Transfusion strategies in bleeding critically ill adults: a clinical practice guideline from the European Society of Intensive Care Medicine Purpose: To develop evidence-based clinical practice recommendations regarding transfusion practices and transfusion in bleeding critically ill adults.Methods: A taskforce involving 15 international experts and 2 methodologists used the GRADE approach to guideline development. The taskforce addressed three main topics: transfusion support in massively and non-massively bleeding critically ill patients (transfusion ratios, blood products, and point of care testing) and the use of tranexamic acid. The panel developed and answered structured guideline questions using population, intervention, comparison, and outcomes (PICO) format.Results:The taskforce generated 26 clinical practice recommendations (2 strong recommendations, 13 conditional recommendations, 11 no recommendation), and identified 10 PICOs with insufficient evidence to make a recommendation.Conclusions:This clinical practice guideline provides evidence-based recommendations for the management of massively and non-massively bleeding critically ill adult patients and identifies areas where further research is needed. # Introduction Patients admitted to the intensive care unit (ICU) frequently experience bleeding due to a variety of causes, with incidences of bleeding up to 50% reported in some ICU populations, and this in turn is associated with increased morbidity and mortality [bib_ref] Risk factors and impact of major bleeding in critically ill patients receiving..., Lauzier [/bib_ref] [bib_ref] Prediction of bleeding by thromboelastography in ICU patients with haematological malignancy and..., Russell [/bib_ref] [bib_ref] Risks of bleeding and thrombosis in intensive care unit patients with haematological..., Russell [/bib_ref]. While transfusion of blood products is one of the cornerstones in treatment of bleeding critically ill patients, administration of blood products also carries risks, both theoretical and measurable. Challenges exist in researching bleeding in critically ill patients, particularly with the varied definitions used to describe massive and non-massive bleeding. Massive bleeding by convention can be described as greater than 10 units in 24 h or 4 units in 1 h [bib_ref] Update on massive transfusion, Pham [/bib_ref]. Although difficult to manage, clinicians can readily recognize massive bleeding. However, consistent definitions in non-massive bleeding are elusive. Non-massive bleeding has clinical implication given resources and blood products required to manage these patients. To establish evidence-based interventions to reduce the resources used in non-massive bleeding, consistent nomenclature is required. Treating bleeding in critically ill patients is a dynamic and complex process which is challenging to study, and extrapolating results from studies conducted in nonbleeding patients, or those who are less severely ill may not always be justified. Moreover, transfusion strategies during bleeding may involve multiple concurrent strategies for monitoring coagulopathy, transfusing blood products, and administering medications to support coagulation. Consequently, there is substantial worldwide variation in the treatment of critically ill patients with bleeding, and the availability of transfusion protocols in ICUs [bib_ref] Cardiovascular Dynamics S, Transfusion Guideline Task Force of the E (2019) Transfusion..., De Bruin [/bib_ref]. ## Scope and objectives of this guideline Recognizing wide variation in transfusion practice, the European Society of Intensive Care Medicine (ESICM) created a taskforce (TF) to develop evidence-based recommendations for transfusion guidelines in the ICU and to identify knowledge gaps for future research priorities. The TF divided its recommendations into two sets of guideline recommendations. The first addressed transfusion in non-bleeding critically ill patients [bib_ref] Transfusion strategies in non-bleeding critically ill adults: a clinical practice guideline from..., Vlaar [/bib_ref]. This manuscript includes guidelines for transfusion in critically ill patients with bleeding, including a wide variety of patient populations, not all of which are addressed in other guidelines. The TF developed this guideline to assist critical care clinicians working in adult ICUs, with a scope including a broad set of patient populations cared for in the ICU, and transfusion-related interventions of relevance to bedside clinicians caring for bleeding patients, including use of blood products, transfusion ratios, point of care testing, and use of pharmacological agents to manage fibrinolysis (primarily tranexamic acid . Blood pressure monitoring and targets, fluid resuscitation, vasopressor management, and bleeding source control, were considered to be beyond the scope of this guideline. Given the rapidity with which critically ill patients with bleeding can deteriorate, having a standardized approach to transfusion in these patients can be of great assistance to clinicians working in time-pressured circumstances. However, TF acknowledges that while this guideline can provide recommendations for transfusion practice in critically ill patients, specific patient characteristics and clinical circumstances may require the use of an individualized approach, integrating patient values and preferences, local resources, and patient judgement. # Methods ## Taskforce membership The TF included 15 clinicians with expertise in critical care medicine, anesthesiology, hematology, cardiac surgery, gastroenterology and transfusion medicine, along with methodologists experienced in guideline development using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref]. TF members were chosen based on their content and methodology expertise. The TF and methodologists were jointly involved in all aspects of the development of the guideline including development of PICO (population, intervention, comparison, and outcomes) questions, updating literature searches, assessing quality of evidence, formulation of recommendations, and manuscript writing. As the guideline did not have a patient representative on the panel, perspectives on patient values and preferences for transfusion and outcomes were obtained from a literature review. ## Conflict of interest At the beginning of the guideline process, and prior to submission of the manuscript, all TF members disclosed potential conflict of interest (COI). These included financial, intellectual, and personal COI. TF members were excused from voting on recommendations on any PICO questions where the TF chair considered significant COI to exist. ## Sponsorship The ESICM sponsored the development of this guideline and ESICM representatives were updated throughout the guideline process. There was no industry involvement in any aspect of the guideline. ## Question development and outcome prioritization The initial list of PICO questions was developed by the TF chairs (AV, MC). TF members were invited to submit additional PICO questions on topics related to blood product ## Take-home message In this clinical practice guideline, we highlight the current evidence for management of bleeding ICU patients and areas for further research. transfusions, transfusion protocols, point of care testing, and use of other medication in massively and non-massively bleeding critically ill patients. Following discussion of each PICO via teleconference, the TF voted anonymously on the questions in May 2019, using an online survey, rating the priority of each PICO on a scale of 1-10, with the highest rated PICOs being addressed in the TF guideline. The TF chose to address "massive" vs. "nonmassive" bleeding separately. We used the author definitions of massive (ex. use of > 10 units of red blood cells (RBC) in 24 h or > 6 units in 6 h) and non-massive bleeding. A list of potentially relevant outcomes for each PICO question was developed at a general TF meeting (ESICM Lives 2019, Berlin, Germany). Outcomes were prioritized according to standard methods used in GRADE, using an anonymous online voting system, with each outcome being rated from 1 to 9, as "critical" (rating 7-9), "important" (4-6), or "limited importance" (1-3), according to the relative importance of each outcome to patients [bib_ref] GRADE guidelines: 2. Framing the question and deciding on important outcomes, Guyatt [/bib_ref]. Critical outcomes were mortality (all-cause or bleedingrelated), quality of life, functional recovery and stroke. Important outcomes included myocardial infarction, renal failure requiring renal replacement therapy (RRT), acute respiratory distress syndrome (ARDS), transfusion-related lung injury (TRALI), volume overload, venous thrombosis, length of stay (ICU and hospital), post-transfusion infections, and hemodynamic stability. ## Search strategy and study inclusion For each PICO question, a methodologist (SO) updated searches from published systematic reviews and developed new search strategies, with the input of other TF members (supplementary materials). We searched MEDLINE, EMBASE, and Cochrane databases for each PICO up to September 2019, along with trial databases (clinicaltrials. gov and ISRCTN) to identify in-progress trials, which were incorporated into the literature reviews as they became available. Search results were uploaded into Rayyan [bib_ref] Rayyan: a web and mobile app for systematic reviews, Ouzzani [/bib_ref] for screening. Two reviewers from the TF screened the search results for relevant English-language systematic reviews (SRs), randomized controlled trials (RCTs), and observational studies. Any citation identified by either reviewer as potentially relevant underwent full text review, which were in turn also screened by two reviewers, with disagreements about inclusion at the full text resolved by discussion, with input from a third TF member. ## Data abstraction and risk of bias assessment Using a standardized, piloted data abstraction form, the methodology team conducted data abstraction for all included studies. To ensure consistency and prevent transcription errors, a second reviewer validated the data. With input from other TF members, the methodology team also conducted risk of bias assessments for each included study using the Cochrane Risk of Bias tool for RCTs, or the Newcastle-Ottawa risk of bias assessment tool. ## Data analysis and rating of evidence When there was sufficient evidence for data pooling, metaanalyses for each PICO question were conducted using Rev-Man v 5.3. For all outcomes, we compared fixed-and random-effects estimates, generally using fixed-effects models when the number of studies was very small (5 or fewer) or there were concerns that small-study effects may be impacting the pooled estimate; otherwise we used random-effects models [bib_ref] Random-effects meta-analysis of inconsistent effects: a time for change, Cornell [/bib_ref]. For dichotomous variables, we reported relative risk (RR) and absolute risk difference (RD). For continuous variables mean difference (MD), or standardized mean difference (SMD), as appropriate, each with a corresponding 95% confidence interval (95% CI). Exploratory, post-hoc subgroup analyses were performed to explore potential sources of statistical heterogeneity (e.g. patient population, interventions, comparators, and outcomes reported). Following GRADE guidance, if unexplained heterogeneity was found, we rated down the certainty/quality of the evidence for that outcome. If heterogeneity was explainable using subgroup analysis, the panel considered this in formulating recommendations and implementation considerations. For questions in which insufficient quantitative data were available to conduct a meta-analysis, the evidence was summarized in narrative fashion. ## Evidence summaries and formulation of recommendations The methodology team (SO, JCD) developed evidence summaries for each PICO question (supplementary materials), including information on study design, population, intervention, pooled estimates of effect for each outcome, and a rating of the overall quality of evidence. We rated the certainty of evidence for each outcome as "high, " "moderate, " "low, " and "very low. " In accordance with GRADE, the task force initially categorized the certainty of evidence for each outcome as high if it originated from RCTs and low if it originated from observational data. We subsequently rated down the quality of the evidence by one or two levels if results from individual studies were at serious or very serious risk of bias [bib_ref] GRADE guidelines: 4. Rating the quality of evidence-study limitations (risk of bias), Guyatt [/bib_ref] there were serious inconsistencies (heterogeneity) in the results across studies [bib_ref] Rating the quality of evidence-inconsistency, Guyatt [/bib_ref] the evidence was indirect [bib_ref] GRADE guidelines: 8. Rating the quality of evidence-indirectness, Guyatt [/bib_ref] , the data were imprecise [bib_ref] GRADE guidelines 6. Rating the quality of evidence-imprecision, Guyatt [/bib_ref] , or publication bias was thought to be likely. Evidence from observational data could be rated upwards if effect sizes were large, there was evidence of a dose-response gradient, or all plausible confounding would either reduce a demonstrated effect or suggest a spurious effect when results showed no effect. Evidence to decision (EtD) frameworks were completed by a subgroup of TF members for each PICO question to develop a draft recommendation considering the balance of desirable and undesirable effects, certainty of effects, resource considerations, feasibility, acceptability, and equity issues. While the TF planned to meet in March 2020 for final discussion and voting on the results, this meeting was cancelled in light of the coronavirus disease 2019 (COVID-19) pandemic. Instead, the TF used Panel Voice to vote on the strength and direction of the recommendation, after reviewing the EtD framework and draft recommendations created by each subgroup. A minimum of two rounds of voting were held to achieve consensus, if a consensus was not reached after two rounds a third round was held. We achieved approval on all recommendations after 2 rounds of voting. A priori, the task force chair decided that recommendations had to receive at least 80% of the vote of the panel to be approved [bib_ref] Use of GRADE grid to reach decisions on clinical practice guidelines when..., Jaeschke [/bib_ref]. Executive summary of recommendations: recognizing significant variation in transfusion practices to correct for anemia and/or coagulopathy in bleeding critical care patients, the ESICM assembled a task force to summarize the existing evidence regarding transfusion practices and transfusion avoidance strategies in bleeding, critically ill adults. The TF chose to address "massive" vs. "non-massive" bleeding separately. We used the author definitions of massive (ex. use of > 10 units of RBC in 24 hours or > 6 units in 6 hours) and non-massive bleeding. In addition, the task force aimed to develop clinical practice recommendations, identify knowledge gaps, and areas for future research. ## Transfusion support in massively bleeding, critically ill adults ## Part 1: massively bleeding patients The following recommendations pertain to patients with massive bleeding. ## Transfusion ratios ## Recommendation We suggest use of high-ratio transfusion strategies (at least one unit plasma per two units of packed red blood cells) vs. low-ratio transfusion strategies in critically ill patients with massive bleeding due to trauma (Conditional recommendation, low certainty of evidence). We make no recommendation regarding the use of fixed high-ratio transfusion strategies in critically ill patients with non-traumatic massive bleeding (No recommendation, very low certainty evidence). ## Evidence summary We evaluated both randomized and non-randomized evidence regarding transfusion ratios in trauma [bib_ref] Optimal dose, timing and ratio of blood products in massive transfusion: results..., Mcquilten [/bib_ref]. Given concerns regarding residual confounding in the observational data, the panel relied primarily on evidence from the two available RCTs. [bib_ref] Effect of a fixed-ratio (1:1:1) transfusion protocol versus laboratory-results-guided transfusion in patients..., Nascimento [/bib_ref] , in which high FFP: transfusion and high platelet ratios 1:1:2 compared to 1:1:1. The pooled results did not result in a mortality benefit at 24 h (RR 0.75, 95% CI 0.52-1.08; RD − 4.2%, 95% CI − 8.1 to 1.4%, moderate certainty) and 30 days (RR 0.93, 95% CI 0.72-1.2; RD − 1.7%, 95% CI − 7 to 5, low certainty), though these results were limited by imprecision. Higher transfusion ratios may result in better clinical hemostasis, reducing probability of death by exsanguination (RR 0.7, 95% CI 0.51-0.96, RD − 23.7%, 95% CI − 38.8 to − 3.2, low certainty) although certainty is limited by inconsistency between the two studies. There appeared to be no difference in rates of stroke, myocardial infarction (MI), ARDS/TRALI, congestive heart failure (CHF), infections, and venous thrombo embolism (VTE) although these results were limited by serious or very serious imprecision and cannot rule out a meaningful effect. There is moderate certainty that high transfusion ratio results in a greater proportion of patients receiving plasma (RR 1.2, 95% CI 1.01 to 1.43; mean difference 2 units, 95% CI 0.99 to 3.01) and platelets (RR 1.4, 95% CI 1.07-1.83; MD 6 95% CI 4.66-7.34), without a difference in RBCs transfused (MD 0 units, 95% CI − 1.11 to 1.11). In non-trauma patients, we identified several observational studies, 3 in mixed populations [bib_ref] Should all massively transfused patients be treated equally? An analysis of massive..., Etchill [/bib_ref] [bib_ref] Association between ratio of fresh frozen plasma to red blood cells during..., Mesar [/bib_ref] [bib_ref] Experience with a massive transfusion protocol in the management of massive haemorrhage, Sinha [/bib_ref] 2 in cardiac and vascular surgery [bib_ref] Association between ratio of fresh frozen plasma to red blood cells during..., Mesar [/bib_ref] [bib_ref] Massive transfusion in cardiac surgery: the impact of blood component ratios on..., Delaney [/bib_ref] , and 2 in postpartum hemorrhage [bib_ref] Hemostatic resuscitation in peripartum hysterectomy pre-and postmassive transfusion protocol initiation, Dutta [/bib_ref] [bib_ref] Retrospective study to investigate fresh frozen plasma and packed cell ratios when..., Weiniger [/bib_ref]. The overall certainty of evidence was very low for all outcomes for these groups, with limitations due to study design and imprecision. High ratio transfusion may result in more plasma transfused (MD 4.15 units, 95% CI 0.28 to 8.02), with no difference in platelets (MD 2.92, 95% CI − 2.52 to 8.36) or PRBCs (0.49, 95% CI − 2.55 to 3.52), though certainty of evidence is very low. Although the large reduction in mortality with the use of higher ratios seen in observational studies is more modest (and only seen for early death due to exsanguination) and less precise in the RCTs, it is reassuring that the direction and magnitude of the effects are similar, showing a reduction in early and late mortality with highration transfusion strategies. Additionally, the improved hemostasis demonstrated in the PROPPR trialprovides a sensible mechanism by which high-ratio transfusion could prevent deaths, this could be driven by the higher number of platelets received. Very few undesirable clinical effects were seen leading the panel to determine that even if of uncertain magnitude, the desirable effects likely outweigh the undesirable effects. It should be noted that few undesirable clinical effects were seen, the investigators did not seek to explore these at the initiation of the study. Due to the lack of certainty for many outcomes, along with the resource implications for increased use of plasma and platelets, the panel chose to make a conditional recommendation for fixed, high-ratio transfusion in trauma patients with massive bleeding. The panel decided on the basis of the limited existing evidence that no recommendation for or against the use of fixed high-ratio transfusion could be made outside of the trauma setting, especially given potential differences in pathophysiology and coagulopathy compared to nontraumatic bleeding, and the resource implications of increased plasma and platelet transfusions. ## Implementation issues The PROPPRand Nascimento [bib_ref] Effect of a fixed-ratio (1:1:1) transfusion protocol versus laboratory-results-guided transfusion in patients..., Nascimento [/bib_ref] studies compared high RBC: plasma:platelets ratios 1:1:1 transfusion ratios to a low ratio of 2:1:1, or transfusion guided by coagulation testing. If a fixed high-ratio transfusion approach is used, the 1:1:1 ratio is the most reasonable approach to initiate empiric transfusion when massive hemorrhage is suspected. Although the panel chose not to make a recommendation regarding fixed-dose transfusion ratios outside of the setting of trauma, many centers have developed massive transfusion protocols to cover all clinical scenarios, based upon extrapolation from the trauma literature. While the TF judged that the existing evidence does not support high-ratio transfusion outside of trauma, there may be important clinical impacts from the use of standardized massive transfusion protocols, beyond the effects of altered transfusion ratios alone, such as having a coordinated and efficient response to acute bleeding [bib_ref] The effect of massive transfusion protocol implementation on the survival of trauma..., Consunji [/bib_ref]. ## Platelets ## Recommendation We make no recommendation regarding the use of cryopreserved or cold-stored platelets in bleeding patients with massive or non-massive hemorrhage (No recommendation, very low certainty of evidence). ## Evidence summary There is little evidence regarding the use of cryopreserved or cold-stored platelets for the treatment of hemorrhage in comparison to conventionally stored (room temperature, 20-24 °C), "standard" platelets. We identified two small studies, one comparing cryopreserved platelets to standard platelets and one comparing cold-stored platelets to standard platelets. The first study was a single center non-randomized observational study of standard (fresh apheresis) platelets and cryopreserved platelets (frozen at −80 °C and later reconstituted in thawed plasma) in a broad set of hemorrhaging patients [bib_ref] The use of cryopreserved platelets in the treatment of polytraumatic patients and..., Bohonek [/bib_ref]. Multiple clinical outcomes were evaluated, including 30-day survival, overall blood product use, TXA and fibrinogen concentrate use, and adverse events. There was no appreciable difference in 30-day mortality (RR 1.26, 95% CI 0.41-3.88; RD 5%, 95% CI − 11.2 to 5.49; very low certainty) or other outcomes. The second study was a single center two-stage pilot RCT of the use of cold-stored (2-6 °C) platelets adult cardiothoracic surgery patients; the first stage utilized platelets stored in the cold for up to 7 days, while the second stage utilized those stored in cold for 8-14 days [bib_ref] Apelseth TO (2020) A pilot trial of platelets stored cold versus at..., Strandenes [/bib_ref]. The primary outcome reported was the difference in median blood loss (as measured by chest drain output): the difference in median blood loss between room temperature and cold-stored up to 7 days was − 216 ml (95% CI − 465.7 to 33.68, very low certainty); the difference between room temperature and cold-stored for 8-14 days was 986 mL (95% CI − 296.13 to 2268.1, very low certainty). Secondary outcomes (total blood usage, adverse events, ICU length of stay, mortality) were comparable among those receiving cold-stored and standard platelets, but the number of events was very small in this pilot study. ## Justification Despite similarities in nomenclature, cryopreserved and cold-stored platelets are dissimilar blood products, and the rationale for their preparation and use equally dissimilar. Cryopreserved platelets are intended to have a substantially longer shelf-life than standard apheresis platelets (years versus days), thus reducing potential limitations in the platelet supply and providing products where and when standard platelets are not available. Cold-stored or cryo-stored platelets, on the other hand, have potentially longer shelf-lives than standard units and, based on in vitro and preliminary clinical studies, may be more hemostatically active than their room-temperature counterparts. The TF identified two published clinical studies on the use of these products compared to standard platelets, and despite the fact that each study did not demonstrate results unfavorable to cryopreserved or sold-stored platelets, both had sample sizes that were too small to provide anything beyond a very low degree of certainty in their results. Therefore, while both cryopreserved and cold-stored platelets are theoretically appealing, it was judged that there was insufficient evidence to make a recommendation for or against their use in the bleeding patients. ## Prothrombin complex concentrate and plasma ## Recommendation We make no recommendation for the use of PCC versus plasma alone in massively bleeding patients due to very low certainty of evidence from observational studies only (No recommendation, very low certainty of evidence). ## Evidence summary For all patient populations, only observational studies were included in the analysis [bib_ref] Use of prothrombin complex concentrate for excessive bleeding after cardiac surgery, Arnekian [/bib_ref] [bib_ref] Comparative analysis of prothrombin complex concentrate and fresh frozen plasma in coronary..., Biancari [/bib_ref] [bib_ref] Safety and efficacy of prothrombin complex concentrate as first-line treatment in bleeding..., Cappabianca [/bib_ref] [bib_ref] Use of prothrombin complex concentrate for management of coagulopathy after cardiac surgery:..., Fitzgerald [/bib_ref] [bib_ref] An exploratory cohort study comparing prothrombin complex concentrate and fresh frozen plasma..., Ortmann [/bib_ref]. Thereby, risk of bias is high, most importantly related to a mismatch in disease severity. For cardiac surgery, none of the relevant patient outcomes differed between arms. There is a reduction in RBC transfusions in favour of the PCC arm, but chest tube output was not different. For trauma, pooling of data suggests a decrease in mortality, but this was found in a single study only. Of note, all trauma studies reported a decrease in transfusion requirements in the PCC arm, which is congruent with a mortality benefit. However, there were considerable differences in the comparator arms, hampering any recommendation. For liver transplant and TBI, there was insufficient data. Taken together, there is insufficient data on efficacy and safety of PCC in all categories of bleeding patients. With the lack of evidence and concern for safety, PCC use should be reserved for clinical trials. ## Justification There was no clear signal of harm, in particular no increase in thromboembolic events in the PCC arm; however, this is based on very low certainty of evidence. Thereby, we do not recommend against the use of PCC. However, it is not clear how robust the data were gathered, hampering the weighing of benefit and harm. Other concerns that preclude a recommendation to use PCC relate to cost-effectiveness and to a lack of knowledge on potential conflict of interest related to funding sources of the included studies. ## Research priorities The TF rated optimal management of massive bleeding as a clear priority. The very low level of evidence of benefit across all patient populations as well as the absence of harm of PCC, point towards a strong research priority assessing the efficacy and safety of the use of PCC in the treatment of bleeding. ## Fibrinogen ## Recommendation We make no recommendation regarding the use of early empiric fibrinogen replacement in critically ill patients with massive hemorrhage due to trauma (No recommendation, low certainty evidence). ## Evidence summary In patients with massive bleeding due to trauma, it is unclear whether or not early, empiric fibrinogen administration is beneficial, compared to a strategy of fibrinogen replacement once hypofibrinogenemia is documented. The 5 RCTs [bib_ref] The effect of fibrinogen concentrate and fresh frozen plasma on the outcome..., Akbari [/bib_ref] [bib_ref] Early fibrinogen concentrate therapy for major haemorrhage in trauma (E-FIT 1): results..., Curry [/bib_ref] [bib_ref] Reversal of trauma-induced coagulopathy using first-line coagulation factor concentrates or fresh frozen..., Innerhofer [/bib_ref] [bib_ref] Fibrinogen in the initial resuscitation of severe trauma (FiiRST): a randomized feasibility..., Nascimento [/bib_ref] identified are small, with inconsistent and imprecise impact upon overall mortality (RR 1.02, 95% CI 0.33-3.11; RD 0.3%, 95% CI − 10.3 to 32.6, low certainty) and deaths due to hemorrhage (RR 0.77, 95% CI 0.27-2.18; RD − 2.3%, 95% CI − 7.4 to 12, low certainty). The impact upon other patient outcomes, including transfusion requirements are similarly unclear, without any clear signal for harm nor benefit. ## Justification While observational studies demonstrate a relation between hypofibrinogenemia and coagulopathy as well as with adverse outcome of bleeding due to trauma [bib_ref] Early coagulopathy in trauma patients: an on-scene and hospital admission study, Floccard [/bib_ref] [bib_ref] Impact of fibrinogen levels on outcomes after acute injury in patients requiring..., Inaba [/bib_ref] [bib_ref] ) Prevalence, predictors and outcome of hypofibrinogenaemia in trauma: a multicentre observational..., Hagemo [/bib_ref] , thus providing a strong theoretical rationale for supplementation of fibrinogen during bleeding, clinical evidence for early fibrinogen supplementation remains unclear. The existing RCTs demonstrate that it is feasible to increase fibrinogen levels and FIBTEM values with fibrinogen concentrates, suggest that fibrinogen may reduce transfusion needs in patients with a low fibrinogen level, but the impact of an early/empiric fibrinogen replacement strategy compared to one guided by coagulation testing remains unclear. Similarly, the ideal, fibrinogen dose and target level are not clear. Observational studies in trauma suggest a relation with low levels and mortality; conversely a possible association between higher fibrinogen levels and mortality [bib_ref] ) Prevalence, predictors and outcome of hypofibrinogenaemia in trauma: a multicentre observational..., Hagemo [/bib_ref] as well as with thrombosis [bib_ref] The impact of blood product ratio and procoagulant therapy on the development..., Wirtz [/bib_ref]. More evidence is need regarding empirical and lab-based supplementation before a recommendation for or against early fibrinogen can be made; at the present time, either approach is justifiable on theoretical grounds. ## Implementation issues If a fibrinogen-based strategy is chosen, studies in trauma suggest that this would confer the greatest benefit in those with low fibrinogen lab values; however, this threshold may be different in other populations; thus, if an early fibrinogen replacement strategy is used, it would ideally incorporate rapid laboratory testing to guide clinicians on when empiric fibrinogen should not be used. ## Point of care testing ## Recommendation We suggest for either for viscoelastic or conventional coagulation assays to guide transfusions in massively bleeding trauma critically ill patients (Conditional recommendation, low quality of evidence). For evidence summary and justifications, please see below section on point of care testing. ## Part 2: transfusion support in non-massively bleeding critically ill adults ## Rbc transfusion ## Recommendation In patients with non-massive bleeding after vascular surgery, we suggest restrictive (7.5-8 g/ d/L) red blood cell transfusion threshold (Conditional recommendation, low certainty). ## Evidence summary A single RCT [bib_ref] Low vs high hemoglobin trigger for transfusion in vascular surgery: a randomized..., Moller [/bib_ref] of patients undergoing vascular surgery evaluated a restrictive (8 g/dL) vs. liberal ( ## Implementation issues The restrictive threshold suggested by the TF includes a slightly higher range than that recommended for most populations in part 1 of the guideline, including the recommendation for a restrictive transfusion threshold of 7.5-8 g/dL recommended for patients undergoing cardiac surgery, a population of similar age and with similar vascular comorbidities. This difference reflects the thresholds studied in the available clinical trials, but also reflects the significant cardiovascular comorbidities in this patient population, and clinical uncertainty given the limited direct evidence available to guide practice. As a result, there may remain some variability in how clinicians implement this restrictive strategy, based upon the volume of bleeding, ease of definitive hemorrhage management, presence of active cardiac disease, and patient symptoms. ## Recommendation In patients with non-massive postpartum hemorrhage, we suggest restrictive transfusion, guided by presence of shock and symptoms potentially attributable to anemia (e.g. dyspnea, syncope, tachycardia, angina, neurological symptoms) or hemoglobin < 6 g/dL, rather than at a liberal target hemoglobin of 9 g/dL (Conditional recommendation, low certainty). ## Evidence summary A single randomized controlled trialof anemic postpartum patients with a hemoglobin (Hb) of 49-79 g/L found that that a restrictive red cell transfusion strategy guided by patient symptoms compared with liberal transfusion target (Hb > 89 g/L) may result in no difference in terms of quality of life, measured by SF-36 questionnaire (MD 0.1, 95% CI − 3.5 to 3.3, low certainty), incidence of venous thrombosis (RR 0.99, 95% CI 0.14 -6.97, low certainty), post-transfusion sepsis or infection (RR 1.08, 95% CI 0.62-1.87, low certainty), or transfusion reactions (RR 0.14, 95% CI 0.01-2.72, very low certainty). There were moderate resource savings associated with reducing blood transfusion, including reduced mean number of transfusions (MD 2 units) and mean cost reduction of € 249 in the restrictive threshold arm. Evidence related to quality of life, although of critical importance in this particular cohort of patients, had to be rated as low certainty due to the lack of blinding at the time of assessment of the SF-36 questionnaire. Imprecision related to the reporting of post-transfusion sepsis and hospital-associated venous thromboembolism resulted in a low level of certainty in the pooled effects, while the number of transfusion reactions was very small, resulting in a very low level of certainty for very serious imprecision. Given the lack of clear evidence that liberal transfusion improves outcomes, including quality of life, and the increased use of blood products required, the panel chose to issue a conditional recommendation for restrictive transfusion for symptomatic patients only(e.g. dyspnea, syncope, tachycardia, angina, neurological symptoms), along with a lower asymptomatic limit of 6 g/dL Hb to ensure 'buffer' in the event of unrecognized ongoing hemorrhage. ## Implementation issues Evidence in this setting is limited to a single trial, creating some concerns around the acceptability of a restrictive threshold for RBC transfusion, in particular whether there is a lower limit. In patients with minor hemorrhage, no symptoms, the decision to transfusion can be discussed with the patient, as preferences may vary. The TF suggested a restrictive transfusion threshold which is consistent with guidance from other societies, including the Royal College of Obstetricians and Gynaecologists [bib_ref] Book blood transfusions in obstetrics, Green [/bib_ref] which adopt both clinical and hematological criteria to guide the decision to perform blood transfusion. In patients with severe shock, uncontrolled bleeding a higher threshold may be considered, anticipating ongoing blood loss. ## Recommendation In patients with non-massive gastrointestinal bleeding, we suggest restrictive (7 g/dL) transfusion vs. liberal (9 g/dL) red blood cell transfusion threshold (Conditional recommendation, moderate certainty). ## Evidence summary A total of four RCTs [bib_ref] Transfusion strategies for acute upper gastrointestinal bleeding, Villanueva [/bib_ref] [bib_ref] Effect of early blood transfusion on gastrointestinal hemorrhage, Blair [/bib_ref] [bib_ref] Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a..., Jairath [/bib_ref] [bib_ref] Acute anemia in high digestive hemorrhage. Margins of secruity for their handling..., Villarejo [/bib_ref] ## Justification The certainty of evidence for rebleeding, hospital length of stay, mean number of transfusions and proportion of patients receiving transfusion and mortality, stroke, volume overload consisted of moderate certainty of evidence. In comparison, there was low certainty of evidence for quality of life, myocardial infarction, acute kidney injury and transfusion reactions. Evidence was rated down for imprecision due to the low event rate, target sample size not met, and wide confidence interval. Overall, gastrointestinal (GI) bleeding patients, the panel had moderate certainty that a restrictive transfusion strategy is safe, and possibly results in improved outcomes, with fewer resources. ## Implementation issues There are no significant implementation considerations as the studies included those with gastrointestinal and portal hypertensive bleeding. ## Platelets ## Recommendation We make no recommendation for the use of a restrictive vs a liberal platelet transfusion threshold in non-massively bleeding patients with thrombocytopenia (No recommendation, very low certainty evidence). ## Evidence summary We identified only one retrospective cohort study examining platelet transfusion in thrombocytopenic patients who had intracranial hemorrhage (ICH) [bib_ref] Aspirin response test role in platelet transfusion following intracerebral hemorrhage, Engel-Haber [/bib_ref] and had a platelet transfusion. The study had two cohorts (1) participants with ICH with reduced platelet activity based on the aspirin response test who received platelets (2) participants with ICH who received platelets. Each cohort was compared to aspirin responders and participants with ICH who did not receive platelets; outcomes examined included hematoma volume and expansion. There was no effect in hematoma size (RR 0.71, 95% CI 0.34-1.47) or expansion (RR 1.44, 95% CI 0.92-2.24, very low certainty) [bib_ref] Aspirin response test role in platelet transfusion following intracerebral hemorrhage, Engel-Haber [/bib_ref]. The evidence is of very low certainty due to the absence of studies evaluating platelet transfusion thresholds in bleeding patients with thrombocytopenia. The clinical effects and resource implications of higher vs lower platelet transfusion thresholds in bleeding patients are unclear. As a result, the TF did not make a specific recommendation of transfusion thresholds for patients with non-massive bleeding. ## Implementation issues We make no recommendation for the use of a restrictive or a liberal platelet transfusion threshold in bleeding patients with thrombocytopenia, and as such either strategy could be considered based on individual patient characteristics. However, recommendations made in Part 1 of the guidelines set lower limits after which prophylactic platelet transfusion should be considered, irrespective of bleeding. ## Recommendation We suggest using a restrictive platelet transfusion strategy (no transfusion) in patients with intracranial hemorrhage (spontaneous or traumatic intracerebral hemorrhage) who are on antiplatelet therapy (Conditional recommendation, moderate certainty evidence). We make no recommendation for the use of a restrictive (no transfusion) vs liberal platelet transfusion strategy in critically ill patients with non-massive bleeding who are on antiplatelet therapy (No recommendation, very low certainty of evidence). ## Evidence summary Two randomized trials have investigated platelet transfusion in patients on antiplatelet therapy with spontaneous intracranial hemorrhage (ICH), neither finding a benefit with platelet transfusion [bib_ref] Aspirin response test role in platelet transfusion following intracerebral hemorrhage, Engel-Haber [/bib_ref] [bib_ref] Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral..., Baharoglu [/bib_ref].The PATCH trial [bib_ref] Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral..., Baharoglu [/bib_ref] included 190 non-thrombocytopenic patients with ICH, with a Glasgow Coma Scale (GCS) score > 8 who had received antiplatelet medications. The composite endpoint of death or dependence at 3 months was higher in patients receiving platelet transfusion than in those who did not (RR 2.05, 95% CI 1.18-3.56, p = 0.014), there was no significant difference in the individual outcomes including mortality. The second RCT compared postsurgical hemorrhage in patients with antiplatelet therapy and who underwent craniotomy for acute ICH, finding liberal platelet transfusion (in comparison to restrictive platelet transfusion) was not associated with a difference in post-surgical bleeding volume. Overall, the pooled evidence from these two RCTs, suggests there is no difference in mortality at 3 months (RR 0.71, 95% CI 0.44-1.14) overall mortality (RR 0.84, 95% CI 0.58-1.22), disability at 3 months or by the ADL, or bleeding volume. We identified only one retrospective single center study comparing platelet transfusion strategies in patients on antiplatelet agents with non-massive bleeding for ICH [bib_ref] The effect of platelet and desmopressin administration on early radiographic progression of..., Kim [/bib_ref]. This was a case control study in patients with GI bleeding, patients who did not receive platelet transfusion had a lower mortality (RR 0.21, 95% CI 0.06-0.73), less cardiac event (RR 0.55, 95% CI 0.31-0.98) and lower recurrent bleeding (RR 0.71, 95% CI 0.56-0.9). ## Justification Antiplatelet therapy effect lasts for up to 10 days leading to an increase in hemorrhage occurrence and severity. Observational studies have reported a poorer outcome in patients with ICH receiving antiplatelet therapy. Transfusion of platelets in this setting might offset antiplatelet therapy effect, improve hemostasis and outcome. However, the two existing RCTs [bib_ref] Aspirin response test role in platelet transfusion following intracerebral hemorrhage, Engel-Haber [/bib_ref] [bib_ref] Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral..., Baharoglu [/bib_ref] reported similar, or possibly worse outcomes in patients receiving platelet transfusions. Given the lack of evidence for any desirable effects, the possible adverse effects related to platelet transfusion, the cost of transfusion and the fact that platelets are a limited resource, the panel made a conditional recommendation to not administer platelets in patients on antiplatelet agents with ICH. The PATCH Trial [bib_ref] Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral..., Baharoglu [/bib_ref] did included patients with ICH who have a GCS > 8 which may limit the generalizability to ICU patients. There is even less evidence to guide platelet transfusion decisions in critically ill patients with non-massive bleeding other than ICH and on antiplatelet agents. While patients on antiplatelet therapy are at higher risk of GI bleeding and higher risk of severe bleeding and recurrent bleeding. However, cease of antiplatelet therapy or platelet transfusion might expose patients to major cardiac events including myocardial infarction. The benefit of one or the other platelet transfusion strategy might be impacted by the source of bleeding (ulcerous, variceal upper GI bleeding, colonic). Given the substantial uncertainties, we did not make a recommendation for or against platelet transfusion for critically ill patients on antiplatelet agents with bleeding other than ICH. ## Implementation issues Given the lack of evidence, decisions about transfusing platelets in patients on antiplatelet agents need to be based upon individual considerations, including the severity and location of bleeding, consideration of risks of transfusion, and availability of blood products. Enthusiasm for platelet transfusion should be tempered given the lack of benefit in ICH, in which even small difference in hemorrhage volumes would be expected to have an impact upon patient outcome; the benefit in other populations is likely to be even less certain. ## Fibrinogen ## Recommendation We suggest the empiric use of fibrinogen concentrate in critically ill patients with non-massive bleeding after cardiac surgery, using either fixed dose (2-4 g) or titrated to FIBTEM clot firmness, to maintain a fibrinogen level over 1.5 g/dL necessary for clot formation and platelet aggregation, after giving the empiric fibrinogen dose if available [bib_ref] Platelet aggregation: involvement of thrombin and fibrin (ogen), Lisman [/bib_ref] (Conditional recommendation, low certainty of evidence). We make no recommendation regarding the empiric use of fibrinogen concentrate in other critically ill patients with non-massive bleeding (No recommendation, low certainty of evidence). ## Evidence summary We identified six RCTs evaluating the use of fibrinogen in patients with non-massive bleeding after cardiac surgery one comparing fibrinogen to FFP in major vascular surgery, and one comparing fibrinogen concentrate plus FFP to FFP alone in a mixed surgical population [bib_ref] Effect of fibrinogen concentrate on intraoperative blood loss among patients with intraoperative..., Bilecen [/bib_ref] [bib_ref] Exogenous fibrinogen pertains beneficial effects in managing postcardiac surgery bleeding: a randomized..., Esmaeelzadeh [/bib_ref] [bib_ref] Fibrinogen concentrate vs. fresh frozen plasma for the management of coagulopathy during..., Morrison [/bib_ref] [bib_ref] Effects of fibrinogen concentrate as first-line therapy during major aortic replacement surgery:..., Rahe-Meyer [/bib_ref] [bib_ref] Randomized evaluation of fibrinogen vs placebo in complex cardiovascular surgery (REPLACE): a..., Rahe-Meyer [/bib_ref] [bib_ref] Surgical Clinical Outcome RG (2015) Randomized, doubleblinded, placebo-controlled trial of fibrinogen concentrate..., Ranucci [/bib_ref] [bib_ref] Transfusion and hematologic variables after fibrinogen or platelet transfusion in valve replacement..., Tanaka [/bib_ref] In the two small non-cardiac surgery studies, the number of events was small, and overall certainty of evidence was low due to very serious imprecision [bib_ref] Fibrinogen concentrate vs. fresh frozen plasma for the management of coagulopathy during..., Morrison [/bib_ref]. ## Justification The use of fibrinogen in patients with bleeding after cardiac surgery results in reductions in blood loss and use of blood products which are cost-effective; however, impact upon other patient-important outcomes, including mortality, is unclear. The TF determined there was insufficient evidence to provide guidance regarding the use of empiric fibrinogen concentrate in non-massive bleeding outside of the context of cardiac surgery. ## Implementation issues Fibrinogen is vital for the clot formation and platelet aggregation; the dose of fibrinogen varied between studies, ranging between 1 and 4 g, and used varied targets, [bib_ref] Effect of fibrinogen concentrate on intraoperative blood loss among patients with intraoperative..., Bilecen [/bib_ref] FIBTEM clot firmness [bib_ref] Fibrinogen concentrate vs. fresh frozen plasma for the management of coagulopathy during..., Morrison [/bib_ref] [bib_ref] Effects of fibrinogen concentrate as first-line therapy during major aortic replacement surgery:..., Rahe-Meyer [/bib_ref] [bib_ref] Randomized evaluation of fibrinogen vs placebo in complex cardiovascular surgery (REPLACE): a..., Rahe-Meyer [/bib_ref] [bib_ref] Surgical Clinical Outcome RG (2015) Randomized, doubleblinded, placebo-controlled trial of fibrinogen concentrate..., Ranucci [/bib_ref] , or fixed-dose [bib_ref] Exogenous fibrinogen pertains beneficial effects in managing postcardiac surgery bleeding: a randomized..., Esmaeelzadeh [/bib_ref] [bib_ref] Transfusion and hematologic variables after fibrinogen or platelet transfusion in valve replacement..., Tanaka [/bib_ref]. These studies used clinical bleeding as the trigger to initiate administration of fibrinogen concentrate rather than coagulation testing or FIBTEM. Once coagulation test results are available, they can be used alongside clinical assessment of bleeding to guide decisions about further fibrinogen administration. While ideal fibrinogen targets are unclear, it would be reasonable to maintain a fibrinogen level over 1.5 g/dL necessary for clot formation and platelet aggregation, after giving the empiric fibrinogen dose [bib_ref] Platelet aggregation: involvement of thrombin and fibrin (ogen), Lisman [/bib_ref]. Fibrinogen concentrate may not be available in all centers, in which case cryoprecipitate may be a reasonable alternative. While the recent FIBRES trial suggests that outcomes between fibrinogen concentrate and cryoprecipitate are similar in patients with cardiac-surgeryrelated bleeding-related to hypofibrinogenemia [bib_ref] Effect of fibrinogen concentrate vs cryoprecipitate on blood component transfusion after cardiac..., Callum [/bib_ref] , rapid administration of fibrinogen administration in bleeding patients may be more easily achieved, as storage and reconstitution of the product (concentrate) is likely easier from a logistical standpoint compared to cryoprecipitate. ## Plasma ## Recommendation We make no recommendation for a restrictive plasma versus a liberal plasma transfusion strategy for non-massively bleeding patients with or without coagulopathy (No recommendation, low certainty evidence). ## Evidence summary The panel sought evidence comparing liberal/empiric use of plasma to restrictive plasma transfusion, or no transfusion, in non-massively bleeding platelets. One RCT [bib_ref] The effect of fibrinogen concentrate and fresh frozen plasma on the outcome..., Akbari [/bib_ref] was identified that evaluated the use of plasma in 90 blunt trauma (injury severity score > 16) patients who received RBCs transfusion and had a fibrinogen level < 5.88 g/L [bib_ref] The effect of fibrinogen concentrate and fresh frozen plasma on the outcome..., Akbari [/bib_ref]. Patients were randomized to receive: 1) fibrinogen, 2) FFP (2 units), or 3) RBC transfusion alone. This study included non-massively bleeding patients, with a mean RBC transfusion requirement of 2 ± 1.1 (fibrinogen group), 2.7 ± 0.7 (FFP group) and 2.9 ± 0.9 (control group [bib_ref] Lowvolume resuscitation with normal saline is associated with microvascular endothelial dysfunction after..., Torres [/bib_ref] , in rat models of hemorrhagic [bib_ref] Lowvolume resuscitation with normal saline is associated with microvascular endothelial dysfunction after..., Torres [/bib_ref] and septic shock improved survival with FFP compared resuscitation with crystalloids [bib_ref] Plasma resuscitation improved survival in a cecal ligation and puncture rat model..., Chang [/bib_ref] with restoration of EG. ## Justification The use of a liberal plasma transfusion strategy incorporating 2 empiric units of FFP in non-massively bleeding trauma patients did not demonstrate any benefit but did raise the possibility of harm (e.g. sepsis). However, this data is from one small RCT [bib_ref] The effect of fibrinogen concentrate and fresh frozen plasma on the outcome..., Akbari [/bib_ref] and is of low certainty, limited by imprecision and risk of bias. The panel thus made no recommendation for plasma transfusion in patients without massive bleeding, or coagulopathy. ## Point of care vs. conventional coagulation testing ## Recommendation We suggest either viscoelastic testing or conventional coagulation testing to guide transfusions in massive and non-massively bleeding cirrhotic patients, liver transplant patients or critically ill trauma patients (Conditional recommendation, low certainty evidence). ## Evidence summary In massively bleeding cirrhotic patients, based on two RCTs [bib_ref] Thromboelastography-guided blood component use in patients with cirrhosis with nonvariceal bleeding: a..., Kumar [/bib_ref] [bib_ref] Thromboelastography-guided blood product transfusion in cirrhosis patients with variceal bleeding: a randomized..., Rout [/bib_ref] , there was uncertainty as to the effects of the implementation of viscoelastic on mortality (RR 0.82, 95% CI 0.59-1.13, low certainty), rebleeding (RR 0.71, 95% CI 0.47-1.07, very low certainty), transfusion associated cardiac overload (RR 0.48, 95% CI 0.18-1.3, low certainty) and red cell transfusion (RR 1.06, 95% CI 0.67-1.68, low certainty). In these trials, there was evidence that the use of viscoelastic testing may reduce transfusion associated lung injury (RR 0.25, 95% CI 0.11-0.56, low certainty), acute respiratory distress syndrome (RR 0.11, 95% CI 0.01-0.81, low certainty), platelet transfusion (RR 0.14, 95% CI 0.05-0.43, low certainty) and fresh frozen plasma transfusion (RR 0.29, 95% CI 0.11-0.77, low certainty). In massively bleeding liver transplant patients, based on the evidence pooled from a Cochrane Systematic reviewand an observational study [bib_ref] Rotational thromboelastometry or conventional coagulation tests in liver transplantation: comparing blood loss,..., Smart [/bib_ref] , there was uncertainty as to the effects of viscoelastic on mortality (RR 0.67, 95% CI 0.13-3.4, low certainty), red cell transfusion (MD − 12.22, 95% CI − 71.08 to 46.64, very low certainty) and platelet transfusion (MD − 2.8, − 14.92 to 9.32, very low certainty). There was, however, evidence that elastic may result in less blood loss (MD -1.13, 95% CI − 1.85 to − 0.41, very low certainty) and FFP Transfusion (MD − 8.7, 95% CI − 16.3 to − 1.1, very low certainty) in massively bleeding liver transplant patients. In massively bleeding critically ill trauma patients, in a randomised trial [bib_ref] Goaldirected hemostatic resuscitation of trauma-induced coagulopathy: a pragmatic randomized clinical trial comparing..., Gonzalez [/bib_ref] , the use of viscoelastic testing did not result in a significant mortality reduction (RR 0.54, 95% CI 0.29-1.02, very low certainty). ## Justification Even though the positive effects of viscoelastic testing on a limited number of outcomes such as TRALI and ARDS might be moderate (in particular in the cirrhotic population), the limited number of studies, the substantial heterogeneity, the wide confidence intervals, and the imprecision in the estimates, determine the overall low confidence in the certainty of these results. These observations are applicable to all subgroups but are especially true in the case of trauma patients. ## Recommendation We suggest either viscoelastic testing or conventional coagulation testing to guide transfusions in bleeding cardiac surgery patients (Conditional recommendation, very low certainty of evidence). We suggest using either viscoelastic testing or conventional coagulation testing to guide transfusion in extra corporeal membrane oxygenation (ECMO) patients with non-massive bleeding (Conditional recommendation, very low certainty evidence). ## Evidence summary In non-massively bleeding cardiac surgery patients, based on two recent systematic reviews [bib_ref] Viscoelastic blood tests use in adult cardiac surgery: meta-analysis, meta-regression, and trial..., Meco [/bib_ref] [bib_ref] Routine use of viscoelastic blood tests for diagnosis and treatment of coagulopathic..., Serraino [/bib_ref] ## Justification There is uncertainty as to the effects of viscoelastic in non-massively bleeding cardiac surgery patients on clinically important outcomes. Most treatment effects were observed in outcomes that are particularly susceptible to performance bias, are of limited importance to patients, and demonstrated high heterogeneity. Moreover, most studies included in the systematic review [bib_ref] Viscoelastic blood tests use in adult cardiac surgery: meta-analysis, meta-regression, and trial..., Meco [/bib_ref] [bib_ref] Routine use of viscoelastic blood tests for diagnosis and treatment of coagulopathic..., Serraino [/bib_ref] , were at unclear or high risk of bias. Two studies [bib_ref] Diagnostic amd therapeutic medical devices for safer blood management in cardiac surgery:..., Murphy [/bib_ref] [bib_ref] Patient blood management interventions do not lead to important clinical benefits or..., Roman [/bib_ref] , assessed the resource requirements and cost-effectiveness of this technology in the cardiac surgery population suggesting small cost savings over usual care, but substantial uncertainty remains. The single RCT [bib_ref] A pilot randomised controlled trial of a totational thromboelastometry-based algorithm to treat..., Buscher [/bib_ref] in patients undergoing ECMO provides only very low certainty evidence for the differences between viscoelastic testing and conventional coagulation testing. ## Implementation issues Despite the very low certainty provided by the available evidence, many centers have adopted the use of viscoelastic testing to guide transfusions, due to perceived efficiency, specificity, and rapidity of testing. However, for centers without viscoelastic testing, resource considerations and staff education needs, would likely play a role in deciding whether it should be adopted, in light of the limited evidence available regarding its impact upon patient outcomes and blood product use. ## Part 3. tranexamic acid (txa) in bleeding critically ill adults ## Txa in patients with traumatic intracranial hemorrhage recommendation We recommend the use of early (< 3 h from trauma) TXA in critically ill patients with bleeding or suspected bleeding due to trauma (Strong recommendation, high certainty). ## Evidence summary The landmark multi-centre CRASH-2 RCT demonstrated that administration of TXA results in a reduction of death (RR 0.91, 95% CI 0.85-0.97; RD − 1.4%, 95% CI − 2.4 to − 0.5, high certainty), with no difference in venous thrombosis, stroke, myocardial infarction or need for surgical intervention [bib_ref] Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion..., Shakur [/bib_ref]. The risk of seizures was not reported, though reassuringly no increase in seizures was noted in the CRASH-3 study, which evaluated the use of TXA in trauma patients with isolated traumatic brain injury [bib_ref] Effects of tranexamic acid on death, disability, vascular occlusive events and other..., Collaborators [/bib_ref]. ## Justification Compared to placebo, TXA results in small but clinically meaningful reductions in bleeding death and overall mortality, with trivial undesirable effects. TXA is inexpensive, likely cost-effective, [bib_ref] Cost-effectiveness analysis of administering tranexamic acid to bleeding trauma patients using evidence..., Guerriero [/bib_ref] acceptable, and feasible to implement in most settings. ## Implementation issues The dose of TXA given in CRASH-2 was a loading dose of1 g IV over 10 min, followed by 1 g IV over 8 h. While some centers may use point of care testing (e.g. TEG/ ROTEM) to guide management of bleeding patients, the task force recommends early empiric use of the loading dose of TXA prior to such testing as point of care measurements have varying sensitivity for identifying hyperfibrinolysis [bib_ref] The incidence and magnitude of fibrinolytic activation in trauma patients, Raza [/bib_ref] and earlier administration of TXA may be more effective at reducing mortality [bib_ref] The importance of early treatment with tranexamic acid in bleeding trauma patients:..., Collaborators [/bib_ref]. However, to date there is limited evidence to guide the use of very early, prehospital administration of TXA [bib_ref] Prehospital tranexamic acid: what is the current evidence?, Napolitano [/bib_ref]. ## Recommendation We suggest the use of TXA in critically ill patients with acute traumatic brain injury and bleeding due to trauma (Conditional recommendation, moderate certainty). ## Evidence summary A recent systematic review identified 9 RCTs which reported all-cause mortality, including unpublished data from CRASH-3, reporting that TXA does not reduce allcause mortality (RR 0.95, 95% CI 0.88-1.02; RD − 1%; 95% CI − 2.5 to 0.4%, moderate certainty) or disability as assessed with the disability rating scale (MD − 0.18, 95% CI − 0.43 to 0.08, moderate certainty [bib_ref] Efficacy and safety of tranexamic acid in acute traumatic brain injury: a..., Lawati [/bib_ref]. Data from the largest trial, CRASH-3, suggests that TXA may reduce head-injury associated death when excluding patients with severe traumatic brain injury (TBI) whom are unlikely to survive with or without treatment (Glasgow Coma Score of 3 or bilateral unreactive pupils at baseline) (RR 0.89, 95% CI 0.8 to 1; RD -1.5 95% CI -2.8 to 0.4%). There appears to beno effect on risk of stroke, MI, venous thromboembolism, sepsis, surgical intervention, or seizure. ## Justification The use of TXA may not result in a reduction in mortality or disability in all patients, but there may be a reduction in head-injury-related mortality in patients who have mild to moderate TBI, as well as a reduction of progression of intracranial hemorrhage. Although the clinical relevance of these findings is unclear, most patients would likely accept TXA, given the demonstrated safety profile of TXA in this population, the possibility of concomitant non-head injuries for which TXA is indicated as per the previous recommendation, and the low cost and acceptability and feasibility of the intervention. Given the lack of certainty around patient-important effects, the panel chose to make a conditional recommendation for the use of TXA in this population. ## Implementation issues All studies used similar dosing to CRASH-2, with 1 g IV TXA loading dose followed by an infusion of 1 g IV maintenance infusion over a longer period of time. Some patients with TBI have other associated traumatic injuries; this recommendation supports the use of TXA in trauma with or without TBI, while the severity and nature of injuries is being assessed. As in the general trauma population, there is a suggestion that if TXA is given, it is most likely to be effective when given early, within 3 h although the prehospital may not be more effective [bib_ref] Effects of tranexamic acid on death, disability, vascular occlusive events and other..., Collaborators [/bib_ref] [bib_ref] Effect of out-of-hospital tranexamic acid vs placebo on 6-month functional neurologic outcomes..., Rowell [/bib_ref]. While some centers may use viscoelastic testing to guide interventions, early empiric use of TXA may still be beneficial, as point of care results may not be sensitive for hyperfibrinolysis [bib_ref] The incidence and magnitude of fibrinolytic activation in trauma patients, Raza [/bib_ref]. ## Recommendation We make no recommendation regarding the use of TXA in critically ill patients with subarachnoid hemorrhage (No recommendation, low certainty evidence). ## Evidence summary A number of trials have evaluated anti-fibrinolytic therapies in patients with aneurysmal subarachnoid hemorrhage (SAH), 10 of which evaluated IV TXA [bib_ref] Treatment of subarachnoid hemorrhage from ruptured intracranial aneurysm with tranexamic acid: a..., Chandra [/bib_ref] [bib_ref] Antifibrinolysis with tranexamic acid in aneurysmal subarachnoid hemorrhage: a consecutive controlled clinical..., Fodstad [/bib_ref] [bib_ref] Immediate administration of tranexamic acid and reduced incidence of early rebleeding after..., Hillman [/bib_ref] [bib_ref] Tranexamic acid in subarachnoid hemorrhage. A double-blind study, Kaste [/bib_ref] [bib_ref] Prolonged antifibrinolysis: an effective non-surgical treatment for ruptured intracranial aneurysms, Rs [/bib_ref] [bib_ref] Benefits and risks of antifibrinolytic therapy in the management of ruptured intracranial..., Tsementzis [/bib_ref] [bib_ref] Effect of tranexamic acid on rebleeding after subarachnoid hemorrhage: a double-blind controlled..., Van Rossum [/bib_ref] [bib_ref] Antifibrinolytic treatment in subarachnoid hemorrhage, Vermeulen [/bib_ref]. These studies demonstrated no change in mortality (RR 1.01, 95% CI 0.88-1.16;RD − 0.3%, 95% CI − 3.2 to 4.2%, moderate certainty) or poor functional outcome (RR 1.05, 95% CI 0.95-1.15; RD − 0.4%, 95% CI − 1.9 to 5.8, low certainty), but a reduced risk of rebleeding (RR 0.6, 95% CI 0.44-0.8; RD − 7.8%, 95% CI − 11 to − 3.9, moderate certainty), offset by an increased risk of stroke (RR 1.29, 95% CI 1.01 to 1.67; RD 6.1%, 0.2% to 14.1%, low certainty). Only the recent ULTRA trial reported rates of venous thrombosis, which were rare but similar between groups. Most trials were several decades old, with only the three most recent trials evaluated TXA within clinical context with the use of calcium channel blockers and endovascular coiling of aneurysms, though results appear generally consistent between older and newer trials [bib_ref] Immediate administration of tranexamic acid and reduced incidence of early rebleeding after..., Hillman [/bib_ref]. ## Justification The panel did not make a recommendation regarding the use of TXA in SAH. The effects of TXA appear mixed, with a decreased risk of rebleeding, and a similar magnitude of increased stroke (both of which are themselves of uncertain clinical relevance in the context of these older studies in which diagnostic procedures may vary). Overall, there appears to be little impact upon mortality and the risk of poor functional outcome, although the evidence is insufficiently precise to rule out a clinically meaningful effect. The panel judged the available evidence as insufficient to make a recommendation, as the values and preferences of patients and clinicians regarding the risk of rebleeding vs. stroke may vary, such as when securement of aneurysm may be delayed. ## Implementation issues Given the uncertainty of the evidence and variations in local practice, decisions around the use of TXA in the population need be based upon individual factors, such as clinician concerns around risk of stroke vs. rebleeding, and time until definitive securement of aneurysm. Widespread use of TXA in this setting should await further evidence. TXA in patients with non-traumatic intracranial hemorrhage. ## Recommendation We make no recommendation regarding the use of TXA in critically ill patients non-traumatic intracranial hemorrhage (No recommendation, moderate certainty). ## Evidence summary Three RCTs have evaluated IV TXA in non-traumatic ICH, the majority of data from the large TICH-2 trial which evaluated IV TXA in the acute phase of patients with ICH [bib_ref] Tranexamic acid for spontaneous intracerebral hemorrhage: a randomized controlled pilot trial (ISRCTN50867461), Sprigg [/bib_ref]. These studies demonstrate no change in mortality (RR 1.02, 95% CI 0.88-1.19; RD 0.4%, 95% CI − 2.5 to 4, moderate certainty), poor functional outcome (RR 0.98, 95% CI 0.93-1.04; RD − 1.4%, 95% CI − 4.9 to 2.8; moderate certainty). Other outcomes, including stroke, myocardial infarction, venous thromboembolism, seizure, and length of stay were also similar, although certainty was only moderate for all outcomes, limited my imprecision. ## Justification While the quality of evidence for critical outcomes was moderate, the point effect and confidence intervals for TXA did not indicate either benefit or harm in patients with ICH. There is thus moderate evidence of no effect, but the use or non-use of TXA in this setting would be reasonable pending further evidence. The panel thus chose to make no recommendation for or against the use of TXA compared to no TXA in this setting. ## Implementation issues Further evidence is required before changes in practice regarding TXA use should be considered. Decisions around the use of TXA should recognize that the effects of TXA in this population remain uncertain. Transfusion ratios in massive bleeding More high-quality, randomized data of massive transfusion protocols including high-ratio transfusion vs. low-ratio transfusion are required in trauma and non-trauma patients with massive bleeding More RCT data on impacts of massive transfusion protocols guided by empiric transfusion ratios vs. guided by point of care testing Cold-stored platelets RCTs involving conventional and cold-stored platelets are needed in patient populations where rapid control of hemorrhage is vital, such as trauma-associated or obstetric hemorrhage. Key outcomes include clinical and blood product use, effects on measured hemostatic parameters, and patient-important outcomes conventional coagulation testing, with and without fixed ratio blood product transfusions are needed to determine whether thomboelastography improves patient outcomes and impacts blood product use in critically ill patients TXA in trauma and traumatic brain injury More research is required to identify subgroups most likely to benefit from the use of TXA and the role of individualized patient use guided by thromboelastometry and conventional coagulation tests TXA in subarachnoid hemorrhage More research is needed on the role of TXA in specific patient populations, eg. those with delayed or challenging aneurysm securement ## Recommendation We suggest not using high-dose IV TXA in critically ill patients with gastrointestinal bleeding (Conditional recommendation, high certainty evidence). We make no recommendation regarding the use of low-dose IV TXA or enteral TXA in critically ill patients with gastrointestinal bleeding (No recommendation, moderate certainty evidence). ## Evidence summary Five studies, including the large HALT-IT trial [bib_ref] Effects of a high-dose 24-h infusion of tranexamic acid on death and..., Collaborators [/bib_ref] ## Justification There is high certainty of harms with use of high-dose IV TXA and no clear benefit with its general use in gastrointestinal hemorrhage. Though the subgroup analysis suggests low-dose/enteral TXA may be helpful, the included studies are small and results imprecise; furthermore data on potential harms (DVT, PE, seizure) were not reported in most of these trials. While the quality of evidence for critical outcomes was moderate, the panel judged that the lack of data on the potential adverse effects of TXA in GI bleeding, especially in light of the harms seen in the HALT-IT trial, were insufficient to make a recommendation for or against the use of lower dose or enteral TXA until more data are available. ## Implementation issues There may be a role for "rescue" TXA in patients with massive exsanguination or refractory hemorrhage, for whom the risk of death due to bleeding is very high unless hemostasis is achieved, as the risk of increased seizures and VTE would be less important. If used as rescue, lower doses than those used in the HALT-IT trial may reduce the risk of these complications, as these were not observed in trials evaluating lower doses of IV TXA (< 4 g IV/24 h). ## Recommendation We suggest the early use of TXA in critically ill patients with postpartum hemorrhage (Conditional recommendation, high certainty). ## Evidence summary Two RCTs evaluating the use of TXA for postpartum hemorrhage [bib_ref] Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities..., Collaborators [/bib_ref] [bib_ref] High-dose tranexamic acid reduces blood loss in postpartum haemorrhage, Ducloy-Bouthors [/bib_ref] found a small reduction in risk of death from hemorrhage (RR 0.81, 95% CI 0.65-1; RD − 0.4%, 95% CI − 0.7 to 0, high certainty) with no effect on overall mortality (RR 0.88, 95% CI 0.54-1.05; RD − 0.3%, 95% CI − 0.7 to 0.1; high certainty) or hysterectomy (RR 0.93, 95% CI 0.46-1.89; RD − 0.2%, 95% CI − 1.9 to 3.1; high certainty). ## Justification TXA may reduce deaths due to hemorrhage in critically ill patients with postpartum hemorrhage, without an impact on all-cause mortality. The absolute mortality effect of TXA in patients with post partum heamorrhage (PPH) is small (< 1%), but may be higher in the subset of women who are critically ill. Despite the very small size of the effect, given the young age and generally high baseline health status of these patients, even a small potential reduction in mortality is desirable, especially given the high certainty that TXA has minimal harmful effects, and its low cost and high acceptability by clinicians and patients. ## Implementation issues Low-dose TXA, 1 g IV, should be given as early as possible if there are concerns that the patient may have significant PPH or signs of shock, as data from WOMAN indicate that TXA is most likely to be helpful within 3 h of onset of bleeding [bib_ref] Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities..., Collaborators [/bib_ref]. ## Recommendation We recommend the use of TXA in critically ill patients with bleeding post-cardiac surgery (Strong recommendation, high certainty). ## Evidence summary Numerous RCTs have evaluated dosing strategies of TXA, summarized in a recent systematic review, including the largest trial by Myles et al. [bib_ref] Tranexamic acid in patients undergoing coronary-artery surgery, Myles [/bib_ref]. TXA had no effect upon mortality (RR 0.75, 95% CI 0. ## Justification There is high certainty that TXA reduces the volume of bleeding, need for surgery, and transfusion risk in bleeding patients' post-cardiac surgery; the reduced risk of reoperation is likely of major significance to most patients. While there is an increased risk of seizures, this is small (< 1%) and likely dose-dependent, with low incidence if given in low (< 4 g/24 h) doses. The panel judged that almost all patients would trade a reduced risk of reoperation and transfusion for this small increase, especially as the risk is likely smaller when TXA is given in lower doses. ## Implementation issues Given the risk of seizures with higher dose TXA, clinicians should aim to keep cumulative doses below 50 mg/ kg, and exercise caution should be used before given TXA to patients with a known history of seizures and/or renal failure. Clinicians caring for patients with critically ill patients bleeding after cardiac surgery should evaluate the dose and timing of TXA given in the operating room to ensure that higher doses are not given. # Discussion This international guideline provides guidance for clinicians caring for critically ill patients with massive and non-massive bleeding. The taskforce generated 26 clinical practice recommendations (2 strong recommendations, 13 conditional recommendations, 11 no recommendation), and identified 11 PICOs with insufficient evidence to make a recommendation as factors such as clinical effects, certainty of evidence, resource use, variation in patient and clinician values, and acceptability and feasibility of implementation were too varied to result in a consensus recommendation. A summary of recommendations can be found in, and identified research priorities in [fig_ref] Table 2: Research priorities [/fig_ref]. The strengths of this guideline include the breadth of expertise of the TF and rigorous GRADE methodology adherence. However, the guideline is not without limitations. First, the search was completed in September 2019, and ideally would be updated every 2 years. In light of the global pandemic, the completion of the guideline was delayed. Second, our systematic reviews were not registered a priori, as we adopted a rapid systematic review approach common in guideline methodology. Lastly, we did not have patient representation on the TF [fig_ref] Table 3: Ongoing trials of transfusion strategies in critically ill patients PRBC, 3 plasma,... [/fig_ref]. In general, the evidence supporting transfusion practice in patients with massive or non-massive bleeding does not provide high certainty of effects for many outcomes. Current practice is often driven by transfusion thresholds which are based upon physiologic extrapolation and confounded observational evidence. For instance, although there are numerous studies evaluating transfusion ratios in massive hemorrhage, we were only able to identify two RCTs, which demonstrated more modest findings than the observational evidence, and no RCTs evaluating transfusion ratios outside of the trauma population, despite the widespread practice of incorporating highratio transfusion into hospital massive transfusion protocols. Given the large number of lives lost and resources spent caring for critically ill patients with bleeding, there is an urgent need for high-quality evidence to guide clinicians. In addition, many studies evaluated specific subpopulations of critically ill patients, resulting in gaps in areas where the task force did not believe extrapolation # Conclusions This clinical practice guideline provides a summary of evidence and clinical guidance for transfusion in critically ill patients with massive and non-massive bleeding and identifies areas where further research is needed. The Guidelines in Intensive Care Development and Evaluation (GUIDE) group provided methodological support throughout the guideline development process. We also thank Gordon Guyatt for his mentorship. # Declarations ## Conflicts of interest None. ## Open access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the ## Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. [table] Table 2: Research priorities [/table] [table] Table 3: Ongoing trials of transfusion strategies in critically ill patients PRBC, 3 plasma, 1 platelet Noninferiority of coagulopa- [/table]	None	https://link.springer.com/content/pdf/10.1007/s00134-021-06531-x.pdf	None
7fce685855a090baca869d306c637d9371a81fdd	pubmed	Brazilian guidelines for the management of candidiasis – a joint meeting report of three medical societies: Sociedade Brasileira de Infectologia, Sociedade Paulista de Infectologia and Sociedade Brasileira de Medicina Tropical	Brazilian guidelines for the management of candidiasis – a joint meeting report of three medical societies: Sociedade Brasileira de Infectologia, Sociedade Paulista de Infectologia and Sociedade Brasileira de Medicina Tropical Candidemia Treatment Antifungals a b s t r a c t Candida infections account for 80% of all fungal infections in the hospital environment, including bloodstream, urinary tract and surgical site infections. Bloodstream infections are now a major challenge for tertiary hospitals worldwide due to their high prevalence and mortality rates. The incidence of candidemia in tertiary public hospitals in Brazil is approximately 2.5 cases per 1000 hospital admissions. Due to the importance of this infection, the authors provide a review of the diversity of the genus Candida and its clinical relevance, the therapeutic options and discuss the treatment of major infections caused by Candida. Each topography is discussed with regard to epidemiological, clinical and laboratory diagnostic and therapeutic recommendations based on levels of evidence. ଝ This article was originally published in Braz J Infect Dis. 2012;16(Suppl. 1):S1-34. # Introduction ## Importance of genus candida in contemporary medicine Among the fungi of medical interest, yeasts of the genus Candida are of great importance because of the high frequency that they colonize and infect human hosts. Candida species are found in the gastrointestinal tract in 20-80% of healthy adults. Approximately 20-30% of women have vaginal Candida colonization. [bib_ref] Epidemiology of hematogenous infections due to Candida spp, Colombo [/bib_ref] These commensal micro-organisms become pathogenic when there are changes in the mechanisms of host defense or when anatomical barriers secondary to burns are compromised or invasive medical procedures occur. Changes in host defense mechanisms may be due to physiological changes in childhood (prematurity) and aging but are more often associated with degenerative diseases, malignancies, congenital or acquired immunodeficiencies and immunosuppression induced by drugs and medical procedures.In the medical community, oral candidiasis and vaginitis caused by Candida account for a significant number of clinical complaints brought to colleagues of different specialties. Candida is the predominant genus among the yeasts of the autochthonous microbiota of the oral cavity and other segments of the gastrointestinal tract. The prevalence of oral cavity colonization by yeasts in normal individuals varies, but most authors report rates of approximately 20-40% in the general population. [bib_ref] Denture contamination by yeasts in the elderly, Vanden Abbeele [/bib_ref] Among the 20 species of Candida of medical importance, Candida albicans is the most prevalent yeast in the oral cavity (accounting for more than 90% of isolates), along with other sites of colonization by this fungus. If there is a disruption of local defense mechanisms, metabolic dysfunction or the presence of diseases associated with immunosuppression, the colonized subject can develop infection and disease. [bib_ref] Epidemiology of hematogenous infections due to Candida spp, Colombo [/bib_ref] Currently, oral candidiasis is the most prevalent opportunistic infection among patients living with AIDS; it is considered a marker of the progression of the immunological deterioration that affects this population. Among treatment-naïve patients infected with human immunodeficiency virus (HIV) or those with no response to highly active anti-retroviral therapy, episodes of oral candidiasis usually become recurrent and may progress to esophagitis. [bib_ref] The mouth in HIV/AIDS: markers of disease status and management challenges for..., Johnson [/bib_ref] Vulvovaginal candidiasis is the second leading cause of infectious leucorrhea. It is responsible for approximately 13 million cases of vaginitis documented annually in North American patients. Surveys reveal that 75% of women experience an episode of vaginal candidiasis during childbearing years, with the estimation that 5% of these women have recurrent episodes. [bib_ref] Vulvovaginal candidiasis caused by non-albicans Candida species: new insights, Kennedy [/bib_ref] Candida vulvovaginitis can be sporadic or recurrent, and infections are termed primary or secondary according to the presence or absence of comorbidities associated with this condition. Primary vulvovaginitis is idiopathic and accounts for the vast majority of cases. Secondary vulvovaginitis can have different causes, including hormonal imbalances, metabolic disorders, medications (i.e., antibiotics, contraceptives) and diseases associated with immunosuppression. [bib_ref] Candida infections of the genitourinary tract, Achkar [/bib_ref] In the hospital environment, Candida infections account for 80% of all fungal infections, including bloodstream, urinary tract and surgical site infections. Pulmonary infections caused by Candida are poorly documented in clinical practice. [bib_ref] Fungal infections in ICU patients: epidemiology and the role of diagnostics, Morace [/bib_ref] Bloodstream infections are now a major challenge for tertiary hospitals worldwide due to their high prevalence and mortality rates. [bib_ref] Hospital acquired candidemia: the attributable mortality and excess length of stay, Wey [/bib_ref] The incidence of candidemia in tertiary public hospitals in Brazil is approximately 2.5 cases per 1000 hospital admissions, a rate considered two to ten times higher than those registered in European and American hospitals and similar to the rates in neighboring countries. [bib_ref] Epidemiology of candidemia in Brazil: a nationwide sentinel surveillance of candidemia in..., Colombo [/bib_ref] [bib_ref] Incidence, risk factors and predictors of outcome of candidemia: survey in 2..., Bassetti [/bib_ref] [bib_ref] Epidemiology of candidemia: 3-year results from the emerging infections and the epidemiology..., Diekema [/bib_ref] In addition to infection in the bloodstream, urinary candidiasis is common in hospitalized patients. This laboratory finding is controversial, as it may reflect different clinical possibilities that range from a simple contamination of biological material at the time of collection to a colonization of the urinary tract, sepsis or localized invasive disease caused by Candida spp. In most cases, candiduria involves colonization but not urinary infection. 12 ## Diversity of the genus candida and its clinical relevance The genus Candida has become recognized as the nomen conservandum, first at the International Botanical Congress held in Montreal in 1959. This genus consists of approximately [bib_ref] Hepatosplenic candidiasis, a contraindication to marrow transplantation, Bjerke [/bib_ref] species, of which about 20 have been linked to cases of human mycosis.Most of the yeasts have no known sexual form, and identification at the species level is obtained by analyzing their micromorphological characteristics and biochemical profiles. Morphological characterization of the majority of isolates of this genus consists of the observation of its capacity to produce blastoconidia, pseudo-hyphae (sometimes true hyphae) and eventually chlamydospores (C. albicans and Candida dubliniensis). In fact, Candida spp. have great genetic diversity and distinct morphological and biochemical characteristics but traditionally have been classified in the same genus. [bib_ref] A Candida-based view of fungal sex and pathogenesis, Bennett [/bib_ref] Despite the large number of Candida species already described, the main species of clinical interest are C. albicans, Candida parapsilosis, Candida tropicalis, Candida glabrata, Candida krusei, Candida guilliermondii and Candida lusitaniae. However, several cases of superficial and invasive diseases and emerging species of Candida have been described, involving isolates of C. dubliniensis, Candida kefyr, Candida rugosa, Candida famata, Candida utilis, Candida lipolytica, Candida norvegensis, Candida inconspicua, among others. [bib_ref] Importance of Candida species other than Candida albicans as opportunistic pathogens, Coleman [/bib_ref] Recently, molecular tools have been used in the revision of the taxonomy. These tools are essential for the characterization of some species as agents of emerging infections in the human host, including C. dubliniensis, Candida pseudorugosa, Candida metapsilosis and Candida orthopsilosis; these last two were associated with the complex "psilosis", formerly characterized as C. parapsilosis genotypes I, II and III. [bib_ref] Candida orthopsilosis and Candida metapsilosis spp. nov. to replace Candida parapsilosis groups..., Tavanti [/bib_ref] [bib_ref] Prevalence rates and antifungal susceptibility profiles of the Candida parapsilosis species complex:..., Gonç Alves [/bib_ref] C. albicans is undoubtedly the most frequently isolated species of superficial and invasive infections at different anatomical sites and in studies worldwide. It is well known as a potentially pathogenic yeast exhibiting pathogenicity and virulence factors including the capacity to adhere to epithelia and various mucous membranes, dimorphism-producing filamentous structures that assist in tissue invasion, significant thermotolerance and the production of enzymes such as proteases and phospholipases. [bib_ref] Adaptation, adhesion and invasion during interaction of Candida albicans with the host-focus..., Hiller [/bib_ref] This species is naturally sensitive to all systemic antifungal drugs, but cases of acquired resistance to azoles have been reported in patients who have prolonged exposure to these drugs; additionally, few isolates resistant to echnocandins have been also reported. [bib_ref] Fitness and virulence costs of Candida albicans FKS1 hot spot mutations associated..., Ben-Ami [/bib_ref] Resistance to amphotericin B is considered anecdotal. [bib_ref] Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences, Sanglard [/bib_ref] C. dubliniensis has been recognized as a new species whose morphological and biochemical characteristics are very similar to those of C. albicans. Molecular tests are needed to differentiate the two species. This new species was first described in Ireland, where 17-35% of patients with HIV infection have oral colonization or infection with C. dubliniensis. [bib_ref] Candida dubliniensis: characteristics and identification, Sullivan [/bib_ref] In a Brazilian study that evaluated 548 yeast samples stored in a mycology yeast collection, it was determined that 2% of samples originally identified as C. albicans were actually C. dubliniensis. [bib_ref] Candida dubliniensis identification in Brazilian yeast stock collection, Mariano [/bib_ref] This emerging species seems to be less pathogenic than C. albicans, but it has a high probability of developing resistance to azoles. [bib_ref] Non-albicans Candida spp. causing fungemia: pathogenicity and antifungal resistance, Krcmery [/bib_ref] C. parapsilosis is an important agent of candidemia and is responsible for 15-30% of candidemias in most series published in Brazil. [bib_ref] Epidemiology of candidemia in Brazil: a nationwide sentinel surveillance of candidemia in..., Colombo [/bib_ref] [bib_ref] Species distribution and antifungal susceptibility profile of Candida spp. bloodstream isolates from..., Godoy [/bib_ref] In the Northern Hemisphere, the occurrence is higher among children and premature newborns, but C. parapsilosis in Brazil can be found in all age groups. [bib_ref] Nosocomial candidiasis: emerging species, reservoirs and modes of transmission, Pfaller [/bib_ref] The frequency of C. parapsilosis varies between public and private hospitals in Brazil but is prevalent in the public setting. [bib_ref] Prospective observational study of candidemia in São Paulo, Brazil: incidence rate, epidemiology,..., Colombo [/bib_ref] [bib_ref] Nosocomial fungaemia: a 2-year prospective study, Costa [/bib_ref] Characteristically, C. parapsilosis grows in glucose solution, has great capacity to produce "biofilm" and often colonizes the skin of health professionals. Several studies have reported outbreaks of candidemia due to C. parapsilosis associated with the presence of a central venous catheter (CVC) and the use of parenteral nutrition. [bib_ref] Candida parapsilosis fungemia associated with implantable and semiimplantable central venous catheters and..., Levin [/bib_ref] Clinical isolates of this species are usually sensitive to amphotericin B and triazoles. [bib_ref] Non-albicans Candida spp. causing fungemia: pathogenicity and antifungal resistance, Krcmery [/bib_ref] However, data generated by the SENTRY -a global candidemia surveillance network -identified some samples of C. parapsilosis resistant to fluconazole. [bib_ref] Candida bloodstream infections: comparison of species distribution and resistance to echinocandin and..., Pfaller [/bib_ref] High minimum inhibitory concentration (MIC) values for echinocandins have been described against clinical isolates of C. parapsilosis. However, in most cases, these values are still within the range of susceptibility to this class of drugs. [bib_ref] Correlation of MIC with outcome for Candida species tested against caspofungin, anidulafungin,..., Pfaller [/bib_ref] In comparative clinical trials performed with caspofungin, micafungin and anidulafungin, the three echinocandins available for clinical use, their therapeutic results for infections caused by C. parapsilosis were similar to those obtained with infections caused by C. albicans. [bib_ref] Comparison of caspofungin and amphotericin B for invasive candidiasis, Mora-Duarte [/bib_ref] [bib_ref] Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase..., Kuse [/bib_ref] [bib_ref] Anidulafungin versus fluconazole for invasive candidiasis, Reboli [/bib_ref] Aside from a clinical study conducted by Moura-Duarte et al. that observed a higher number of cases of persistent candidemia due to C. parapsilosis in patients treated with caspofungin than those treated with amphotericin B, the rate of therapeutic success obtained for infections caused by C. parapsilosis was similar to the rate for C. albicans infections. [bib_ref] Comparison of caspofungin and amphotericin B for invasive candidiasis, Mora-Duarte [/bib_ref] Thus far, in this context, although some authors suggest that there is a possibility of rebound infections caused by C. parapsilosis in patients exposed to echinocandins, data from clinical trials indicate that echinocandins have good efficacy in C. parapsilosis infections. [bib_ref] Caspofungin-nonsusceptible Candida isolates in cancer patients, Kofteridis [/bib_ref] [bib_ref] Caspofungin use in patients with invasive candidiasis caused by common non-albicans Candida..., Colombo [/bib_ref] [bib_ref] Comparative efficacy of echinocandins and nonechinocandins for the treatment of Candida parapsilosis..., Kale-Pradhan [/bib_ref] An important aspect to be considered regarding C. parapsilosis is the recent change in the taxonomy: due to the sequencing of different essential genes of clinical isolates of C. parapsilosis, Tavanti et al. characterized the genetic heterogeneity of this taxon. As a result, "complex psilosis" was reclassified to include three species: C. parapsilosis, C. orthopsilosis and C. metapsilosis. [bib_ref] Candida orthopsilosis and Candida metapsilosis spp. nov. to replace Candida parapsilosis groups..., Tavanti [/bib_ref] The biological differences that may be presented by species within the "complex psilosis" are still not completely understood. However, the isolates from the three species may exhibit differences in patterns of susceptibility to antifungal agents and biofilm production. [bib_ref] Prevalence rates and antifungal susceptibility profiles of the Candida parapsilosis species complex:..., Gonç Alves [/bib_ref] [bib_ref] Biofilm production and evaluation of antifungal susceptibility amongst clinical Candida spp. isolates,..., Melo [/bib_ref] C. tropicalis is a potential opportunistic agent when the host is neutropenic and when there is suppression of bacterial flora due to antibiotic use and damage to the gastrointestinal mucosa. C. tropicalis is the second or third most common etiologic agent of candidemia in patients with cancer, particularly leukemia, and less frequently in patients with solid tumors. [bib_ref] Importance of Candida species other than C. albicans as pathogens in oncology..., Wingard [/bib_ref] In Brazil, unlike countries in Europe and in the United States, C. tropicalis accounts for a substantial number of documented cases of candidemia in non-neutropenic patients or patients with cancer. [bib_ref] Epidemiology of candidemia in Brazil: a nationwide sentinel surveillance of candidemia in..., Colombo [/bib_ref] [bib_ref] Species distribution and antifungal susceptibility profile of Candida spp. bloodstream isolates from..., Godoy [/bib_ref] [bib_ref] Prospective observational study of candidemia in São Paulo, Brazil: incidence rate, epidemiology,..., Colombo [/bib_ref] [bib_ref] Nosocomial fungaemia: a 2-year prospective study, Costa [/bib_ref] [bib_ref] High rate of nonalbicans candidemia in Brazilian tertiary care hospitals, Colombo [/bib_ref] [bib_ref] Candida tropicalis fungemia in a tertiary care hospital, Goldani [/bib_ref] Clinical isolates of this species are susceptible to amphotericin B and most of the azoles. However, some authors have documented the occurrence (usually <5%) of isolates resistant to fluconazole. Considering that this species has a strong phenomenon of partial inhibition of growth in in vitro tests (trailing), there is some doubt as to whether the rates of in vitro resistance to fluconazole are overestimated. [bib_ref] Influence of different susceptibility testing methods and media on determination of the..., Alp [/bib_ref] C. glabrata has emerged as an important hospital pathogen, representing the second or third most common species among the agents of candidemia reported in medical centers in Europe and the United States. [bib_ref] The epidemiology of hematogenous candidiasis caused by different Candida species, Abi-Said [/bib_ref] In Latin America, data generated from case series documented until 2005 show that the isolation of C. glabrata candidemia accounted for no more than 5-8% of all episodes of fungemia in public hospitals. [bib_ref] Epidemiology of candidemia in Brazil: a nationwide sentinel surveillance of candidemia in..., Colombo [/bib_ref] [bib_ref] Epidemiology of opportunistic fungal infections in Latin America, Nucci [/bib_ref] Recently, data from cohorts of private hospitals and medical centers that perform large numbers of organ transplants, where the practice of prophylaxis with fluconazole in high risk patients seems to be more common, indicate that the prevalence of C. glabrata among the causative agents of fungemia reaches more than 10% of the cases. [bib_ref] Secular trends of candidemia in a tertiary care hospital, Sampaio Camargo [/bib_ref] Clinical isolates of C. glabrata are less susceptible to fluconazole. Most series documented that 50% of C. glabrata strains have reduced susceptibility to fluconazole and that 10-20% of strains are resistant to this drug. [bib_ref] International surveillance of bloodstream infections due to Candida species: frequency of occurrence..., Pfaller [/bib_ref] Consequently, increases in the rates of colonization/infection by C. glabrata have been observed in different groups of patients exposed to fluconazole. [bib_ref] The effect of empiric and prophylactic treatment with fluconazole on yeast isolates..., Safran [/bib_ref] In addition to therapeutic issues with azoles in infections associated with C. glabrata, Pfaller et al. observed that isolates of C. glabrata may have lower in vitro susceptibility to amphotericin B and suggested the need for higher doses of polienic for the treatment of invasive infections caused by this agent. [bib_ref] Geographic variation in the susceptibilities of invasive isolates of Candida glabrata to..., Pfaller [/bib_ref] Another epidemiologic aspect of this pathogen is its high prevalence in elderly patients. In a multicenter study, which evaluated samples of candidemia in 17 medical centers in the state of Iowa, it was observed that C. glabrata is more prevalent in elderly patients and accounted for 25% of all fungemias documented in patients over 65 years. [bib_ref] Age-related trends in pathogen frequency and antimicrobial susceptibility of bloodstream isolates in..., Diekema [/bib_ref] C. krusei is an occasional hospital pathogen that is particularly isolated from patients with hematologic malignancies and/or who are undergoing allogeneic hematopoietic stem cell transplant (HSCT). [bib_ref] Invasive infection due to Candida krusei in immunocompromised patients not treated with..., Iwen [/bib_ref] Some authors reported increased occurrence of fungemias caused by C. krusei in neutropenic patients exposed to prolonged courses of fluconazole. [bib_ref] Importance of Candida species other than C. albicans as pathogens in oncology..., Wingard [/bib_ref] This yeast is naturally resistant to fluconazole, but in most cases, it is sensitive to voriconazole (cross-resistance is uncommon in this species). [bib_ref] In vitro activity of voriconazole and other antifungal agents against clinical isolates..., Drago [/bib_ref] Invasive infections caused by C. guilliermondii are still infrequent, although there are several case reports, especially in patients with cancer. [bib_ref] Candida guilliermondii fungemia in patients with hematologic malignancies, Girmenia [/bib_ref] Despite the lack of information available in the literature, there are reports of in vitro resistance of clinical samples of C. guilliermondii to amphotericin B, triazoles and echinocandins. The clinical relevance of these in vitro data is still debated; thus, clinical and laboratory monitoring of patients treated with these drugs is recommended to identify treatment failure. [bib_ref] New and emerging yeast pathogens, Hazen [/bib_ref] C. lusitaniae is infrequently a causative agent of invasive disease but has been reported as a candidemia agent in immunocompromised patients. From a total of 86 reported cases of invasive disease by this species, 70 were identified in patients with cancer. Often, clinical isolates of C. lusitaniae have primary or secondary resistance to amphotericin B, but they are very sensitive to all triazoles. [bib_ref] Candida lusitaniae: frequency of recovery, colonization, infection and amphotericin B resistance, Merz [/bib_ref] The epidemiological and therapeutic peculiarities presented by different species of Candida spp. justify the need to identify yeast at the species level when these micro-organisms are associated with systemic diseases. This procedure is fundamental for choosing the best therapeutic approach to be administered to patients. In summary, it is important to note that C. krusei isolates are completely resistant to fluconazole and that, more often than other species (except C. krusei), C. glabrata samples can be resistant to or can require higher doses of azoles for successful treatment. Likewise, higher doses of amphotericin B should be used in the treatment of invasive infections caused by C. krusei and C. glabrata. Finally, clinical isolates of C. lusitaniae may be resistant to amphotericin B. [bib_ref] Candida bloodstream infections: comparison of species distribution and resistance to echinocandin and..., Pfaller [/bib_ref] [bib_ref] Geographic variation in the susceptibilities of invasive isolates of Candida glabrata to..., Pfaller [/bib_ref] In this context, it is important to recognize that, for the clinician, the support of mycological diagnostics is essential for the prevention, control and treatment of Candida infections. Full identification of yeast species is necessary; this information is essential not only for the definition of therapeutic choice but also for the control of hospital infection rates at different sites and during the investigation of outbreaks. [bib_ref] Epidemiology of hematogenous infections due to Candida spp, Colombo [/bib_ref] In this sense, it is important to know the wide range of manual and automated commercial systems available that allow rapid and accurate identification of yeasts of clinical interest. [bib_ref] Multicenter evaluation of the new VITEK 2 advanced colorimetric yeast identification card, Hata [/bib_ref] These guidelines suggest that all medical centers that treat patients at risk for developing invasive fungal infections must have a microbiology laboratory able to identify the main fungal species of medical interest. There is no technical, medical or administrative element that supports the clinical staff of tertiary hospitals for working in medical centers without the basic support of mycological diagnosis. With regard to susceptibility testing, in view of discussions concerning the existing clinical validation of cutoff points for different therapeutic classes and the difficulty of access to this test for most medical centers in Brazil, it is not possible to recommend its universal use. Therefore, the best scientific evidence available on clinical-laboratory susceptibility tests was generated by in vitro assays performed with Candida species and fluconazole. [bib_ref] International surveillance of bloodstream infections due to Candida species: frequency of occurrence..., Pfaller [/bib_ref] [bib_ref] Role of antifungal susceptibility testing in patient management, Forrest [/bib_ref] Thus, the indication for antifungal susceptibility testing has been evaluated in two different scenarios: during epidemiological investigation and while assisting the clinician at the bedside. In the first scenario, susceptibility tests are needed for surveillance studies of species distribution and for monitoring MICs for different antifungal drugs in several hospital facilities. This allows us to identify and characterize temporal trends and the geographic emergence of pathogens resistant to different drugs, thus supporting a safe indication of empirical therapy. [bib_ref] Lass-Flörl C. In vitro susceptibility testing in fungi: what is its role..., Perkhofer [/bib_ref] While at the bedside, there are four indications for performing susceptibility testing with azole: (a) to evaluate the susceptibility to antifungal agents in patients with hematogenous candidiasis with poor response to the drug in use, information that, along with species identification, is important for guiding a possible change in regimen; (b) to evaluate the susceptibility to fluconazole in a sample of Candida spp. isolated from invasive infections in the event that this triazole was started empirically; (c) to shorten the time therapy started with echinocandin or a lipid formulation of amphotericin B, introducing sequential therapy with oral fluconazole (deescalation); and (d) for superficial infections with C. glabrata or other Candida strains that may be resistant to fluconazole and to assess the possible in vitro activity of a new oral triazole, such as voriconazole. [bib_ref] Candida infection in HIV positive patients, Traeder [/bib_ref] If the medical center decided to make the clinical results of in vitro antifungal susceptibility tests available, testing should be performed by reference laboratories using standardized methodology from regulatory authorities such as the CLSI and EUCAST, or using methods known to be equivalent to these tests, such as E-TEST and Vitek-2. 57-60 ## Therapeutic options for infections caused by candida spp. During the last decade, the traditional therapeutic compounds, consisting mainly of polienic, imidazole and first-generation triazoles, have been expanded with the development and validation of new systemic antifungal agents. Among the new antifungal agents active against Candida spp. developed in the last decade, we highlight the secondgeneration triazoles and a novel class of antifungal agents, the echinocandins. ## Polienic Nystatin and amphotericin B are natural antifungals discovered in the 1950s and obtained from aerobic bacteria (Streptomyces noursey and Streptomyces nodosus, respectively) that have broad-spectrum antifungal activities. In Candida infections, nystatin is reserved for superficial infections due to its topical action. Amphotericin B is indicated for severe forms of invasive candidiasis. The primary mechanism of action is the interaction with steroid components of the cell membranes of eukaryotic cells, leading to rupture. Other mechanisms have been suggested, such as the production of oxygen free radicals by phagocytes in the host. There are different formulations of amphotericin B for intravenous infusion: a deoxycholic acid formulation (amphotericin B deoxycholate or conventional) and lipid formulations (colloidal dispersion, lipid complex and liposomal). The safest lipid formulations in clinical use are amphotericin B lipid complex and liposomal formulation; the latter has lower toxicity and greater tolerability compared to the former formulation. [bib_ref] Amphotericin B and its new derivativesmode of action, Baginski [/bib_ref] Conventional amphotericin B is primarily associated with acute infusion events, including fever, chills, nausea, vomiting, bronchospasm and rash. Fewer side effects are experienced with the lipid complex formulation (two-hour infusion) and particularly with the liposomal formulation (one-hour infusion). The most serious adverse effects are related to the nephrotoxicity of conventional amphotericin B, including the deterioration of renal, cardiac and hematopoietic functions. Of these, renal failure is the most common, occurring in 12-80%, depending on the criteria adopted for renal failure and the population evaluated. [bib_ref] Amphotericin B: side effects and toxicity, Laniado-Laborín [/bib_ref] Among the various alternatives to reduce nephrotoxicity, hydration with 500 mL of isotonic saline solution produces better results without compromising effectiveness, but it can be limited in critically ill patients. [bib_ref] Antifungal treatment strategies in high risk patients, Rüping [/bib_ref] Among the lipid formulations of amphotericin B, the liposomal formulation causes a lower incidence of nephrotoxicity. [bib_ref] A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B..., Wingard [/bib_ref] [bib_ref] Drug-induced nephrotoxicity caused by amphotericin B lipid complex and liposomal amphotericin B:..., Safdar [/bib_ref] Amphotericin B is fungicidal and is active against various Candida species. Secondary resistance is rare. There are data suggesting that amphotericin B MICs for C. glabrata and C. krusei are higher, requiring the use of higher doses of polienic. There is evidence that primary and/or secondary resistance to amphotericin B can occur with clinical isolates of C. lusitaniae. [bib_ref] Uncommon opportunistic fungi: new nosocomial threats, Groll [/bib_ref] [bib_ref] Invasive candidiasis, Pappas [/bib_ref] Azoles The azoles are a therapeutic class of great clinical utility because of their broad spectrums of action (especially voriconazole and posaconazole), their safety and the availability of oral and intravenous formulations (fluconazole and voriconazole). This therapeutic class can be divided into two groups: the imidazoles and triazoles. The first imidazole with topical action, clotrimazole, was launched in 1960, and it is still being used for superficial candidiasis. In turn, the triazole compounds are subdivided into first-generation (itraconazole and fluconazole) and second-generation (voriconazole and posaconazole) compounds. Isavuconazole, a new secondgeneration triazole, is still under clinical investigation. [bib_ref] History of the development of azole derivatives, Maertens [/bib_ref] The azole derivatives are characterized by their selective inhibition of the production of ergosterol, a steroid found in the fungal cell membrane. Their mode of action is the inhibition of fungal 14-␣-demethylase, a cytochrome p450dependent enzyme. Its catalyzing process is essential for the conversion of lanosterol into ergosterol, other actions that can contribute to the antifungal activity have been described, such as inhibition of the yeast transformation into mycelium, the decrease in fungal cell adhesion and the accumulation of steroids that are potentially toxic to fungal cells once the conversion of lanosterol into ergosterol is blocked. [bib_ref] Oral azole drugs as systemic antifungal therapy, Como [/bib_ref] Mechanisms of resistance related to drug efflux, as described with C. glabrata, invariably lead to cross-resistance. Mutations in the gene ERG-11 and changes in the target enzyme 14-␣demethylase, as described with C. krusei and fluconazole, may not cause cross-resistance, as the second-generation triazoles (voriconazole and posaconazole) have higher avidity for the target enzyme. [bib_ref] Newer triazole antifungal agents: pharmacology, spectrum, clinical efficacy and limitations, Aperis [/bib_ref] Recently, there has been discussion regarding harmonization of the breakpoints of susceptibility to fluconazole, and the MIC value limit for susceptible strains was decreased to 2 g/mL for C. albicans, C. parapsilosis and C. tropicalis. [bib_ref] Comparison of the broth microdilution (BMD) method of the European Committee on..., Pfaller [/bib_ref] Based on this change, higher rates of resistance to fluconazole are expected. [bib_ref] Epidemiology of invasive candidiasis, Arendrup [/bib_ref] Because the triazoles are cleared via the hepatic metabolism, many drug interactions are possible. ## Ketoconazole Ketoconazole was the first imidazole developed for oral therapy of fungal infections. It has a wide spectrum of action against agents of dermatomycoses, endemic mycoses (including paracoccidioidomycosis and histoplasmosis) and isolates of Candida spp. Given its limited efficacy in systemic fungal infections in immunocompromised hosts and its toxicity (hepatotoxicity and depression of steroidogenesis), this drug was replaced by fluconazole and itraconazole in most indications (first-generation triazole). [bib_ref] Oral azole drugs as systemic antifungal therapy, Como [/bib_ref] ## Itraconazole Itraconazole is a soluble triazole that is available in capsule form. Its intravenous formulation and oral solution, both in cyclodextrin, are not currently available in Brazil. Although it can be used for infections caused by Candida, the primary indication is for mild to moderate endemic mycoses, such as paracoccidioidomycosis, histoplasmosis, coccidioidomycosis, blastomycosis, chromoblastomycosis, phaeohyphomycosis and sporotrichosis, in addition to dermatomycosis. [bib_ref] Practice guidelines for the management of patients with histoplasmosis. Infectious Diseases Society..., Wheat [/bib_ref] [bib_ref] Guidelines in paracoccidioidomycosis, Shikanai-Yasuda [/bib_ref] Because it is well tolerated in long-term use, and considering its excellent availability in keratinized and subcutaneous tissues, itraconazole can be used in chronic mucocutaneous candidiasis and onychomycosis. It is considered as an alternative drug in cases of oral and vaginal candidiasis. Considering that only the capsule formulation is available in Brazil, itraconazole is not indicated for treatment of hematogenous candidiasis and other invasive forms of mycosis. [bib_ref] New and investigational triazole agents for the treatment of invasive fungal infections, Sarro [/bib_ref] ## Fluconazole Fluconazole is a water-soluble triazole for parenteral and oral use (100 mg and 150 mg) that has antifungal activity against dermatophytes, Cryptococcus neoformans and most Candida spp., except for C. krusei, which has primary resistance, and C. glabrata, which has a lower susceptibility to fluconazole, particularly when isolated from patients with prior exposure to this antifungal. Fluconazole has an excellent safety profile, good absorption in the gastrointestinal tract and distribution in different compartments of the body, including the central nervous system and the eyes. Fluconazole is effective in the treatment of superficial and deep infections by Candida spp., including cases of oroesophageal candidiasis, hematogenous candidiasis and candiduria and its complications. [bib_ref] Fluconazole for the management of invasive candidiasis: where do we stand after..., Charlier [/bib_ref] Most cases of toxicity to fluconazole are related to drug-induced hepatitis and are often asymptomatic. GI intolerance is not frequent, and leukopenia and thrombocytopenia are rare. Unlike ketoconazole, there is no blockage in hormonal synthesis with fluconazole. The dose should be reduced patients with creatinine clearance <50 mL/min. [bib_ref] An update of its pharmacodynamic and pharmacokinetic properties and therapeutic use in..., Goa [/bib_ref] ## Voriconazole Voriconazole is a triazole available in tablets of 50 mg and 200 mg and vials of 200 mg for intravenous administration whose carrier is cyclodextrin. It has a broader spectrum of action than fluconazole, and it is active against Candida species that include C. glabrata and C. krusei, C. neoformans, Trichosporon sp., Aspergillus spp., Fusarium spp., Scedosporium apiospermum, Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis and Paracoccidioides brasiliensis. It is not active against Scedosporium prolificans and agents of mucormycosis. The oral formulation has good bioavailability and allows for safe sequential therapy and therapeutic levels in different tissues, including the central nervous system. Dose adjustments are needed in cases of moderate hepatic impairment, and the risks-benefits should be measured in severe forms of liver failure. Renal elimination of the active form is minimal, with no need for dose adjustment when using the oral formulation. However, the use of the intravenous form must be evaluated on a case-by-case basis in patients with creatinine clearance under 50 mL/min, as the excipient (cyclodextrin) can be accumulated in patients with renal failure. Regarding safety, the main adverse effects are transient visual disturbances (up to 30% of patients) reversible with discontinuation of the drug, elevations of transaminases and bilirubin, skin reactions and photosensitivity (up to 25%); with use, it is recommended to avoid sun exposure and/or to use sunscreen. [bib_ref] Voriconazole: a review of its use in the management of invasive fungal..., Scott [/bib_ref] In the treatment of esophageal candidiasis, voriconazole has clinical efficacy similar to fluconazole. Although its use is most important in invasive aspergillosis, in a study with non-neutropenic patients with candidemia or invasive candidiasis, voriconazole exhibited similar efficacy and less renal toxicity compared to conventional amphotericin B followed by fluconazole. [bib_ref] Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of..., Walsh [/bib_ref] [bib_ref] Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia..., Kullberg [/bib_ref] Posaconazole Posaconazole is a triazole whose chemical structure has been modified from the itraconazole molecule. This azole has a broad antifungal spectrum that acts in vitro and in vivo against isolates of Candida spp., including C. krusei and some isolates of C. glabrata resistant to fluconazole, Aspergillus spp., Fusarium spp., dematiaceous fungi and some agents of mucormycosis. To date, posaconazole is only available in an oral solution that is administered three to four times per day. The absorption can decrease in certain conditions, such as when the patient is receiving a proton pump inhibitor. An oral formulation in tablet form with a single daily administration and improved absorption and an intravenous formulation are under development. While the main indication is prophylaxis of fungal infections in patients with acute myelogenous leukemia and myelodysplastic syndrome receiving remissioninducing therapy as well as transplant recipients of allogeneic hematopoietic stem cells with chronic graft-versus-host disease, the triazole treatment is also indicated as a rescue treatment in several fungal infections, including oropharyngeal candidiasis. However, its unique availability in an oral suspension formulation may be a limitation for patients who are clinically unstable and/or with problems swallowing and absorbing drugs that require oral treatment. [bib_ref] Use of posaconazole in the treatment of invasive fungal infections, Mehta [/bib_ref] This drug is not yet available for clinical use in Brazil. ## Echinocandins Echinocandins are a new class of antifungal exclusively for parenteral use that are classified as inhibitors of the enzyme complex 1,3-␤-d-glucan synthase, which synthesizes 1,3-␤-dglucan, an essential polysaccharide component of the fungal cell wall. The echinocandins are rapidly fungicidal for Candida species and fungistatic for Aspergillus species. [bib_ref] Echinocandins: the newest class of antifungals, Sucher [/bib_ref] Currently, three drugs represent this therapeutic class: caspofungin, micafungin and anidulafungin. By acting on an exclusive structure of fungal cells (the cell wall), the echinocandins are currently among the most safe and well-tolerated drugs. When present, the adverse effects are mild, such as fever, phlebitis at the infusion site and transient elevation of liver enzymes. In addition to fever, other symptoms mediated by histamine release may rarely occur, including rash, facial swelling, pruritus, sensation of warmth and bronchospasm. Given the small hepatic metabolism of these drugs, few (caspofungin and micafungin) or no drug interactions (anidulafungin) occur with the use of these drugs. [bib_ref] Echinocandins: the newest class of antifungals, Sucher [/bib_ref] ## Caspofungin Caspofungin has been available for clinical use in Brazil for almost a decade. Its formulation is available in vials of 50 mg and 70 mg. The dose needed for invasive candidiasis is 70 mg, followed by 50 mg daily. The elimination of the drug occurs by spontaneous hydrolysis and acetylation in the liver; it does not undergo oxidative metabolism by the cytochrome complex P450-dependent enzyme, which explains its low interference with other drugs metabolized in the liver. This antifungal has no renal elimination; therefore, dose adjustment in patients with renal failure is not indicated. In cases of moderate hepatic failure, it is recommended to use a low dosage (35 mg/day in adults). There are no clinical data regarding its use in patients with severe hepatic impairment. It has good distribution in different body fluids and tissues, and its concentration is limited in the cerebrospinal fluid, urine and eyes. [bib_ref] The pharmacology and clinical use of caspofungin, Hope [/bib_ref] Caspofungin has a large plasma protein binding capacity. This drug should not be used in pregnant women, and there is little clinical information regarding pediatric indications; however, case series suggest that it is an effective and safe choice even in this group. [bib_ref] Caspofungin for the treatment of pediatric fungal infections, Fisher [/bib_ref] Caspofungin has been evaluated in patients with candidemia and/or invasive candidiasis in a randomized trial comparing conventional amphotericin B, which had the same success rate and lower toxicity. [bib_ref] Comparison of caspofungin and amphotericin B for invasive candidiasis, Mora-Duarte [/bib_ref] Anidulafungin This echinocandin is available in vials of 100 mg. Among the few randomized clinical trials available for this drug, two studies have validated its clinical use in esophageal candidiasis and invasive candidiasis/candidemia, both in comparison to fluconazole. In the candidemia/invasive candidiasis study, anidulafungin was one of the few antifungal drugs that yielded the best therapeutic result versus the comparator (fluconazole) in a clinical study involving patients with candidemia. [bib_ref] Anidulafungin versus fluconazole for invasive candidiasis, Reboli [/bib_ref] Experiences with anidulafungin in the pediatric population, in which the safety and efficacy of caspofungin and micafungin have been demonstrated, are very limited. [bib_ref] Caspofungin: in pediatric patients with fungal infections, Garnock-Jones [/bib_ref] [bib_ref] Micafungin: a brief review of pharmacology, safety, and antifungal efficacy in pediatric..., Lehrnbecher [/bib_ref] This echinocandin has less hepatic metabolism and may be indicated for patients with moderate or severe hepatic impairment without any need for dose adjustment. [bib_ref] Anidulafungin, a new echinocandin: effectiveness and tolerability, Menichetti [/bib_ref] Micafungin This drug has been sold in vials of 100 mg for several years in Japan and has recently begun being sold in the U.S. and Brazil. Among the echinocandins, micafungin is the drug involved in the largest number of phase II and III studies involving patients with candidiasis. In candidemia and invasive candidiasis, studies were compared to liposomal amphotericin B [fig_ref] Table 1 -: Pharmacological aspects of systemic antifungals [/fig_ref] show the pharmacological aspects and antifungal dosages for systemic use. Below, we discuss the treatment of major infections caused by Candida. The recommendations for therapy are indicated for adult patients and were based on levels of evidence according to the strength of the recommendation and the quality of evidence from the American Society of Infectious Diseases, adapted from the Canadian Ministry of Health, 91 as shown in [fig_ref] Table 3 -: Strength of recommendation and quality of evidence [/fig_ref]. ## Dosage and drug interactions of antifungals Each topography was discussed with regard to epidemiological, clinical and laboratory diagnostic and therapeutic recommendations. The therapeutic options for treating candidiasis are summarized in [fig_ref] Table 4 -: Therapeutic regimens for candidiasis [/fig_ref]. ## Treatment ## Oral candidiasis ## Epidemiological aspects Oral candidiasis is considered superficial candidiasis that affects patients with changes in local or systemic immunity, either due to age (premature neonates and the elderly), prosthesis use, exposure to immunosuppressive drugs (chemotherapy, corticosteroids), antibiotics or the presence of diseases such as cancer, diabetes, sarcoidosis, cirrhosis, malnutrition, xerostomy and AIDS. [bib_ref] Mucosal candidiasis, Vazquez [/bib_ref] In clinical practice, most cases of candidiasis are observed in pediatric patients, who exhibit immaturity of the defense mechanisms of the mucosa, and the elderly, whose defense mechanisms are senescent or even because of the use of dental prostheses. [bib_ref] A study of Candida esophagitis in elderly patients attending a district general..., Weerasuriya [/bib_ref] The pathological conditions most commonly associated with oral candidiasis in adult patients are AIDS, diabetes and exposure to antibiotics and/or corticosteroids for different conditions. Therefore, all adult patients presenting with oral candidiasis without obvious cause should be investigated for HIV infection.C. albicans accounts for approximately 90% of the isolates causing oroesophageal candidiasis, but C. tropicalis, C. krusei, C. glabrata, C. parapsilosis and C. dubliniensis can also be detected. [bib_ref] Invasive oroesophageal candidiasis: current and developing treatment options, Vazquez [/bib_ref] In AIDS patients unresponsive to antiretroviral therapy, episodes of oropharyngeal candidiasis become recurrent, requiring prolonged use or repeated cycles of therapy with triazoles. In this scenario, there is an increase in episodes of candidiasis by Candida non-albicans isolates resistant to fluconazole or even in the risk of selecting resistant strains of C. albicans to this drug. [bib_ref] A randomized study of the use of fluconazole in continuous versus episodic..., Goldman [/bib_ref] ## Clinical and laboratory diagnosis Clinical manifestations are varied and depend on the host's immune status and the extent of oral candidiasis. The largest clinical experience of infectious disease is in the form of pseudomembranous candidiasis. The most common symptoms are oral discomfort, burning pain and the presence of removable white plaque under erythematous mucosa. These conditions make feeding difficult, and they can compromise the regularity of oral drug treatments. [bib_ref] Clinical findings and risk factors for Candida esophagitis in outpatients, Underwood [/bib_ref] However, other clinical presentations are known. Erythematous candidiasis presents itself as erythematous infiltrate with reduced papillae when present on the tongue. Patients using dental prostheses with oral candidiasis have chronic erythema and discomfort in the region of the prosthesis. Angular cheilitis caused by Candida spp. manifests as discomfort, erythema, and fissures in the angular region of the lips. [bib_ref] Oral candidal infections and antimycotics, Ellepola [/bib_ref] The clinical presentation is usually very characteristic of this condition, particularly when it is pseudomembranous. However, clinical diagnosis should be confirmed by laboratory investigation as follows: (a) by direct mycological examination, with scrapes of lesions in KOH preparations or by Gram staining, where the specimen is analyzed by the presence of fungal elements consistent with Candida spp. and/or (b) by culturing in selective fungal medium (preferably chromogenic medium to identify different species), where the yeast is isolated and the agent is forwarded to complete identification. [bib_ref] Johns 3rd MM. Esophageal candidiasis, Golub [/bib_ref] Culture is particularly important in cases of recurrent candidiasis in patients with AIDS, in cases of poor response to conventional therapy or when an injury that is suggestive of candidiasis arises in patients receiving any antifungal drug. In these situations, the identification of the agent species and testing for susceptibility to antifungal agents are necessary recommendations for optimizing a new therapeutic indication in view of the possibility of infection by strains of Candida spp. resistant to one or all triazoles. [bib_ref] Fluconazole for the treatment of candidiasis: 15 years experience, Cha [/bib_ref] [bib_ref] Gastrointestinal infections in immunocompromised hosts, Thom [/bib_ref] Therapeutic recommendations The goal of treatment is to eliminate the signs and symptoms of the disease, reduce or eliminate colonization and prevent ## Topical therapy (uncomplicated infection) Nystatin 100,000-400,000 IU/mL and 4-6 mL four to five times a day for 14 days (B-II) should be administered. Successful treatment depends on the time of contact with the oral mucosa for at least two minutes. It is worth mentioning that this drug has a low tolerance and high sugar content as a vehicle. It also has cariogenic potential and should be used with caution in diabetic patients. [bib_ref] Oral candidal infections and antimycotics, Ellepola [/bib_ref] In the U.S. and Europe, an oral clotrimazole solution is available for use three to five times a day for 14 days (B-II). In these countries, topical therapy is the rule in mild and/or early candidiasis, even in patients with AIDS. [bib_ref] Clinical practice guidelines for the management of candidiasis: 2009 update by the..., Pappas [/bib_ref] Unfortunately, in Brazil, clotrimazole is not available in formulations suitable for oral use. In this context, in view of the difficulties in handling nystatin, topical therapy is restricted to only a few patients. ## Systemic therapy The best therapeutic option for systemic candidiasis is oral fluconazole; the other options are considered only in patients unresponsive or intolerant to this drug (A-I). [bib_ref] Fluconazole for the treatment of candidiasis: 15 years experience, Cha [/bib_ref] Fluconazole 200 mg PO in the first day and 100 mg/day for 7-14 days (A-I). In patients with oropharyngeal candidiasis refractory to fluconazole, the options are as follows: - Itraconazole 200 mg orally BID with food for 7-14 days (A-II). [bib_ref] Fluconazole compared with itraconazole in the treatment of esophageal candidiasis in AIDS..., Barbaro [/bib_ref] [bib_ref] A randomized double-blind study of caspofungin versus fluconazole for the treatment of..., Villanueva [/bib_ref] [bib_ref] A randomized, double-blind trial of anidulafungin versus fluconazole for the treatment of..., Krause [/bib_ref] [bib_ref] A randomized, double blind, parallel-group, dose-response study of micafungin compared with fluconazole..., Dewet [/bib_ref] The use of these drugs should be reserved for treatment of esophageal candidiasis refractory to fluconazole (B-I). Given that oral candidiasis is related to the imbalance between the colonizing agent and the local or systemic defense mechanisms, we should try to act toward control of the underlying disease and/or removal of the predisposing conditions. Otherwise, the trend favors chronicity of the process, as it occurs in patients with prostheses and AIDS that is unresponsive to antiretroviral therapy. ## Esophageal candidiasis ## Epidemiological aspects Esophageal candidiasis is considered a form of semi-invasive candidiasis that primarily affects patients with AIDS, cancer, diabetes, previous esophageal diseases, malnutrition and alcoholism, along with those in therapies using corticosteroids, antibiotics, H2 receptor antagonists and proton-pump inhibitors. [bib_ref] Mucosal candidiasis, Vazquez [/bib_ref] In clinical practice, most cases of esophageal candidiasis occur in AIDS patients, followed by lower frequencies of diabetics and critically ill patients exposed to multiple antibiotic cycles. [bib_ref] Johns 3rd MM. Esophageal candidiasis, Golub [/bib_ref] Clinical and laboratory diagnosis Candida esophagitis can be oligosymptomatic, but its main clinical manifestations include dysphagia, odynophagia and retroesternal burning. In children, nausea, vomiting and dehydration are the main signs. Although the presence of concomitant oral and esophageal candidiasis is common, particularly in AIDS patients, the absence of oral candidiasis does not exclude esophagitis diagnosis. Complications include bleeding, perforation and stenosis. [bib_ref] Gastrointestinal infections in immunocompromised hosts, Thom [/bib_ref] In AIDS patients, the diagnosis is usually made based only on clinical data and treatment response. However, taking into account many other opportunistic diseases that affect the esophagus in immunocompromised patients (e.g., herpes and cytomegalovirus), laboratory investigation is mandatory for a definitive diagnosis.Endoscopy reports often reveal white plaques that may or may not be accompanied by ulcerated lesions. Apart from the morphological findings, it is recommended to perform a scrap (brush) to obtain a sample for microscopic examination and culturing, in addition to a mucosal biopsy. [bib_ref] Johns 3rd MM. Esophageal candidiasis, Golub [/bib_ref] The microscopic examination of fungal elements is performed with a sample obtained by scraping on a slide with KOH or by Gram stain. The culture is performed with a sample obtained by scraping or biopsy. A biopsy should be processed with hematoxylin-eosin staining and silver methenamine (Grocott). [bib_ref] Johns 3rd MM. Esophageal candidiasis, Golub [/bib_ref] The definitive diagnosis of esophageal candidiasis is made when, in addition to the clinical and morphological endoscopic findings, we identify fungal elements on microscopic examination and/or observe the presence of fungal elements in tissue, confirming invasion by the pathogen. From an academic point of view, the isolated identification of Candida in culture but no fungal elements by microscopic examination and biopsy may represent colonization of the gastrointestinal tract and not infection. [bib_ref] Gastrointestinal infections in immunocompromised hosts, Thom [/bib_ref] ## Therapeutic recommendations Systemic therapy is recommended for cases of esophageal candidiasis (B-II). This starts with empirical systemic therapy (A-I) with fluconazole 200 mg PO or IV in the first day, followed by 100 mg QD for 14-21 days (A-I). When endoscopy is not performed at the time of diagnosis, it should be performed if no improvement occurs within 3-5 days. [bib_ref] Invasive oroesophageal candidiasis: current and developing treatment options, Vazquez [/bib_ref] In patients with esophageal candidiasis refractory to fluconazole, the options are as follows: - Voriconazole 200 mg BID for 14-21 days. This drug was validated in a comparative clinical trial with fluconazole in patients with esophageal candidiasis (A-I). [bib_ref] A randomized, double blind, double-dummy, multicenter trial of voriconazole and fluconazole in..., Ally [/bib_ref] ## Vulvovaginal candidiasis ## Epidemiological aspects Vaginal candidiasis is highly prevalent in women during their childbearing life; approximately 75% have at least one episode lifelong, and 5-10% can develop a recurrence (defined as at least four episodes of vaginitis by Candida spp. within one year).The most frequent predisposing factors for vaginal candidiasis include exposure to high levels of estrogens (birth control, pregnancy and hormone replacement), uncontrolled diabetes mellitus, use of topical and systemic antibiotics and inadequate hygiene habits. Most women with recurrent vaginal candidiasis do not have underlying diseases associated with systemic immunosuppression, and recurrence may be secondary to a deficiency in the local immune response to the agent. [bib_ref] Candidíase vulvovaginal: uma revisão de literatura, Holanda [/bib_ref] Vulvovaginal candidiasis is usually classified as complicated or uncomplicated, pending on the severity of the clinical presentation and basic conditions of the host. Uncomplicated forms of vaginitis account for more than 90% of cases and have an excellent response to short oral or topical therapy. Patients with more complicated vaginitis require a prolonged antimycotic therapy. [bib_ref] Estudo dos aspectos clínicos, epidemiológicos e atualizaç ão terapêutica das vulvovaginites por..., Novawack [/bib_ref] C. albicans is the most frequent cause of vaginitis, accounting for approximately 74-95% of cases, followed by C. glabrata in approximately 14.5% of cases. The non-albicans species are more common in recurrent forms and may be found in 10-20% of these patients. C. glabrata is the species most frequently identified in these cases. [bib_ref] Prevalência e susceptibilidade de leveduras vaginais, Galle [/bib_ref] [bib_ref] Pathogenesis and treatment of recurrent vulvovaginal candidiasis, Sobel [/bib_ref] Clinical and laboratory diagnosis Considering that 30% of women may have Candida colonization and there is a wide differential diagnosis for infectious leukorrhea, the diagnosis of C. vulvovaginitis should be based on clinical and laboratory findings. [bib_ref] Vulvovaginal candidosis, Sobel [/bib_ref] Candidiasis involves the vulva and the vaginal lumen, causing intense itching, burning, local discomfort, dysuria, vaginal discharge and dyspareunia. Clinical examination revealed swelling and redness of the vulva and/or vagina, vaginal discharge that looks like milk and, eventually, vulvar carved cracks. [bib_ref] Candidíase vulvovaginal: aspectos clínicos, tratamento oral com azólicos e suscetibilidade in vitro, Costa [/bib_ref] Clinical diagnosis must be performed by the following tests: 117 - Direct microscopic examination with the addition of KOH (10%) or Gram stain to search for fungal elements, complemented by evaluation of the vaginal pH (infection usually occurs with a pH between 4 and 4.5); - Culture in specific material. To decrease costs, some authors recommend prompt culture only for complicated or recurrent vulvovaginal candidiasis. Therapeutic recommendations Non-complicated vulvovaginal candidiasis. Topical therapy: although most patients prefer oral medications, a metaanalysis comparing 17 studies of uncomplicated vulvovaginal candidiasis revealed similar efficacy between oral and vaginal drugs. [bib_ref] Oral versus intra-vaginal imidazole and triazole anti-fungal agents for the treatment of..., Watson [/bib_ref] There is evidence that topically applied azole therapy over a period of 3-7 days is more effective than nystatin, with improvement of symptoms and negative cultures in 80-90% of patients who completed therapy (A-I). Generally, higher concentrations and doses of topical medications are effective over a period of 3 days. Lower doses of the same formulations require more prolonged therapy. [bib_ref] Clinical practice guidelines for the management of candidiasis: 2009 update by the..., Pappas [/bib_ref] The options for topical therapy are numerous and include the following: - Butaconazole 2% cream, 5 g/day; - Clotrimazole cream 1%, 5 g/day; - There are formulations containing combination therapy with other agents that will not be commented upon in the text: - Systemic therapy: the use of oral triazoles is a safe and efficient alternative to topical therapy. There is a large amount of clinical experience in treating vulvovaginal candidiasis with fluconazole 150 mg QD, single dose (A-I). [bib_ref] Clinical practice guidelines for the management of candidiasis: 2009 update by the..., Pappas [/bib_ref] Another option to this drug is itraconazole 200 mg QD for 3 days or 400 mg single dose (B-II). [bib_ref] Clinical and mycological efficacy of single-day oral treatment with itraconazole (400 mg)..., Urunsak [/bib_ref] Systemic therapy with triazoles is not indicated in pregnant women. The treatment of sexual partners is not recommended in uncomplicated cases but may be considered in recurrent cases. [bib_ref] Sexually transmitted diseases treatment guidelines, Kimberly [/bib_ref] Complicated vulvovaginal candidiasis. - Moderate and severe cases and/or immunocompromised patients: prolonged topical and systemic therapy should be administered to these patients. Topical therapy is recommended for at least 7-14 days using any of the formulations listed above (A-I). [bib_ref] Clinical practice guidelines for the management of candidiasis: 2009 update by the..., Pappas [/bib_ref] In case of systemic therapy, the following drugs can be considered: - Fluconazole 150 mg/day, repeated two or three times 72 h apart (A-I); - Itraconazole 200 mg/day for 3 days (B-II). ## Recurrent vulvovaginal candidiasis. - If the diagnosis of recurrent vulvovaginal candidiasis is made and if there is no identification of or possibility to control or remove the triggering factors, suppressive therapy with triazoles for six months is an effective control measure for recurrent episodes (A-I). [bib_ref] Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis, Sobel [/bib_ref] ## Urinary candidiasis ## Epidemiological aspects The term candiduria refers to the growth of Candida spp. in urine cultures collected by appropriate techniques; this finding is not necessarily accompanied by signs and/or symptoms of urinary tract infection (UTI). Candiduria is very frequent among patients exposed to risk factors; up to 20% of hospitalized patients may have candiduria during their hospitalization, particularly intensive care unit (ICU) patients. [bib_ref] Candiduria in critically ill patients admitted to intensive care medical units, Alvarez-Lerma [/bib_ref] This laboratory finding fosters dilemmas regarding its interpretation, as it can represent a simple contamination of the urine collection, candiduria asymptomatic cystitis or pyelonephritis, primary renal candidiasis, ureteropelvic fungus ball or disseminated candidiasis with renal manifestations. Among hospitalized patients, the factors most often related to the development of candiduria are advanced age, female gender, broad-spectrum antibiotics, the use of corticosteroids and immunosuppressive drugs, the presence of urinary tract abnormalities, diabetes, delayed vesical catheterization, postoperative of major surgery and malignancies. [bib_ref] Candida urinary tract infections -epidemiology, Sobel [/bib_ref] Series of cases from Brazil confirm that the three most prevalent species isolated from urine in hospitalized patients are C. albicans, C. tropicalis and C. glabrata. These studies measure prevalences ranging from 35.5 to 70% for C. albicans, 4.6-52.5% for C. tropicalis and 7-8.8% for C. glabrata. [bib_ref] Candiduria in hospitalized patients: a review, Nucci [/bib_ref] [bib_ref] Nosocomial urinary tract infections by Candida species, Oliveira [/bib_ref] [bib_ref] Candiduria in hospital patients: a study prospective, Kobayashi [/bib_ref] [bib_ref] Candida colonization in intensive care unit patients' urine, Passos [/bib_ref] ## Clinical and laboratory diagnosis In outpatients not exposed to the risk factors mentioned, in most cases, the identification of Candida in urine reflects inadequate collection or processing of the sample and consequent contamination of the culture. In patients exposed to risk factors for UTI by Candida, the finding of candiduria may signify colonization or infection. In these patients, the counting of colonies is highly variable and directly dependent on the methodology used to collect material. Thus, the isolation of Candida in the urine may occur even in the absence of disease, and there is considerable controversy regarding the value of colony counts obtained in culture, a procedure with low specificity and sensitivity in differentiating between patients colonized and infected by this agent. [bib_ref] Candiduria: a clinical and therapeutic approach, Colombo [/bib_ref] Some authors suggest that there is a greater relationship between candiduria and UTI when the colony count in the urine culture reaches values of approximately 10,000-100,000 CFU/mL. [bib_ref] Controversies in the diagnosis of candiduria: what is the critical colony count, Sobel [/bib_ref] [bib_ref] Yeasts in the urine: solutions for a budding problem, Fisher [/bib_ref] However, scores below that can be measured in patients with Candida UTI, particularly in cases of pyelonephritis acquired by the hematogenous route due to systemic candidiasis, in which the kidneys function as filters and may reflect low counts in the urine. In this sense, there is no consensus among authors on the specific cutoff value for the interpretation of quantitative urine cultures for the recognition of patients with infection of the lower UTI or pyelonephritis. [bib_ref] Candidemia from urinary tract source: microbiological aspects and clinical significance, Ang [/bib_ref] ## Therapeutic recommendations - The best therapeutic approach for patients with candiduria should be defined on individual basis, considering clinical and epidemiological data to classify each patient into one of the following conditions: (1) no prior risk factors for candiduria, (2) exposure to risk factors but unlikely to be a case of disseminated candidiasis, or (3) exposure to risk factors for candiduria with septicemia without defining etiology and possible/probable systemic dissemination. 102,12 - The therapeutic approach suggested for these three different scenarios are the following. (1) No prior risk factors for candiduria: in this category, we have patients without underlying diseases who did not undergo catheterization and who have no history of previous use of corticosteroids and antibiotics. They should not receive systemic antifungal agents. It is recommended to request a new collection of material and, if yeasts are found, to investigate the possibility of fungal genital mucositis in the vagina or the glans (C-III). [bib_ref] Nosocomial candiduria: a review, Lundstrom [/bib_ref] (2) Predisposed to candiduria, but unlikely to be disseminated candidiasis: this category includes asymptomatic outpatients or inpatients who underwent catheterization and/or other predisposing factors for candiduria. In these patients, the initial approach is the removal of the predisposing factors with subsequent clinical and laboratory follow-up (C-III). In the vast majority of patients, candiduria resolves after the introduction of these measures. Patients with symptoms of cystitis and with positive urine for yeasts should be treated with antifungal agents (B-III). [bib_ref] Clinical practice guidelines for the management of candidiasis: 2009 update by the..., Pappas [/bib_ref] [bib_ref] Candida urinary tract infections -treatment, Fisher [/bib_ref] If it is not possible to remove the system, it is at least recommended to change it. 140 ## Peritoneal candidiasis related to dialysis ## Epidemiological aspects Peritoneal dialysis is a modality of renal replacement therapy that currently accounts for only 10-20% of dialysis modalities. It can be performed continuously with an oriented procedure performed at home or intermittently, which has been completely abandoned. Among the complications of peritoneal dialysis, infection ranks second place after cardiovascular events, and fungal infections account for 2-14% of peritonitis cases. [bib_ref] Fungal peritonitis complicating peritoneal dialysis during an 11-year period: report of 46..., Bibashi [/bib_ref] The overall mortality in most series ranges from 10 to 25% of cases, and there are a few reports of up to 50% deaths. [bib_ref] Septicemia in dialysis patients: incidence, risk factors and prognosis, Powe [/bib_ref] Among the fungal peritonitis diseases, 80-90% are caused by Candida, particularly isolates of C. albicans, C. parapsilosis and C. tropicalis. [bib_ref] Candida parapsilosis peritonitis has more complications than other Candida peritonitis in peritoneal..., Chen [/bib_ref] The risk factors for the occurrence of fungal peritonitis in patients on peritoneal dialysis are not completely known. [bib_ref] Factors predicting outcome of fungal peritonitis in peritoneal dialysis: analysis of a..., Wang [/bib_ref] The basic conditions most commonly reported in patients with fungal peritonitis include diabetes, the prior occurrence of peritonitis by other agents and the previous use of antibiotics. [bib_ref] Fungal peritonitis in peritoneal dialysis patients, Prasad [/bib_ref] ## Clinical and laboratory diagnosis Diagnosis is made through clinical signs and symptoms of peritonitis, which are represented by abdominal pain, distention, and fever associated with clouding of the dialysis fluid, whose cell count increases due to the neutrophil count (>100 leukocytes/mm 3 ). Etiologic evidence is obtained by identification of yeasts in bacterioscopic examination of the peritoneal fluid, with growth of Candida spp. in culture. [bib_ref] Fungal peritonitis complicating peritoneal dialysis during an 11-year period: report of 46..., Bibashi [/bib_ref] [bib_ref] Fungal peritonitis in peritoneal dialysis patients, Prasad [/bib_ref] Therapeutic recommendations The guidelines for the treatment of fungal peritonitis are based on case reports and open-label studies of limited groups of patients. Among the key recommendations for the treatment of this complication, the authors suggest that the early removal of the dialysis catheter is essential to the success of the therapy (B-II). [bib_ref] Update on fungal peritonitis and its treatment, Matuszkiewicz-Rowinska [/bib_ref] The largest experience in the treatment of fungal peritonitis is with fluconazole or amphotericin B (B-II). Many authors recommend starting with amphotericin and completing treatment with fluconazole after clinical improvement (B-II). [bib_ref] Update on fungal peritonitis and its treatment, Matuszkiewicz-Rowinska [/bib_ref] Some authors suggest the use of intraperitoneal fluconazole concomitantly with the systemic use of amphotericin B (C-III). [bib_ref] Intraperitoneal fluconazole for fungal peritonitis in CAPD: report of two cases, Kameoka [/bib_ref] The treatment period is usually four to six weeks. It is essential to monitor the patient by abdominal ultrasound to rule out collections and to guide the treatment time (B-III). [bib_ref] Update on fungal peritonitis and its treatment, Matuszkiewicz-Rowinska [/bib_ref] There is little reliable information regarding doses of antifungal agents, but the authors suggest the use of 0.7 mg/kg to 1 mg/kg/day of amphotericin B and 400 mg/day of fluconazole. [bib_ref] Treatment of fungal peritonitis with a combination of intravenous amphotericin B and..., Wong [/bib_ref] If implantation of a new peritoneal catheter is an option, this procedure should be performed with a minimum interval of four to six weeks after the initiation of treatment (C-III). According to recent studies, at least 40% of patients with fungal peritonitis cannot continue with peritoneal dialysis. Another modality for renal replacement therapy is needed. [bib_ref] Treatment of fungal peritonitis with a combination of intravenous amphotericin B and..., Wong [/bib_ref] Among the new drugs, caspofungin has experienced the most success. It may be considered for patients with poor responses to conventional treatment and can be used at 50-100 mg/day with good tolerability (B-II). [bib_ref] Caspofungin for the treatment of less common forms of invasive candidiasis, Cornely [/bib_ref] However, in view of the pharmacological similarities and therapeutic success of echinocandins, it is believed that all echinocandins can be used with these conditions (C-III). ## Postoperative peritoneal candidiasis ## Epidemiological aspects Postoperative peritonitis caused by Candida species occurs with significant frequency in the hospital. The majority of cases are related to episodes of secondary or tertiary peritonitis, when cases of acute abdomen perforated by bacterial peritonitis are subsequently followed by fungal peritonitis. The perforation of the upper digestive tract is more frequently associated with contamination of the peritoneal cavity by Candida compared to the ileum and appendix, occurring in 5-64% of the perforated cases. [bib_ref] Significance of Candida recovered from intraoperative specimens in patients with intra-abdominal perforations, Sandven [/bib_ref] ## Clinical and laboratory diagnosis The pathological significance of Candida spp. isolation in the peritoneal fluid and drains of patients undergoing surgery involving manipulation of the gastrointestinal tract is uncertain. The disruption of the anatomical barrier of the gastrointestinal tract can lead to the isolation of transitional agents in the abdominal cavity or contamination of cultures without evolution of the process to properly fungal peritonitis. [bib_ref] Clinical significance of Candida isolated from peritoneum in surgical patients, Calandra [/bib_ref] Moreover, a case-control study has isolated Candida spp. in the peritonea of patients who developed perforation of the gastrointestinal tract that caused increased mortality. [bib_ref] Candida as a risk factor for mortality in peritonitis, Montravers [/bib_ref] In this context, the interpretation of the identification of Candida in peritoneal fluid should be evaluated on an individual basis, considering the patient's clinical conditions. When Candida is identified in the peritoneal fluid of patients with complicated postoperative recoveries, along with persistent fever and other evidence of peritonitis (for which sepsis is likely from an abdominal source), fungal etiology should be strongly considered. However, in most cases when Candida is isolated in the intraperitoneal fluid cultures of young patients without comorbidities and who have no evidence of systemic infection in postoperative uncomplicated appendicitis, the laboratory finding is generally transitory with no pathological meaning. [bib_ref] Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines..., Solomkin [/bib_ref] ## Therapeutic recommendations Although the isolation of Candida in the abdominal cavity is associated with an increase in postoperative complications and mortality, the clinical and laboratory data that should trigger the use of antifungal agents are still a matter of controversy. If there is suspicion of invasive candidiasis, the patient should be treated according to the appropriate therapy for hematogenous candidiasis. [bib_ref] Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines..., Solomkin [/bib_ref] The most experience in the treatment of peritonitis caused by Candida involves the use of amphotericin B (0.7-1 mg/kg/day) or fluconazole (400-800 mg/day) (B-II).However, the toxicity of amphotericin B and the limited spectrum of fluconazole limit their use in many clinical scenarios. Taking into account the high rate of success of treating hematogenous candidiasis observed in patients with echinocandins and the large sample of surgical patients in these studies, it is believed that all echinocandins constitute good alternatives in this condition (B-I). [bib_ref] Caspofungin for the treatment of less common forms of invasive candidiasis, Cornely [/bib_ref] ## Respiratory tract candidiasis ## Epidemiological aspects Despite the controversies, there is a general concept in the literature that Candida pneumonia is an unusual event, particularly among non-neutropenic patients admitted to ICUs. The highest incidences of C. pneumonia are documented among neutropenic patients with hematologic malignancies or patients undergoing lung transplantation. [bib_ref] Practices in nonneutropenic ICU patients with Candida-positive airway specimens, Azoulay [/bib_ref] In most cases, C. pneumonia is secondary to a hematogenous invasion. In patients undergoing lung transplantation, bronchial anastomosis has been identified as an anatomical site that is potentially more susceptible to colonization and invasion by opportunistic fungi, partly due to the relative ischemia of this region after transplantation. These infections may be complicated by anastomotic dehiscence and subsequent bleeding. [bib_ref] Saprophytic fungal infections and complications involving the bronchial anastomosis following human lung..., Nunley [/bib_ref] In ICU patients, especially those undergoing mechanical ventilation, airway colonization by Candida is found with relative frequency, but with no pathological significance. Tracheobronchial colonization by Candida in ICU patients is the result of impairment of local defense mechanisms, the presence of an endotracheal tube, the use of antacids and the exposure to antibiotics, conditions that lead to substantial changes in the microbiota of the oropharynx and the gastrointestinal and respiratory tracts. [bib_ref] Significance of the isolation of Candida species from respiratory samples in critically..., El-Ebiary [/bib_ref] ## Clinical and laboratory diagnosis The isolation of Candida in the respiratory tract of critically ill patients, even if obtained by bronchoalveolar lavage, does not allow for the diagnosis of pulmonary candidiasis. In most cases, this finding refers to the colonization and/or contamination of the sample during the procedure. Diagnosis by quantitative culture is not reliable for differentiating colonized patients from those with pneumonia caused by Candida. Thus, the final diagnosis is dependent on lung biopsy with demonstration of the presence of fungal elements in the intima of the parenchyma and supplemented by a culture of tissue fragments with growth of Candida spp. [bib_ref] Significance of the isolation of Candida species from respiratory samples in critically..., El-Ebiary [/bib_ref] In practice, this is rarely a definitive diagnosis. ## Therapeutic recommendations In general, the identification of positive cultures for Candida spp. in respiratory tract samples should be considered evidence of local colonization whose risk of progression to pneumonia is usually small (B-II). [bib_ref] Fungal colonization and/or infection in intensive care units. Multicenter study of 1,562..., Alvarez-Lerma [/bib_ref] Special attention is recommended in the investigation of neutropenic patients, patients with cancer or hematologic malignancies, along with patients undergoing HSCT or lung transplantation (B-II). [bib_ref] Pulmonary candidiasis in patients with cancer: an autopsy study, Kontoyiannis [/bib_ref] [bib_ref] Pulmonary candidiasis after hematopoietic stem cell transplantation: thin-section CT findings, Franquet [/bib_ref] [bib_ref] Invasive pulmonary fungal infections in solid organ transplant recipients: a four-year review, Oner-Eyuboglu [/bib_ref] When a definitive diagnosis of pneumonia is reached, the antifungal should be chosen as discussed in the section involving acute disseminated candidiasis; there may be a choice between echinocandins, fluconazole or amphotericin B formulations (B-II). [bib_ref] Caspofungin for the treatment of less common forms of invasive candidiasis, Cornely [/bib_ref] [bib_ref] Recommendations for the treatment of fungal pneumonias, Yamada [/bib_ref] ## Hematogenous candidiasis ## Epidemiological aspects Hematogenous candidiasis encompasses a wide spectrum of clinical episodes, including isolates of Candida or cases in which the fungus is present in the bloodstream and spreads to one or more organs of the infected host. [bib_ref] Epidemiology of hematogenous infections due to Candida spp, Colombo [/bib_ref] Considering that most of the data available for hematogenous Candida infection refer to candidemia, this is the term that will be used in these guidelines. It is believed that the majority of cases of candidemia are acquired via the endogenous route due to the translocation of the pathogen through the gastrointestinal tract, where there is rich colonization by Candida spp. in up to 70% of the general population. Most candidemia events are preceded by colonization by the same species of yeast, which is considered as an independent risk factor for its development. Genotyping methods reveal the similarities between colonizing and infecting strains, confirming the probable endogenous origin of most of the infections caused by these pathogens. [bib_ref] The role of the gastrointestinal tract in hematogenous candidiasis: from the laboratory..., Cole [/bib_ref] Any variables causing injury or imbalance in the microbiota of the gastrointestinal mucosa can be facilitators of translocation of Candida spp. to the mesenteric capillaries. Thus, factors that increase intestinal colonization by Candida (i.e., antibiotics, corticosteroids, ileus or intestinal obstruction) or that determine atrophy or intestinal mucosal damage (i.e., prolonged fasting, total parenteral nutrition, hypotension, surgical procedure, mucositis secondary to chemotherapy or radiotherapy) may potentiate the phenomenon of translocation in the gastrointestinal tract. [bib_ref] The process of microbial translocation, Alexander [/bib_ref] Hematogenous infections by Candida spp. can also be acquired exogenously, either by contamination of invasive medical procedures, prostheses or contaminated infusion solutions, such as the colonization of vascular catheters in central positions. [bib_ref] Nosocomial candidiasis: emerging species, reservoirs and modes of transmission, Pfaller [/bib_ref] Case-control studies conducted during the 1980s and 1990s identified numerous risk factors associated with the occurrence of candidemia in hospitalized patients, including: the use of antibiotics, colonization by Candida spp. at different sites, dialysis, major surgery, the use of a CVC in place, chemotherapy, neutropenia, steroid use and parenteral nutrition. [bib_ref] Nosocomial fungal infections: candidemia, Lunel [/bib_ref] [bib_ref] Hospital acquired candidemia. The attributable mortality and excess length of stay, Wey [/bib_ref] There is a wide geographical variation in the documented etiology patterns of candidemia in different medical centers. In different studies in tertiary hospitals in the public system in Brazil, C. tropicalis and C. parapsilosis are prevalent. [bib_ref] Epidemiology of opportunistic fungal infections in Latin America, Nucci [/bib_ref] [bib_ref] Global distribution and outcomes for Candida species causing invasive candidiasis: results from..., Colombo [/bib_ref] Epidemiology can vary between different institutions; a recent study noted higher incidences of C. glabrata in private hospitals of São Paulo, Rio de Janeiro, Salvador, Belo Horizonte and Curitiba, where the use of fluconazole started in the 1990s. Confirming these data, other series published after 2008 reported rates of candidemia due to C. glabrata and/or C. krusei above 10% in our setting. [bib_ref] Secular trends of candidemia in a tertiary care hospital, Sampaio Camargo [/bib_ref] [bib_ref] Take control over your fluconazole prescriptions: the growing importance of Candida glabrata..., Pasqualotto [/bib_ref] These data reinforce the importance of implementing programs for microbiological surveillance of bloodstream infections for the optimization of control strategies and the treatment of these infectious complications. ## Clinical and laboratory diagnosis Hematogenous candidiasis is an infectious complication that should always be investigated in patients with sepsis after a long period of hospitalization and exposure to risk factors of candidemia, particularly exposure to broad-spectrum antibiotic therapy, invasive medical procedures, immunosuppressive therapy and parenteral nutrition. Brazilian data suggest that 40-50% of these patients are in the ICU at the time of diagnosis. A substantial number of cases have antecedents involving major surgery, particularly with manipulation of gastrointestinal tract. [bib_ref] Epidemiology of candidemia in Brazil: a nationwide sentinel surveillance of candidemia in..., Colombo [/bib_ref] [bib_ref] Epidemiology of opportunistic fungal infections in Latin America, Nucci [/bib_ref] The study of the natural history of patients with candidemia shows that some episodes of fungemia must be transient and self-limited, particularly in non-neutropenic hosts. However, there are no clinical or laboratory data that allow the clinician to identify with certainty which episodes are only transitory and which will lead to cases of disseminated hematogenous candidiasis with tissue invasion and severe sepsis at the moment of the fungemia diagnosis. Another important aspect to consider is that in some patients, infectious complications documented in the viscera appear weeks or months after a candidemia episode, as occurs in some cases of retinitis, meningitis, or osteomyelitis caused by Candida spp. [bib_ref] Candidemia: current epidemiologic characteristics and a long term follow-up of the survivors, Debusk [/bib_ref] [bib_ref] Epidemiology and treatment approaches in management of invasive fungal infections, Kriengkauykiat [/bib_ref] These guidelines will discuss in detail the clinical management of three different scenarios of hematogenous candidiasis: [bib_ref] Skin lesions associated with disseminated candidiasis, Bodey [/bib_ref] In more recent studies, systematic evaluation of fundoscopy performed by an ophthalmologist suggests that ocular involvement occurs in up to 16% of patients with candidemia, being 2-9% of cases of chorioretinitis and 1% of cases of endophthalmitis. [bib_ref] Retinal lesions as clues to disseminated bacterial and candidal infections: frequency, natural..., Rodriguez-Adrian [/bib_ref] [bib_ref] Ocular manifestations of candidemia, Lashof [/bib_ref] Symptoms include blurred vision, bulbar scotomas and pain. The ophthalmologic abnormalities are characterized by cotton wool lesions in the retina and vitreous humor, multiple retinal hemorrhages, Roth spots, and uveitis. However, all ocular structures may be affected. When endophthalmitis occurs, therapy is difficult, and the incidence of sequelae is high. The recognition of ocular involvement in patients with candidemia is crucial because the treatment should be administered for a longer period and may eventually require surgery to control the process. The diagnosis should be made early, before the involvement of the vitreous. [bib_ref] Should all patients with candidemia have an ophthalmic examination to rule out..., Krishna [/bib_ref] In adults, Candida meningitis usually results from the contamination of a neurosurgical procedure and is rarely documented as a complication of candidemia. However, according to data from autopsy series (which may not represent the general population), patients with sepsis who develop Candida fungal lesions in the central nervous system have died in up to 20% of cases. [bib_ref] Filadélfia: Churchill Livingstone, Filler [/bib_ref] Endocarditis caused by Candida usually occurs as a post-surgical complication of valve replacement surgery and in intravenous drug users, particularly those who use heroin. Endocarditis is rarely reported as a single candidemia complication in a patient who did not undergo cardiac surgery. [bib_ref] Filadélfia: Churchill Livingstone, Filler [/bib_ref] Osteoarticular involvement of candidemia is quite rare but may arise as a late complication (more than one year after the alleged episode of fungemia). Bone involvement is recognized by local pain, fever and radiological findings consistent with osteomyelitis. [bib_ref] Filadélfia: Churchill Livingstone, Filler [/bib_ref] The diagnosis of hematogenous candidiasis in at-risk patients requires careful clinical examination to identify skin lesions and ocular changes consistent with candidemia, in addition to blood cultures. Blood cultures are a mandatory procedure in any patient with clinical suspicion of systemic infection by Candida, and some care must be taken to optimize the recovery of the agent: - Follow appropriate antisepsis at the puncture site, and remember that the antiseptic must be allowed to act for a few minutes before performing the collection. - It is desirable that blood cultures be performed before use of antimicrobials, or if this is not possible, blood should be harvested in the period preceding the administration of daily doses of drugs. - Blood volume and number of samples are crucial for a good yield of blood cultures; it is recommended that at least two samples per episode of sepsis be collected and that each sample contain at least 20 mL of blood (divided into two blood culture bottles per sample). 176 - Conventional aerobic bottles for automated blood cultures allow the growth of Candida species. However, the performance of aerobic vials may vary between different products. Bactec system vials have lower sensitivity and a longer time for fungal growth than bottles from the BacTAlert system. There are no appreciable differences between these products when using bottles with selective media for fungi. [bib_ref] Detection of fifteen species of Candida in an automated blood culture system, Horvath [/bib_ref] - It is essential that blood cultures be processed by automated systems, which have better sensitivity and allow for quicker isolation of the agent. It is important to remember that there is a direct relationship between mortality and the time to onset of treatment of candidemia. Accordingly, every effort should be made for early recognition of patients with hematogenous candidiasis. [bib_ref] Clinical practice guidelines for the management of candidiasis: 2009 update by the..., Pappas [/bib_ref] Given the low frequency of the occurrence of visceral lesions in the majority of adult patients with candidemia, the investigation of fungal endocarditis (echocardiography) and lesions in other organs (abdominal imaging) should be reserved for patients who persist with isolation of Candida in blood cultures despite appropriate antifungal therapy or who show signs of clinical deterioration and signs/symptoms suggestive of infection in the abdominal cavity and/or endocarditis. In turn, fundoscopic examination should be performed in all patients with candidemia and visual symptoms. In patients with candidemia but no visual symptoms, it is recommended to perform fundoscopy one week after the initiation of therapy to increase the sensitivity of eye lesion detection. 102,174 3. Chronic disseminated candidiasis (CDC): complication documented in patients with neutropenia that develop suppurative lesions predominantly localized in the liver and spleen (but may occur in other organs, particularly the kidney) that manifest after the recovery of neutrophils and capacity of the host inflammatory response. High fever is the most important symptom and occurs in almost all patients; it is associated with anorexia, weight loss, pain in the right hypochondrium, nausea and vomiting. Hepatosplenomegaly is identified in half of the cases. A significant increase in serum alkaline phosphatase, which can be up to ten times the baseline, is the most important laboratory finding for CDC diagnosis in suspected patients with persistent fever after neutrophil recovery. [bib_ref] Filadélfia: Churchill Livingstone, Filler [/bib_ref] A diagnosis can be confirmed with ultrasound, computerized tomography, magnetic resonance imaging or positron emission tomography (PET-CT) of the abdomen, along with findings of swelling of the affected organs and the presence of multiple abscesses in the liver, spleen and/or kidneys. Blood cultures are usually negative, and if a directed biopsy is conducted, necrotic cellular elements can be identified, and fungal elements are absent. In this context, microbiological confirmation of the process is rarely obtained. In most cases, the patient is treated according to the epidemiological and clinical findings, together with the laboratory evidence of CDC represented by abscesses in abdominal imaging and high levels of alkaline phosphatase. [bib_ref] Filadélfia: Churchill Livingstone, Filler [/bib_ref] [bib_ref] Chronic disseminated candidiasis in patients with acute leukemia: emphasis on diagnostic definition..., Masood [/bib_ref] It is important to remember that this situation can occur in infections by other fungi, including yeast (e.g., Trichosporon) and molds (Fusarium, Scedosporium, etc.). ## Therapeutic recommendations The definition of the best therapeutic strategy to be adopted for patients with hematogenous candidiasis should consider the aspects described below: [bib_ref] Candidemia: impact of epidemiological studies on the treatment and prognosis of a..., Almirante [/bib_ref] - Presence of infectious complications in organs: the occurrence of endophthalmitis, osteomyelitis, endocarditis and CDC are examples of clinical conditions for which antifungal therapy should be extended for periods of four weeks to six months. If prolonged therapy is needed, oral drugs should be chosen. - Severity of the clinical presentation of the case: this issue is controversial, but patients with organ failure are usually treated initially with fast-acting antifungal drugs; fluconazole is generally saved for a second event when there is an initial clinical response and identification of the Candida species. - Determination of Candida species: non-albicans species may exhibit lower susceptibility to fluconazole, requiring dose adjustment or a change in medication. - Risk of renal toxicity while using conventional amphotericin B: the occurrence of acute renal failure in patients in ICUs with renal dysfunction, elderly patients and those receiving other nephrotoxic drugs. - Previous exposure to antifungal prophylaxis regimens and/or empirical therapy: facing a breakthrough infection in a patient exposed to an antifungal agent, a change of therapeutic class is indicated until the involved Candida species and the susceptibility profile of the agent are confirmed. - Presence of an intravascular catheter in a central position: the clinical management of this aspect will be discussed in another section. We currently have the following drugs available for the treatment of invasive candidiasis: amphotericin B and its formulations, fluconazole, voriconazole and echinocandins. ## Candidemia in non-neutropenic patients In the last two years, there have been important changes in the epidemiology of candidemia. Several medical centers have reported fungemia rates greater than 10% in adult patients involving species resistant to fluconazole, particularly C. glabrata and C. krusei. [bib_ref] Secular trends of candidemia in a tertiary care hospital, Sampaio Camargo [/bib_ref] [bib_ref] Take control over your fluconazole prescriptions: the growing importance of Candida glabrata..., Pasqualotto [/bib_ref] [bib_ref] Candidemia epidemiology and susceptibility profile in the largest Brazilian teaching hospital complex, Motta [/bib_ref] Moreover, it is known that the rates of persistent Candida in patients treated with fluconazole are far superior to those of patients treated with drugs most effectives, like echinocandins or formulations of amphotericin B. [bib_ref] Anidulafungin versus fluconazole for invasive candidiasis, Reboli [/bib_ref] [bib_ref] Comparative efficacy of echinocandins and nonechinocandins for the treatment of Candida parapsilosis..., Kale-Pradhan [/bib_ref] In the only study comparing an echinocandin to fluconazole, success rates were significantly higher in patients treated with anidulafungin, even in infections susceptible to fluconazole (C. albicans and C. tropicalis). [bib_ref] Anidulafungin versus fluconazole for invasive candidiasis, Reboli [/bib_ref] However, for the three echinocandins available in the Brazilian market, there have been substantial price reductions in the daily treatment doses used with this therapeutic class. A meta-analysis study evaluating therapeutic results of 7 randomized clinical trials performed in 1.915 patients with candidemia/invasive candidiasis involving three therapeutic classes reported that treatment with echinocandins was associated with decreased mortality. [bib_ref] Impact of treatment strategy on outcomes in patients with candidemia and other..., Andes [/bib_ref] Given the poor prognosis of this infection in Brazil (50% associated mortality in most series), the high rate of successful clinical and laboratory treatment of candidemia when a broadspectrum antifungal drug with fungicidal activity is used from the beginning of treatment, and the lower rates of echinocandin toxicity compared to any formulation of amphotericin B, we understand that the best option for initial treatment of this infectious complication is one of the three echinocandins: anidulafungin (A-I), caspofungin (A-I) or micafungin (A-I). [bib_ref] Comparison of caspofungin and amphotericin B for invasive candidiasis, Mora-Duarte [/bib_ref] [bib_ref] Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase..., Kuse [/bib_ref] [bib_ref] Anidulafungin versus fluconazole for invasive candidiasis, Reboli [/bib_ref] Despite the high MIC values observed with echinocandin when tested against C. parapsilosis, therapeutic results are satisfactory in clinical trials, with no significant differences regarding success rates when compared to infections by other species of Candida. [bib_ref] Prevalence rates and antifungal susceptibility profiles of the Candida parapsilosis species complex:..., Gonç Alves [/bib_ref] [bib_ref] Caspofungin use in patients with invasive candidiasis caused by common non-albicans Candida..., Colombo [/bib_ref] However, with persistent positive blood cultures for C. parapsilosis, it is recommended that another class of antifungal be started (B-II). The best use of fluconazole should be considered in sequential therapy to complete a minimum period of 14 days of treatment after determining the etiological agent and upon documentation of a favorable clinical response to treatment with echinocandins (B-I). [bib_ref] A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus..., Rex [/bib_ref] The best use of voriconazole is as an oral sequential therapy in patients infected with strains resistant to fluconazole and susceptible to voriconazole and as a therapeutic approach for patients with central nervous system involvement/endophthalmitis (B-II). [bib_ref] Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia..., Kullberg [/bib_ref] [bib_ref] Treatment of endogenous fungal endophthalmitis: focus on new antifungal agents, Riddell 4th [/bib_ref] This product should be contraindicated in breakthrough infections after fluconazole therapy and/or invasive infections caused by C. glabrata and C. krusei and in view of the possibility of cross-resistance and limited efficacy in this scenario (B-III). [bib_ref] International surveillance of bloodstream infections due to Candida species: frequency of occurrence..., Pfaller [/bib_ref] [bib_ref] Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia..., Kullberg [/bib_ref] In view of the renal toxicity of amphotericin B deoxycholate, this drug should be avoided in ICU patients, particularly those exposed to conditions or other nephrotoxic drugs (A-I). [bib_ref] Mortality and costs of acute renal failure associated with amphotericin B therapy, Bates [/bib_ref] Fluconazole may be an alternative therapy in clinically stable patients whose infections are considered minor, who were not exposed to regimens of prophylaxis with triazoles, and who are admitted to medical services exhibiting low incidences of infections caused by C. glabrata and C. krusei (B-I). [bib_ref] A randomized trial comparing fluconazole with amphotericin B for the treatment of..., Rex [/bib_ref] Medical centers with rates of incidence exceeding 10% of the fluconazole-resistant strains should not use fluconazole in any patient before the agent is identified (C-III). Lipid formulations of amphotericin B are an alternative therapy for candidemia, but they have greater renal toxicity than echinocandins. The only lipid formulation in the treatment of Candida assessed in a randomized and comparative study with echinocandin was the liposomal formulation of amphotericin B, indicated at a dose of 3 mg/kg/day for the treatment of adults (B-I). [bib_ref] Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase..., Kuse [/bib_ref] The lipid complex of amphotericin B has been used in patients with candidemia, but only in open-label noncomparative studies using doses ranging from 3 mg/kg/day and 5 mg/kg/day (B-II). [bib_ref] Amphotericin B lipid complex for the treatment of patients with acute leukemia..., Sallah [/bib_ref] Lipid formulations of amphotericin B are alternatives for patients who: are unresponsive to echinocandins, are intolerant to this therapeutic class, or develop endocarditis or meningitis (B-III). [bib_ref] Clinical practice guidelines for the management of candidiasis: 2009 update by the..., Pappas [/bib_ref] Patients with endophthalmitis may not respond to echinocandins, given its low penetration in the eye. In this context, better results are expected with fluconazole or voriconazole (B-II). [bib_ref] Ocular manifestations of candidemia, Lashof [/bib_ref] With respect to the time of treatment in all randomized trials conducted with antifungal agents in the last decade, the duration of antifungal therapy was at least 14 days after negative cultures and the disappearance of signs and symptoms of hematogenous candidiasis. [bib_ref] Clinical practice guidelines for the management of candidiasis: 2009 update by the..., Pappas [/bib_ref] In this sense, serial blood cultures must be collected until the infection site is negative, and it is recommended to repeat sampling on the third and fifth day after initiation of therapy (at a minimum) to evaluate the success of the microbial treatment (B-III). [bib_ref] Clinical practice guidelines for the management of candidiasis: 2009 update by the..., Pappas [/bib_ref] Cases of endocarditis, osteomyelitis, meningitis, or CDC require longer treatment; it is very important to check the availability of antifungal drugs with good bioavailability for oral use (B-II). 102 ## Candidemia in neutropenic patients Patients with neutropenia should be treated with drugs with a broad-spectrum antifungal drug with fungicidal activity from the beginning of treatment (A-II). [bib_ref] Guidelines for the use of antimicrobial agents in neutropenic patients with cancer, Hughes [/bib_ref] Given the risk of renal toxicity with conventional amphotericin B, this drug should be avoided in this scenario (B-I). [bib_ref] Mortality and costs of acute renal failure associated with amphotericin B therapy, Bates [/bib_ref] Therefore, echinocandins (A-I), liposomal amphotericin B (B-I) and amphotericin B lipid complex (B-II) are considered alternatives. [bib_ref] Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with..., Walsh [/bib_ref] [bib_ref] Modern antifungal therapy for neutropenic fever, Corey [/bib_ref] Randomized trials of candidemia involving caspofungin and micafungin included approximately 10% neutropenic patients. Although there are no data on the performance of anidulafungin in the treatment of candidemia in neutropenic patients, there is no evidence of pre-clinical or clinical order to suggest that echinocandins have differences in their rates of therapeutic success (B-III). Given the higher incidence of infections caused by C. glabrata and C. krusei in patients with cancer, along with the fact that large percentages of patients with neutropenia are exposed to fluconazole prophylaxis, the recommendation is that the primary treatment of candidemia in patients with cancer and neutropenia not be performed with triazoles (B-II). [bib_ref] Candidaemia in adult cancer patients: risks for fluconazole-resistant isolates and death, Slavin [/bib_ref] The treatment time must meet the same criteria established for non-neutropenic patients (B-I). [bib_ref] Clinical practice guidelines for the management of candidiasis: 2009 update by the..., Pappas [/bib_ref] Infections involving multiple organs or systems must meet the same recommendations given for non-neutropenic patients, along with care for patients referred for C. parapsilosis candidemia treated with echinocandins (B-II). [bib_ref] Prevalence rates and antifungal susceptibility profiles of the Candida parapsilosis species complex:..., Gonç Alves [/bib_ref] [bib_ref] Caspofungin use in patients with invasive candidiasis caused by common non-albicans Candida..., Colombo [/bib_ref] ## Patients with evidence of endophthalmitis All patients with candidemia should have at least one dilatedeye examination performed by an ophthalmologist (A-II). [bib_ref] Clinical practice guidelines for the management of candidiasis: 2009 update by the..., Pappas [/bib_ref] Upon diagnosis of endophthalmitis, the drugs better penetrate into the eyeball are fluconazole and voriconazole (B-III). [bib_ref] Treatment of endogenous fungal endophthalmitis: focus on new antifungal agents, Riddell 4th [/bib_ref] [bib_ref] Use of fluconazole in the treatment of candida endophthalmitis, Akler [/bib_ref] Early intervention with partial vitrectomy and/or an intravitreal antifungal may be necessary in severe cases (B-III). [bib_ref] Endogenous endophthalmitis among patients with candidemia, Parke 2nd [/bib_ref] In these cases, we recommend antifungal therapy for a period of four to six weeks, with monitoring by an ophthalmologist for further characterization of the time of treatment and response to therapy (A-III). 102 ## Patients with evidence of endocarditis In these cases, the greatest experience in the literature involves systemic therapy with an amphotericin B lipid formulation due to the possibility of using high dosages (B-II). [bib_ref] Successful non-surgical treatment of Candida tropicalis endocarditis with liposomal amphotericin-B (AmBisome), Melamed [/bib_ref] Alternatives include echinocandin (B-II) and fluconazole, which should be used when the Candida species is susceptible and the patient is clinically stable (B-III). [bib_ref] Successful medical treatment of Candida albicans in mechanical prosthetic valve endocarditis, Aaron [/bib_ref] [bib_ref] Candida albicans tricuspid valve endocarditis in an intravenous drug addict: successful treatment..., Westling [/bib_ref] [bib_ref] Candida prosthetic valve endocarditis cured by caspofungin therapy without valve replacement, Rajendram [/bib_ref] Although amphotericin B is considered an effective alternative, in view of its potential toxicity and the treatment duration required, its use should be avoided (B-II). [bib_ref] Mortality and costs of acute renal failure associated with amphotericin B therapy, Bates [/bib_ref] A valve replacement is recommended, and systemic therapy should continue for at least six weeks after valve replacement (B-III). 197 ## Patients with chronic disseminated candidiasis Given the low incidence of this complication, there are no comparative data regarding efficacy and tolerability between the different antifungals. The treatment of this condition is always long, so starts with a broad-spectrum fungicidal drug until clinical improvement is achieved, which is followed by oral fluconazole for three to six months (A-III). [bib_ref] Successful treatment of hepatosplenic candidiasis through repeated cycles of chemotherapy and neutropenia, Walsh [/bib_ref] The antifungal should be used until complete resolution of the abscess, as detected by imaging (A-III). [bib_ref] Successful treatment of hepatosplenic candidiasis through repeated cycles of chemotherapy and neutropenia, Walsh [/bib_ref] The greatest experience in treating patients with CDC involves amphotericin B formulations (B-II). [bib_ref] Successful treatment of hepatosplenic candidiasis through repeated cycles of chemotherapy and neutropenia, Walsh [/bib_ref] In case of infection control and as long as the patient continues receiving antifungal drugs, there are no contraindications for starting a new cycle of chemotherapy or for the transplantation of hematopoietic stem cells (B-II). [bib_ref] Tratamiento de las infecciones fúngicas invasora, Pachón [/bib_ref] [bib_ref] Hepatosplenic candidiasis, a contraindication to marrow transplantation, Bjerke [/bib_ref] The therapeutic options are amphotericin B deoxycholate at a dose of 0.6-0.7 mg/kg/day (B-II); an amphotericin B lipid formulation at a dose of 3-5 mg/kg/day (B-II) [bib_ref] Successful treatment of disseminated candidiasis resistant to amphotericin B by liposomal amphotericin..., Gokhale [/bib_ref] ; fluconazole 6 mg/kg/day in stable and non-neutropenic patients who have not previously used fluconazole (B-II) [bib_ref] Fluconazole therapy for chronic disseminated candidiasis in patients with leukemia and prior..., Anaissie [/bib_ref] [bib_ref] Hepatosplenic candidiasis: successful treatment with fluconazole, Kauffman [/bib_ref] and echinocandins in the usual doses (B-II). [bib_ref] Successful treatment with caspofungin of hepatosplenic candidiasis resistant to liposomal amphotericin B, Sora [/bib_ref] As manifestations of CRC result from an exaggerated inflammatory response, the use of corticosteroids as an adjuvant therapy may be useful. In a series of cases, patients who received corticosteroids experienced rapid resolution of fever and general symptoms (B-II). 178 ## Management of a central venous catheter Most patients with candidemia have one venous catheter in the central position upon diagnosis. The reason for removal of the CVC in patients with candidemia is the fact that Candida can colonize the CVC, producing a biofilm, and lack of removal may result in persistence of a focus of infection. Several retrospective studies have analyzed the impact of CVC removal on outcomes such as duration of candidemia and mortality; the majority of these studies reported lower mortality rates when the CVC was removed. [bib_ref] Intravascular catheter exchange and duration of candidemia. NIAID Mycoses Study Group and..., Rex [/bib_ref] [bib_ref] Management of central venous catheters in patients with cancer and candidemia, Raad [/bib_ref] [bib_ref] Epidemiology and predictors of mortality in cases of Candida bloodstream infection: results..., Almirante [/bib_ref] [bib_ref] Analysis of independent risk factors for death among pediatric patients with candidemia..., Pasqualotto [/bib_ref] [bib_ref] Impact of early central venous catheter removal on outcome in patients with..., Rodriguez [/bib_ref] [bib_ref] Candidemia in cancer patients: impact of early removal of non-tunneled central venous..., Liu [/bib_ref] These studies form the basis for recommendations to remove the CVC in the guidelines of candidemia management published in recent years. [bib_ref] Clinical practice guidelines for the management of candidiasis: 2009 update by the..., Pappas [/bib_ref] However, these studies have several limitations, including the lack of multivariate analysis, in particular severity scores, the inclusion of early deaths and, most importantly, the absence of setting a time for the withdrawal of the CVC. A recently published study analyzed 842 episodes of candidemia in adults and conducted a sub-analysis of two randomized trials of candidemia treatment with echinocandins (caspofungin or micafungin) or liposomal amphotericin B. We investigated the effect of early removal (24 or 48 h after initiation of candidemia treatment) in six outcomes: success rate of candidemia treatment, candidemia persistence rate, and mortality rates of Candida applicants at 28 and 42 days. None of the six outcomes was influenced by early removal of the CVC (both in 24 h and in 48 h). [bib_ref] Early removal of central venous catheter in patients with candidemia does not..., Nucci [/bib_ref] Based on this study, adult candidemia and the early removal the CVC (24-48 h after the start of treatment) cannot be recommended if the patient is receiving an echinocandin and liposomal amphotericin B (B-II). In this case, removal of the CVC is recommended if there is persistent (>72 h) isolation of Candida despite treatment. However, the group consensus considered waiting 72 h after the initiation of antifungal therapy to define the need for removal of the CVC, as this cannot be the recommended approach in some scenarios for specific patients. In this sense, in non-neutropenic critically ill patients who have severe sepsis, as well as in breakthrough cases of candidemia in patients receiving more than 3 days of a systemic antifungal agent with activity against the pathogen isolated, early removal of the CVC can be considered (C-III). ## Empirical therapy ## Neutropenic patients Empirical antifungal therapy is instituted in neutropenic patients with fever and neutropenia that persist for a period of four to six days after initiation of broad-spectrum antibiotics. This practice was instituted in the 1980s and 1990s, and some randomized trials have been published initially testing this strategy after comparing different agents. [bib_ref] Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and..., Pizzo [/bib_ref] Acceptable options for empirical therapy that have been tested in randomized trials are lipid preparations of amphotericin B, caspofungin and voriconazole. [bib_ref] Liposomal amphotericin B for empirical therapy in patients with persistent fever and..., Walsh [/bib_ref] [bib_ref] Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients..., Walsh [/bib_ref] [bib_ref] Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with..., Walsh [/bib_ref] More recently, empirical antifungal therapy has been replaced by another strategy called preemptive therapy, which consists of starting antifungal therapy because of fever and other signs of infection. [bib_ref] Preemptive antifungal therapy: still a way to go, Maertens [/bib_ref] This strategy is more relevant when there is suspicion of infection by filamentous fungi (Aspergillus spp., Fusarium spp. and others). Some biomarkers have been tested, including galactomannan (Aspergillus spp.) [bib_ref] Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high..., Maertens [/bib_ref] ## And 1.3 beta-d-glucan for Candida spp., Aspergillus spp. and other fungi. [bib_ref] Beta-d-glucan as a diagnostic adjunct for invasive fungal infections: validation, cutoff development,..., Odabasi [/bib_ref] Regarding invasive candidiasis/candidemia, the most important issue to consider in a neutropenic patient with persistent fever despite antibiotic therapy is to assess the risk of infection. There are three parameters to be evaluated: the use of fluconazole in prophylaxis as well as the presence of gastrointestinal mucositis and a CVC. In addition to the risk, another parameter to be considered is the need for coverage of filamentous fungi. Patients with profound neutropenia (>100 cells/mm 3 ) lasting more than ten days are those with increased risk for developing filamentous fungal infection. [bib_ref] Preemptive antifungal therapy: still a way to go, Maertens [/bib_ref] ## Recommendations for empirical therapy for candidemia/invasive candidiasis in neutropenic patients Amphotericin B deoxycholate should not be used because these patients often have other risk factors for nephrotoxicity, including the underlying disease (e.g., multiple myeloma), its treatment (i.e., anticancer drugs, tumor lysis syndrome) and the use of other nephrotoxic agents (i.e., diuretics, antibiotics) (A-II). [bib_ref] Mortality and costs of acute renal failure associated with amphotericin B therapy, Bates [/bib_ref] Patients who are receiving prophylactic fluconazole, do not have gastrointestinal mucositis and who are not at risk of infection by filamentous fungi may not receive empirical antifungal therapy (C-III). [bib_ref] Clinical practice guideline for the use of antimicrobial agents in neutropenic patients..., Freifeld [/bib_ref] Patients who are not receiving fluconazole and who are not at risk of infection by filamentous fungus should receive fluconazole (B-I). [bib_ref] Clinical practice guideline for the use of antimicrobial agents in neutropenic patients..., Freifeld [/bib_ref] Patients who are receiving fluconazole prophylaxis, yet the clinician considers the possibility of invasive candidiasis, should receive empirical therapy with an agent from another therapeutic class (i.e., a lipid preparation of amphotericin B or an echinocandin -caspofungin or micafungin) (B-II). 219 ## Non-neutropenic patients Candidemia is an important complication of critically ill patients and is associated with high morbidity and mortality. [bib_ref] Epidemiology of nosocomial fungal infections, with emphasis on Candida species, Jarvis [/bib_ref] [bib_ref] Excess mortality, hospital stay, and cost due to candidemia: a case-control study..., Morgan [/bib_ref] Recent studies have shown that the delay in initiating appropriate treatment in patients with candidemia significantly increases mortality. [bib_ref] Time to initiation of fluconazole therapy impacts mortality in patients with candidemia:..., Garey [/bib_ref] [bib_ref] Delaying the empiric treatment of candida bloodstream infection until positive blood culture..., Morrell [/bib_ref] Approximately 40-50% of candidemias occur in patients admitted to the ICU. This population of patients has a high risk of mortality because they are clinically unstable. Thus, ICU patients at high risk for candidemia/invasive candidiasis may benefit from early initiation of an appropriate antifungal. However, unlike in neutropenic patients, empirical therapy has not been adequately tested in non-neutropenic patients, as there are no validated tools to identify patients at risk and because it is difficult to define outcomes to assess the effectiveness of the therapy. Despite these limitations, some attempts have been made to identify patients with invasive candidiasis in units of severely ill patients. [bib_ref] Rules for identifying patients at increased risk for candida infections in the..., Paphitou [/bib_ref] [bib_ref] Multicenter retrospective development and validation of a clinical prediction rule for nosocomial..., Ostrosky-Zeichner [/bib_ref] [bib_ref] Can yeast isolation in peritoneal fluid be predicted in intensive care unit..., Dupont [/bib_ref] [bib_ref] A bedside scoring system (Candida score) for early antifungal treatment in nonneutropenic..., Leon [/bib_ref] [bib_ref] Assessment of preemptive treatment to prevent severe candidiasis in critically ill surgical..., Piarroux [/bib_ref] These scoring systems use clinical information with or without data from Candida colonization and yielded a reasonable correlation with the occurrence of candidemia/invasive candidiasis. More recently, two biological markers have been tested for the early diagnosis of candidemia/invasive candidiasis: 1-3 beta-d-glucan and PCR. In a study in surgical patients, the evaluation of 1-3 beta-d-glucan in the plasma of patients colonized with Candida was useful to trigger the onset of empirical antifungal. [bib_ref] Combined assessment of beta-d-glucan and degree of candida colonization before starting empiric..., Takesue [/bib_ref] In another study, a PCR assay was tested in 225 patients at high risk for candidemia. Using blood culture as the gold standard, the sensitivity and specificity of PCR were 72.1 and 91.2%, respectively. 230 ## Recommendations for empirical therapy for candidemia/invasive candidiasis in non-neutropenic patients Physicians should consider the use of empirical antifungal therapy in critically ill patients with risk factors for candidemia and clinical manifestations of infection that are not responding to treatment for bacterial infections (C-III). The choice of antifungal drug for empirical therapy should be based on the same criteria for the selection of appropriate antifungal treatment for candidemia (see specific section). To support the clinician in the task of selecting patients for empirical antifungal therapy, as experts, it is our opinion that this therapeutic strategy has a greater chance of success when used in ICU patients with sepsis that is unresponsive to antibiotics (excluding other causes of FOI) who have been exposed to three or more risk factors for candidemia for at least 4-7 days of intensive care, particularly those with Candida colonization in non-sterile sites and a history of major surgery in the last two weeks (C-III). ## Prophylaxis ## Neutropenic and hematopoietic stem cell transplant patients Invasive candidiasis/candidemia is a frequent complication in neutropenic patients and recipients of HSCTs who do not receive prophylaxis. In neutropenic patients, the frequency varies depending on the patient receiving chemotherapy. The risk factors include neutropenia, the use of a CVC and primarily gastrointestinal mucositis. [bib_ref] Recent progress and current problems in management of invasive fungal infections in..., Walsh [/bib_ref] Thus, patients receiving intensive chemotherapy are those with increased risk of developing invasive candidiasis. In HSCT, invasive candidiasis/candidemia typically occurs in two stages: first, early after transplantation, the risk factors are the same as patients receiving chemotherapy, as in this phase, they also have a catheter and neutropenia, and mucositis may develop. After the recovery of the blood marrow, autologous HSCT recipients rarely develop invasive candidiasis/candidemia. The receptors of allogeneic HSCT can present with invasive candidiasis if they develop chronic graft versus host disease (GVHD) in the GI tract. Several randomized trials testing different agents have been developed for prophylaxis of invasive candidiasis/candidemia in patients receiving both chemotherapy and HSCT. The agents that exhibited efficacy were fluconazole, itraconazole oral solution (but not capsules), voriconazole, posaconazole, micafungin, caspofungin and intravenous amphotericin B. However, many studies have shown no benefits, either due to methodological problems (low numbers of patients) or because the study population had a high risk of developing invasive candidiasis. [bib_ref] Antifungal prophylaxis for severely neutropenic chemotherapy recipients: a meta analysis of randomized..., Bow [/bib_ref] Recommendations for prophylaxis for candidemia/invasive candidiasis in neutropenic patients receiving HSCT HSCT. Fluconazole is the drug of choice for prophylaxis of invasive candidiasis in the period of neutropenia in recipients of allogeneic HSCT and can be established at the beginning or the end of the conditioning regimen (A-I). [bib_ref] Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation:..., Slavin [/bib_ref] [bib_ref] A controlled trial of fluconazole to prevent fungal infections in patients undergoing..., Goodman [/bib_ref] The standard dose is 400 mg/day, but there is evidence in a randomized study that 200 mg/day is also effective (B-I). [bib_ref] Fluconazole to prevent yeast infections in bone marrow transplantation patients: a randomized..., Macmillan [/bib_ref] An alternative to fluconazole is micafungin, but its use is limited by the need for venous access and its high cost (B-I). [bib_ref] Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in..., Van Burik [/bib_ref] Itraconazole oral solution (not available in Brazil) was also effective, but its use is limited by the high frequency of gastrointestinal side effects (C-I). [bib_ref] A prospective randomized trial of itraconazole vs fluconazole for the prevention of..., Oren [/bib_ref] [bib_ref] Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal..., Winston [/bib_ref] Voriconazole is an alternative that can be used when you need coverage for filamentous fungi based on a comparative study with fluconazole (B-I). [bib_ref] Results of a randomized, double-blind trial of fluconazole vs. voriconazole for the..., Wingard [/bib_ref] Options for prophylaxis of invasive candidiasis in the postpicks are voriconazole and posaconazole (B-I). [bib_ref] Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease, Ullmann [/bib_ref] [bib_ref] Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia, Cornely [/bib_ref] The risk of invasive candidiasis/candidemia is much lower in recipients of autologous HSCT. Thus, prophylaxis is not routinely recommended (C-III). However, prophylaxis (fluconazole) may be indicated in some situations, such as when manipulation of the graft occurs, when severe mucositis is expected, in patients who received fludarabine or cladribine or in those with MBL (mannose-binding lectin) deficiency (B-III). [bib_ref] Epidemiology and treatment approaches in management of invasive fungal infections, Kriengkauykiat [/bib_ref] Neutropenia. The results of randomized trials testing fluconazole in neutropenic patients are not as effective as in HSCT, especially because this population is more heterogeneous. [bib_ref] Antifungal prophylaxis for severely neutropenic chemotherapy recipients: a meta analysis of randomized..., Bow [/bib_ref] In general, the more intensive the chemotherapy regimen is, the higher the risk of invasive candidiasis. Thus, patients with acute myeloid leukemia/myelodysplasia receiving remission induction chemotherapy may benefit from prophylaxis. Although fluconazole is the drug of choice for the prevention of invasive candidiasis, these patients also have a high risk of filamentous fungi; thus, posaconazole (200 mg orally three times a day) may be preferred (A-I). [bib_ref] Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia, Cornely [/bib_ref] For the prevention of invasive candidiasis, itraconazole oral solution (not available in Brazil) can be used, but it has the limitation of gastrointestinal toxicity (C-I). In a meta-analysis of 13 randomized trials, itraconazole oral solution also prevented the occurrence of invasive aspergillosis, and in ten studies, TCTH receptors were also included. [bib_ref] Itraconazole prevents invasive fungal infections in neutropenic patients treated for hematologic malignancies:..., Glasmacher [/bib_ref] Caspofungin was also tested in a randomized study; it is an option, with the exception of requiring venous access for administration (C-I). [bib_ref] Evaluation of caspofungin or micafungin as empiric antifungal therapy in adult patients..., Kubiak [/bib_ref] Prophylaxis for invasive candidiasis/candidemia in situations out of remission induction for acute myeloid leukemia/myelodysplasia is not routinely recommended (C-III). However, in special situations, such as after remission induction regimens for acute lymphoid leukemia in high risk patients, prophylaxis may be useful (C-III). ## Solid organ transplanted patients Solid organ transplant recipients represent a set of hosts susceptible to infectious events, which result from the interaction between endogenous immunosuppression (i.e., uremia, diabetes, liver failure), iatrogenic immunosuppression (resulting from the use of medications to prevent rejection episodes) and surgical procedures and their inherent risks. Among infectious events, fungal infections are important because they usually depend on many immunodepression states. However, the group of transplanted solid organs is heterogeneous with respect to the variables that lead to immunosuppression and, therefore, with respect to the actual state of the resulting immunosuppression, which leads to different rates of fungal infection and different prevalence, including Candida infections. Epidemiology, clinical significance and recommendations for prophylaxis for candidemia/invasive candidiasis in solid organ transplant patients. ## Kidney transplantation Renal transplantation is the most frequent solid organ transplantation and the least technically complex from the surgical point of view because it is an extraperitoneal surgery of short duration. Renal transplantation is the solid organ transplantation with the lowest rate of invasive Candida infections and the one in which the clinical repercussion is least significant. Approximately 50% of yeast infections are caused by Candida species. Of these, over 70-80% represent urogenital infections (especially candiduria, which occurred in 11% of patients in a retrospective study) or esophagogastric infections. Only 0.5-5% of the infections occur in the form of candidemia or disseminated candidiasis. [bib_ref] Hospitalizations for fungal infections after renal transplantation in the United States, Abott [/bib_ref] The most prevalent infections (i.e., UTI and esophagitis) are associated with low morbidity and are infections of secondary importance in the spectrum of fungal infections in kidney transplants. Due to the benign nature of Candida infections in this group and the low rate of candidemia, there is no formal recommendation for chemoprophylaxis. Exceptions are made for situations in which there is a UTI in the donor at the time of transplantation because there are anecdotal reports of transmission to the donor with serious consequences (i.e., loss of graft anastomosis). Prophylaxis depends on exact timing, and single-agent treatment is not established (C-III). [bib_ref] Predictors and outcomes of candiduria in renal transplant recipients, Safdar [/bib_ref] ## Liver transplantation Liver transplantation, the second most frequent solid organ transplantation, is related to high rates of fungal infections (30-40%) mainly due to the complexity of the surgical procedure, which requires an approach through the abdominal cavity and often the bowel, factors known to be related to the occurrence of Candida infections. Among fungal infections, Candida infections represent 80% of the total events, and candidemia (40%), peritonitis and intracavitary abscesses are the most common manifestations. Most events occur before the sixth post-transplant month, and there has been a reduction in the frequency of Candida over the past years, which has been attributed to improved practices and surgical results. [bib_ref] Changes in the spectrum and risk factors for invasive candidiasis in liver..., Husain [/bib_ref] Risk factors that distinguish patients at higher risk for invasive candidiasis are retransplantation, dialysis and kidney failure, the need for large volumes of blood products during surgery, antibiotic therapy before transplantation and biliaryenteric anastomosis. [bib_ref] Changes in the spectrum and risk factors for invasive candidiasis in liver..., Husain [/bib_ref] Contrary to what is observed following kidney transplants, invasive Candida infections are associated with reduced patient survival and considerable morbidity. In this patient population, randomized, placebo-controlled trials have attempted to reduce invasive candidiasis, reflecting the importance of the event. At least six randomized trials (using fluconazole, itraconazole or liposomal amphotericin) and a meta-analysis of these combined studies are available in the medical literature. [bib_ref] Antifungal prophylaxis in liver transplant patients: a systematic review and meta-analysis, Cruciani [/bib_ref] The results of this meta-analysis, which involved total transplanted groups (with no selection criteria for special groups or subgroups), show total reduction of fungal infections, particularly invasive fungal infections (without specific reference to reducing candidemia), consistent with the results of each individual study and regardless of the antifungal agent used. However, a reduction in mortality is not demonstrated. There is a need for treatment of 11.8 patients to prevent one invasive fungal infection. [bib_ref] Antifungal prophylaxis in liver transplant patients: a systematic review and meta-analysis, Cruciani [/bib_ref] Some authors, having identified heterogeneity in patients and the presence of specific risk factors that identify highrisk populations, advocate focusing on this population as a target for prophylactic therapy. [bib_ref] Association of fungal infection and increased mortality in liver transplant recipients, Rabkin [/bib_ref] However, these recommendations are based on observational and uncontrolled studies, decreasing the strength of the recommendation. The focus on higher-risk patients is bolstered by the demonstration (from controlled studies) that prophylaxis can lead to side effects, such as the selection of non-albicans strains with greater potential for resistance to azoles. With the above data available, it is the opinion of this consensus group that antifungal prophylaxis is recommended in liver transplant recipients at greatest risk, recognizing its clinical importance, frequency and the difficulty of establishing the diagnosis in advance. According to the criteria of cost, toxicity and acceptance, we also recommend the use of fluconazole as the drug of choice. [bib_ref] Trends in invasive fungal infections in liver transplant recipients: correlation with evolution..., Singh [/bib_ref] Find below the specific recommendations. - Patients at risk for whom prophylaxis should be recommended in the first month after transplantation: the existence of at least two of the following risk factors in the first month after transplantation: retransplantation, the need for dialysis, the use of antibiotics and wide biliaryenteric anastomosis (B-II). ## Pancreas/kidney transplantation This transplantation modality is also frequently associated with fungal infections because it is performed in diabetic patients and also because of the complexity of the surgery, which involves handling of the intestinal tract. Over 90% of events are caused by Candida species in the form of intra-abdominal infections with or without concomitant candidemia. As is the case with liver transplantation, invasive Candida infections are associated with both reduced grafts and patient mortality. [bib_ref] Intra-abdominal fungal infections after pancreas transplantation: incidence, treatment and outcome, Benedetti [/bib_ref] Although the frequency and clinical impact of Candida infections are very similar with respect to what occurs in liver transplantation, there are no randomized studies evaluating the effectiveness of prophylactic antifungal drugs. There are also no studies reporting specific risk factors for the occurrence of fungal infections in this group of transplant recipients. There is only one controlled observational study with historical groups showing lower rates of Candida infections with fluconazole 400 mg/day for seven days. The practice is widespread in groups that perform pancreatic transplantation, and there is currently little room for the proposition of controlled studies with placebo. [bib_ref] Infectious complications after simultaneous pancreas-kidney transplantation, Michalak [/bib_ref] It is the opinion of this consensus that prophylaxis should be restricted, recognizing the importance of the event and to curb the excessive use of prophylaxis. Fluconazole can be used in a similar scheme to that used for liver transplantation (C-II). ## Thoracic transplantation (heart, lung, heart/lung) In this group of patients, infections occur in 2.2% of patients undergoing heart transplantation and in 9% of patients undergoing lung or heart/lung transplantation. However, unlike what happens with other types of solid organ transplantations, there is a high prevalence of infections by filamentous fungi with high mortality. Candida infections occur in 30% of fungal infections, mainly in the form of hematogenous candidiasis. [bib_ref] Prevalence and outcome of invasive fungal infections in 1,963 thoracic organ transplant..., Grossi [/bib_ref] The low incidence of serious fungal infections in heart transplant does not indicate the use of specific prophylaxis in this population. With respect to lung transplantation, the focus is to prevent the occurrence of filamentous fungi; preventing Candida infection is a less-important goal. Thus, this consensus does not suggest prophylaxis for Candida in this group of patients but reinforces the importance of anti-Aspergillus prophylaxis, which has been adopted by 75% of lung transplantation centers. [bib_ref] A survey of antifungal management in lung transplantation, Dummer [/bib_ref] ## Intestinal transplantation Intestinal transplants are performed infrequently but are associated with high rates of Candida infections by extensive manipulation of the intestinal tract. Data are scarce regarding prophylaxis in this group; treatment with fluconazole should be considered in high-risk patients. ## General recommendations There is no indication for routine prophylaxis against Candida in renal transplant patients (B-II). There is evidence for the use of prophylaxis for Candida in liver transplantation with reduction in invasive events but not in mortality (B-II). Liver transplant patients should receive prophylaxis with fluconazole for one to three months (B-II). The same level of evidence exists for the use of fluconazole in kidney/pancreas or intestinal transplants, but the use of fluconazole is suggested for high-risk patients (C-III). There is no indication for routine prophylaxis against Candida in transplanted heart and/or lung patients (B-II). ## Non-neutropenic patients in the icu There are four randomized and well-designed clinical trials illustrating the benefit of the use of fluconazole in terms of reduction of invasive Candida infection in the ICU, particularly for surgical patients. Despite studies that show the effectiveness of prophylaxis with fluconazole in terms of reduction of invasive Candida infections (but not mortality), it is not possible to establish criteria that are universally applicable for the selection of patients undergoing prophylaxis with this triazole. This fact is due to the large heterogeneity of clinical characteristics in patients admitted to the ICU from different medical centers and the variations in the incidence rates of candidemia in hospitals. Whereas most medical centers have incidence rates of candidemia on the order of 1% among patients in the ICU, 100-200 critically ill patients must be exposed to prophylaxis with fluconazole to prevent one episode of candidemia. In this context, until new criteria for selecting patients at high risk (chance >10% for event) for candidemia are validated, this practice has questionable benefits, as it is associated with increased risk for adverse effects; it also contributes to the development of resistance to triazoles and can lead to increased health care costs. [bib_ref] Multidisciplinary approach to the treatment of invasive fungal infections in adult patients...., Zaragoza [/bib_ref] [bib_ref] Fluconazole prophylaxis in critically ill surgical patients: a meta-analysis, Shorr [/bib_ref] [bib_ref] Evolving role of early antifungals in the adult intensive care unit, Lam [/bib_ref] Conflicts of interest [fig] •: The need for surgical removal of the infectious focus: cases of osteomyelitis and endocarditis are examples of clinical situations in which surgical cleaning (or valve replacement) should be considered in the therapeutic management of patients. [/fig] [table] Table 1 -: Pharmacological aspects of systemic antifungals. [/table] [table] Table 2 -: Antifungal dosages in humans based on renal function. [/table] [table] Table 3 -: Strength of recommendation and quality of evidence. [/table] [table] Table 4 -: Therapeutic regimens for candidiasis. Amphotericin B deoxycholate 0.3-0.5 mg/kg/day IV for 7-14 days B-II Caspofungin 50 mg/day IV or anidulafungin 200 mg/day IV or micafungin 150 mg/day IV for 7-14 days A-I Vulvovaginal candidiasis Topical Topical therapy with azoles for 3-7 days or nystatin for 10-14 days: A-I The treatment of sexual partners is not recommended in uncomplicated cases but may be considered in women with recurrent form Butaconazole 2% cream, 5 g/day Clotrimazole 1% cream, 5 g/day Clotrimazole vaginal tablets, 500 mg/day Miconazole 2% cream, 5 g/day Miconazole 100 mg, 200 mg or 1200 mg (single dose) vaginal suppositories Econazole 150 mg tablets or suppository Terconazole 0.4% or 0.8% cream, 5 g/day Terconazole vaginal suppositories, 80 mg Nystatin vaginal tablets, 100,000 UI (for 10-14 days) Systemic Fluconazole single dose 150 mg PO A-I Itraconazole PO 200 mg/day for 3 days or 400 mg PO single dose B-II Therapy with vaginal suppositories of boric acid 600 mg/day for 14 days is indicated for recurrent candidiasis caused by Candida glabrata [/table] [table] 1: Candidemia: isolation of Candida spp. in the bloodstreams [/table]	None	None	None
aac63ee133991baf77c6af51a3d701b265842f03	pubmed	Diagnosis and Treatment of Leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH)*	Diagnosis and Treatment of Leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH)* Leishmania species with an increased risk of causing mucosal leishmaniasis (ML) include L. (V.) braziliensis mainly, but also L. (V.) guyanensis and L. (V.) panamensis. There are other species that can be associated with ML less frequently. In this document, we refer to these three species as "increased-ML risk species." Geographic regions in which there is an increased risk for ML are defined above. Amazonian-basin regions up to an altitude of approximately 2,000 meters are referred to as "increased-ML risk regions." DIAGNOSIS AND TREATMENT OF LEISHMANIASIS ## Executive summary Guidelines for the clinical management of persons with leishmaniasis were prepared by a Panel of the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). The guidelines are intended for internists, pediatricians, family practitioners, and dermatologists, as well as infectious disease specialists, practicing in the United States and Canada (for simplicity, referred to here as North America). The Panel followed a guideline development process that has been adopted by IDSA, which includes a systematic method of grading both the quality of evidence (very low, low, moderate, or high) and the strength of the recommendation (weak or strong) [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] [fig_ref] Figure 1: Approach and implications to rating the quality of evidence and strength of... [/fig_ref]. In these guidelines, we describe our approaches to the diagnosis and management of cases of cutaneous, mucosal, and visceral leishmaniasis, the three main clinical syndromes caused by infection with Leishmania parasites. Less common or rare syndromes that may require specialized expertise are beyond the scope of these guidelines. Whenever possible, our recommendations are based on randomized clinical trials. However, because of the diversity encompassed by leishmaniasis, which includes a spectrum of diseases caused by >20 Leishmania species found in many areas of the world, many of the recommendations are based on observational studies, anecdotal data, or expert opinion. Although there may be disagreement with some of our recommenda-tions and suggestions, the approaches we describe have been both useful and feasible in North America. Cutaneous leishmaniasis (CL) is the most common leishmanial syndrome worldwide and the one most likely to be encountered in patients in North America. The skin lesions of CL are usually painless and chronic, often occurring at sites of infected sand fly bites. Slow spontaneous healing as cellmediated immunity develops is the usual natural history, accelerated by antileishmanial therapy. A minority of cutaneous infections caused by Leishmania (Viannia) braziliensis (L. [V.] braziliensis) and related species in the Viannia subgenus, including L. (V.) panamensis and L. (V.) guyanensis, are associated with concomitant or late mucosal leishmaniasis (ML), which can cause destructive lesions of the naso-oropharyngeal/ laryngeal mucosa. No universally applicable treatment has been identified for CL; the choice of agent, dose, and duration of therapy should be individualized. Parasite and host factors must be considered, as well as clinical characteristics [fig_ref] Table 1: Clinical Characteristics of Cutaneous Leishmaniasis [/fig_ref]. Visceral leishmaniasis (VL), which reflects dissemination of Leishmania parasites throughout the reticuloendothelial system, is potentially life threatening without treatment. VL is an opportunistic infection in persons with HIV/AIDS or other causes of cell-mediated immunosuppression. The primary goals of therapy for VL and CL/ML are to prevent mortality and morbidity, respectively. The only Food and Drug Administration (FDA)-approved medications for the treatment of leishmaniasis are intravenous liposomal amphotericin B (L-AmB) for VL and oral miltefosine for CL, ML, and VL caused by particular species. For prevention of leishmaniasis in travelers, no vaccines or chemoprophylaxis currently are available; personal protective measures to minimize exposure to sand fly bites are recommended. Our recommendations for the diagnosis and clinical management of leishmaniasis are listed below. Background information about leishmaniasis, a description of our methods, and the evidence summaries that support our recommendations can be found online in the full text, tables, figures, and appendix of the guidelines. ## Recommendations for the diagnosis of leishmaniasis (cutaneous, mucosal, and visceral) I. In a person with a compatible skin lesion(s) and exposure history, what specimen(s) should be collected for diagnostic testing for CL? The content and views expressed in this document are the sole responsibility of the authors and do not necessarily reflect the views or policies of the U.S. Department of Defense, the U.S. Department of Health and Human Services, or the Centers for Disease Control and Prevention. It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. The IDSA and ASTMH consider adherence to these guidelines to be voluntary, with the ultimate determinations regarding their application to be made by the physician in the light of each patient's individual circumstances. II. In a person with manifestations suggestive of New World mucosal leishmaniasis(ML),whattypes ofspecimensshould be obtained for diagnostic testing? ## Recommendations 3. The initial and most prominent mucosal manifestations typically are nasal (e.g., chronic unexplained congestion/ secretions). Oral/palatal, pharyngeal, and laryngeal involvement may develop as ML progresses or, in some persons, may be the first or the only noted abnormalities. The clinical signs, which may evolve over time, may include erythema, edema, hyperemia, infiltration, nodules, erosion, ulceration, and tissue destruction (e.g., perforation of the nasal septum) [FACT, no grade]. 4. Mucosal areas that have macroscopic abnormalities are recommended for specimen collection; biopsy specimens, obtained by an otolaryngologist, are useful for confirming the diagnosis by molecular and traditional methods and for excluding other etiologies . III. During the initial and subsequent evaluations of persons with CL acquired in Central or South America who may have or be at risk for mucosal leishmaniasis (ML), what should be done to assess the possibility of mucosal disease? Recommendations 5. All persons at risk for ML-on the basis of the etiologic agent of the Leishmania infection, if known, and the region in the New World in which infection was acquired-should be questioned about and examined for mucosal symptoms and signs, respectively, even during the initial evaluation [Strong, low]. 6. During all evaluations (i.e., initial and subsequent), persons at risk for ML should be questioned explicitly about the development, evolution, and other characteristics of [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] mucosal symptoms; and they should have a thorough examination of the naso-oropharyngeal mucosa even if they do not have any mucosal symptoms [bib_ref] Leishmania species, Magill [/bib_ref] 1 In Guatemala, the reported cases of CL have been acquired in the northern departments (particularly, El Petén and Alta Verapaz but also Izabal, El Quiché, Baja Verapaz, and Jalapa). [bib_ref] Cochrane reviews on neglected diseases: the case of cutaneous leishmaniasis. The Cochrane..., Gonzalez [/bib_ref] The etiologic agents of CL in Israel primarily include L. major and L. tropica but also L. infantum-chagasi. [bib_ref] Interventions for Old World cutaneous leishmaniasis, Gonzalez [/bib_ref] The species L. (Leishmania) martiniquensis, which was formally named in 2014, has been identified as the etiologic agent of cutaneous and visceral leishmaniasis in the French West Indies (Martinique Island) and Thailand, where it previously was referred to as "L. siamenensis" (not considered a taxonomically valid name). [bib_ref] GRADE guidelines: a new series of articles in the Journal of Clinical..., Guyatt [/bib_ref] In Sri Lanka, L. donovani has been identified as the etiologic agent of cutaneous and visceral leishmaniasis. [bib_ref] Clinical infectious diseases : an official publication of the Infectious Diseases Society..., Wortmann [/bib_ref] Not all Leishmania species that cause CL are included in this map (eg, L. amazonensis in South America). V. What laboratory tests should be used to diagnose leishmaniasis? Recommendations 14. We recommend using multiple diagnostic approaches to maximize the likelihood of a positive Leishmania result, using methods such as visualization of the characteristic amastigote in smears or tissue (histopathology); parasite isolation by in vitro culture; molecular detection of parasite DNA; and, for VL, serologic testing (see VI-VIII and. Simultaneous testing for other diagnoses (e.g., by histopathology and culture) should be considered .. We recommend attempting parasite isolation with the assistance of reference laboratories. We recommend that clinicians contact their leishmaniasis reference laboratory before collecting specimens ( VIII. What is the role of serologic testing in the diagnosis of leishmaniasis? Recommendations 20. Serologic testing is recommended for persons with suspected VL in whom definitive diagnostic tests for the parasite (microscopic identification, culture, and molecular tests for parasite DNA) cannot be conducted or have negative results. The sensitivity and specificity of serologic tests depend on the assay and antigens used, Unusual syndromes: leishmaniasis recidivans, diffuse CL, or disseminated CL It is somewhat controversial whether the presence of small subcutaneous nodules is always associated with complex CL, but certainly complex CL applies if bubonic-like adenopathy is present in regional drainage area of lesions. These findings have been linked to complications or treatment failure when only local treatment is administered. Some experts would not consider systemic therapy needed for a few, small subcutaneous nodules in Old World CL. The highest risk areas for mucosal leishmaniasis (ML) are south of the Amazon basin in parts of Bolivia, Peru, and Brazil (defined here as the "mucosal belt"). Moderate-risk areas are south of Nicaragua to the Amazon basin. Low-risk areas for ML are in NWCL (Viannia)-endemic regions north of Costa Rica. High therapeutic failure rates after treatment with pentavalent antimonial drugs have been observed in CL acquired in Amazonian Bolivia (eg, Madidi National Park) and Southeastern Peru (eg, Manu National Park and Puerto Maldonado). Poor efficacy after using miltefosine in the treatment of L.(V.) braziliensis was reported in Guatemala as well as host factors. Serologic tests cannot be used to assess the response to treatment. Antileishmanial antibodies can be detected years after clinically successful therapy in some persons .. We suggest that tests for antileishmanial antibodies not be performed as the sole diagnostic assay. Antibodies may be undetectable or present at low levels in persons with VL who are immunocompromised because of concurrent HIV/AIDS or other reasons. The potential for false-negative test results limits the utility of serologic assays in this setting [Weak, low]. 22. Serologic testing is not recommended as part of the diagnostic evaluation for CL. The currently available serologic assays are neither sensitive nor specific for the diagnosis of CL . ## Recommendations for the treatment of leishmaniasis ## Cutaneous leishmaniasis IX. In a person with a consistent travel history and compatible skin lesion(s), is it necessary to obtain parasitologic confirmation of the diagnosis of leishmaniasis before starting treatment? Recommendation 23. After a careful diagnostic evaluation in which neither leishmaniasis nor another diagnosis is confirmed, empiric treatment may be indicated on the basis of an individualized risk-benefit assessment [Weak, very low]. Remark: This should be discussed with the patient and reevaluated periodically, taking into account the clinical evolution. ## X. is treatment of clinically manifest cutaneous infection (cl) always indicated? Recommendations 24. We recommend that immunocompetent persons with skin lesions that are caused by infection with Leishmania species that are not associated with increased risk for ML, that are defined as clinically simple lesions [fig_ref] Figure 2: Maps of the Geographic Distribution of Cutaneous Leishmaniasis [/fig_ref] , treatment of clinically simple or healing skin lesions is not required in an immunocompetent patient who concurs with this management [Strong, low; E.C. dissents, recommending that all persons with NWCL receive treatment]. Remark: See XXIV and XXV regarding the management of CL in immunocompromised persons. [bib_ref] Epidemiology of American cutaneous leishmaniasis due to Leishmania braziliensis braziliensis, Jones [/bib_ref]. We suggest that systemic treatment be offered for persons even with healing/recently healed CL lesions caused by increased ML-risk species or when the species is unknown but the infection was acquired in an increased ML-risk region. Risks and benefits of such treatment should be discussed with the patient . Remark: In some cases, watchful waiting, with vigilance for signs and symptoms of ML, may be a reasonable approach. 27. We recommend that any decision to observe a patient with CL without treatment should be reevaluated periodically, and the decision not to treat should be reconsidered if healing does not progress as anticipated [Strong, very low]. [bib_ref] Eustachian tube blockage with consequent middle ear infection in mucosal leishmaniasis. Revista..., Lessa [/bib_ref]. In all cases of CL, wound care, individualized documentation of lesion evolution, and patient education regarding the manifestations and detection of local therapeutic failure/relapse and ML should be routine components of management (see III and XV) . XI. In a person with CL, what could be the consequences of no treatment or suboptimal therapy, and how should persons who received no or suboptimal therapy be monitored? ## Recommendations 29. Potential consequences of inadequate treatment include poor cosmetic outcome due to scarring or superinfection, the persistence of a chronic wound(s), and, with some Leishmania species, destructive and disfiguring [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref] and XXVI. In Canada: via Special Access Program (continued) [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref] and XXVI. In Canada: via Special Access Program (continued) [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref] and lower efficacy. [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] For simplicity, the terminology North America is used to refer to the United States and Canada. [bib_ref] Cochrane reviews on neglected diseases: the case of cutaneous leishmaniasis. The Cochrane..., Gonzalez [/bib_ref] All treatment-related decisions should be individualized. The lists of treatment approaches/drugs and regimens are not all inclusive. For the listed systemic drugs, see [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref] regarding adverse events, monitoring for toxicity, and mitigation approaches. See XXIII-XXV regarding treatment considerations applicable to HIV-coinfected persons and to persons who are immunocompromised for other reasons. See XXVI for considerations for other special populations of patients (eg, young children). [bib_ref] Interventions for Old World cutaneous leishmaniasis, Gonzalez [/bib_ref] See [fig_ref] Table 1: Clinical Characteristics of Cutaneous Leishmaniasis [/fig_ref] and X-XIII for additional perspective. [bib_ref] GRADE guidelines: a new series of articles in the Journal of Clinical..., Guyatt [/bib_ref] The pentavalent antimonial drugs-sodium stibogluconate (Pentostam®) and meglumine antimoniate (Glucantime®)-are considered comparable when dosed on the basis of Sb V content. In general, the daily dose does not have an upper limit in mgs (ie, the daily dose no longer is limited to 850 mg); however, see XXVI for additional perspective and cautionary notes. [bib_ref] Clinical infectious diseases : an official publication of the Infectious Diseases Society..., Wortmann [/bib_ref] Persons newly diagnosed with VL should be assessed for concurrent HIV/AIDS or other causes of cell-mediated immunosuppression. [bib_ref] Epidemiologic investigation of an outbreak of cutaneous leishmaniasis in a defined geographic..., Sanchez [/bib_ref] Liposomal amphotericin is approved by the U.S. Food and Drug Administration for the treatment of VL. The off-label use of amphotericin B deoxycholate is likely to be effective but is generally more toxic (see [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref]. [bib_ref] Leishmania and HIV co-infection: dermatological manifestations, Puig [/bib_ref] An immunocompetent person is defined as someone without an identified congenital or acquired immune defect (eg, HIV/AIDS). In general, L. donovani (India) may be treated with a shorter course of ABLC, whereas L. infantum in Europe requires 10 days duration [bib_ref] Amphotericin B treatment for Indian visceral leishmaniasis: conventional versus lipid formula-tions, Sundar [/bib_ref] [bib_ref] Amphotericin B lipid complex ver-sus meglumine antimoniate in the treatment of visceral..., Laguna [/bib_ref]. [bib_ref] Leishmania major cutaneous leishmaniasis in HIV-positive patients does not spread to extralesional..., Foulet [/bib_ref] See XXIII regarding secondary prophylaxis in patients with HIV/AIDS-associated VL. Chronic maintenance therapy (secondary prophylaxis) should be given until the CD4 T-lymphocyte cell count consistently remains >200-350/mm 3 (see XXIII). [bib_ref] Comparative study of cutaneous leishmaniasis in human immunodeficiency virus (HIV)-infected patients and..., Couppie [/bib_ref] See XIX and XX for additional perspective about treatment alternatives. Parenteral paromomycin appeared promising in clinical trials in India, but it is not available in North America. [bib_ref] American tegumentary leishmaniasis and HIV-AIDS association in a tertiary care center in..., Guerra [/bib_ref] Miltefosine has been effective in treating VL in India and adjacent areas of South Asia where resistance to pentavalent antimonials is prevalent. There is some evidence to support the use of miltefosine for VL acquired in East Africa. There is less available evidence to support its use in southern Europe and Latin America. [bib_ref] The relationship between leishmaniasis and AIDS: the second 10 years, Alvar [/bib_ref] Resistance to pentavalent antimonials is well documented in India and has been reported from other areas. In general, pentavalent antimonial therapy should not be used for persons who acquired VL in India. [bib_ref] Unusual manifestations of tegumentary leishmaniasis in AIDS patients from the New World, Lindoso [/bib_ref] Personal communication Pierre Buffet, on the basis of expert opinion. [bib_ref] Diffuse cutaneous leishmaniasis in an HIV-positive patient in western Africa, Niamba [/bib_ref] Contact information for use in military beneficiaries: To help ensure safe and effective therapy, see full prescribing information for additional details, including potential drug interactions. Expert consultation also is encouraged regarding such issues as whether to start, continue, or interrupt therapy with a particular antileishmanial agent; to adjust the dosage regimen; or to select a different agent if the patient has or develops laboratory abnormalities or comorbid conditions. On principle, minimize the use of other medications/supplements and avoid alcohol. In general, drugs are listed alphabetically in the parenteral and oral categories and in the subcategories (eg, azoles); however, "pentavalent antimonial compounds" are listed before [formula] Force [/formula] # Introduction In the first section, the Panel summarizes background information relevant to the topic. In the second section, the Panel poses questions regarding the diagnosis and treatment of leishmaniasis, evaluates applicable clinical trial and observational data, and makes recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref]. The following 26 clinical questions were answered: [formula] I [/formula] # Background The term leishmaniasis refers to a diverse group of syndromes caused by protozoa of the genus Leishmania, in the Leishmania and Viannia subgenera. The clinical manifestations of infection are variable and reflect a complex interplay between the human host's cell-mediated immune responses and the virulence and tropism of the infecting Leishmania species, >20 of which are known to be pathogenic for humans. Each leishmaniasis-endemic region has particular combinations of parasite species/strains, sand fly species, mammalian reservoir hosts (in zoonotic transmission cycles), and human hosts with different genetic backgrounds. Although Leishmania infection can be subclinical, the three main clinical syndromes are cutaneous leishmaniasis (CL), mucosal leishmaniasis (ML), and visceral leishmaniasis (VL). Less common presentations include diffuse cutaneous leishmaniasis, disseminated cutaneous leishmaniasis, leishmaniasis recidivans, bubonic leishmaniasis, uveitis, and post kala-azar dermal leishmaniasis (PKDL). CL is the most common syndrome worldwide and the one most likely to be encountered in patients in North America. Although autochthonous CL cases acquired in Texas and Oklahoma have been reported, almost all of the cases of CL evaluated in North America occur among immigrants, international travelers, expatriates, and military personnel exposed in leishmaniasis-endemic areas elsewhere in the world. The skin lesions typically are first noticed at the site(s) where Leishmania parasites were inoculated by an infected sand fly. The lesions enlarge slowly and typically ulcerate after weeks to months, although persistently nodular and other forms also occur. The natural history is usually slow spontaneous healing as cell-mediated immunity develops; healing may be accelerated with antileishmanial treatment. A minority of persons infected with L. (V.) braziliensis and related Viannia species in Latin America, particularly in parts of South America, develop metastatic ML after healing of CL or concomitantly with a cutaneous lesion(s). ML can progress to cause destructive lesions of the naso-oropharyngeal/laryngeal mucosa. Leishmaniasis with mucosal lesions also has been reported in the Old World, where the pathogenesis and clinical manifestations of mucosal infection may be different. VL is potentially life threatening and requires prompt evaluation and treatment. In VL, amastigotes (the tissue stage of the parasite) disseminate throughout the reticuloendothelial system and occasionally are found in other organ systems. VL, and less commonly CL or ML, may be opportunistic infections in persons who are immunocompromised because of HIV/AIDS or other reasons. Some experts consider all persons with symptomatic VL to be immunocompromised, some perhaps without an identified immune defect. In these guidelines, immunocompetent VL refers to persons with VL without an identified immune defect. Treatment of leishmaniasis can be challenging. The primary goals of therapy for VL and CL are to prevent mortality and morbidity, respectively. The only FDA-approved medications for leishmaniasis are intravenous liposomal amphotericin B (L-AmB) for VL, and oral miltefosine for CL, ML, and VL caused by particular species. The potential for VL to be life threatening and the high response rate associated with L-AmB therapy justify its side effects and cost. Treatment recommendations for CL are less straightforward, in part because the data from randomized control trials are of variable quality and generalizability. Many CL infections may clinically resolve without treatment. Furthermore, treatment does not necessarily result in parasitologic cure, as evidenced by cases of relapse, especially in the context of immunosuppression. The objective of treatment is clinical healing, not parasitologic cure. For CL, the interrelated goals of treatment include minimizing local tissue damage and cosmetic or functional consequences, accelerating the rate of healing, reducing the likelihood of local recurrences, and decreasing the risk of developing mucosal disease caused by parasites in the Viannia subgenus. The therapeutic strategy depends in part on the infecting species or, as a proxy, whether the infection was acquired in the Americas (New World cutaneous leishmaniasis; NWCL) or elsewhere (Old World cutaneous leishmaniasis; OWCL). Local therapy may be an option for some cases of CL, and use of systemic therapy may be indicated or prudent for others. Clinical resolution of leishmaniasis may not be associated with a parasitologic cure, a definitive method to document parasitologic cure is not available, and even asymptomatic persons may have low concentrations of blood/tissue parasites that could cause infection in a transfusion/transplant recipient. We suggest that persons with a history of leishmaniasis (particularly, but not only, VL) refrain from donating blood; if organ/tissue donation is contemplated pre-or postmortem, pertinent agencies should be informed of the patient's history of leishmaniasis. The practices and policies for screening/deferring potential North American donors for Leishmania infection not only may change over time but also may vary among different places or settings (e.g., in the military vs the civilian sector), as well as for different types of donations, which also might be processed in ways that could decrease the number or the viability of residual parasites. For prevention of leishmaniasis in travelers, no prophylactic medications or vaccines are currently available. Healing of CL may be associated with some protection from clinical disease with subsequent exposure to the same Leishmania species/strain; however, persons should be informed that clinically manifest reinfection is possible and that they should use personal protective measures (PPM) that minimize vector exposure whenever they are in leishmaniasis-endemic areas. These measures include protective clothing, insect repellents such as DEET applied to exposed skin, permethrin applied to clothing, window coverings, and insecticide-impregnated bed nets. Vector control with residual insecticides has been used in settings with peridomestic transmission. Reservoir control depends in part on the infecting Leishmania species. # Methods ## Panel composition The Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH) convened experts in the diagnosis and management of leishmaniasis from the fields of diagnostic parasitology, pediatrics, public health, tropical medicine, and infectious diseases, including experts from leishmaniasis-endemic areas. ## Literature review and analysis Subgroups were formed, each responsible for developing recommendations and evidence support in the specific areas of diagnostic testing; treatment of cutaneous, mucosal, and visceral leishmaniasis; and issues associated with immunocompromised hosts and other special populations. Separate computerized searches of MEDLINE (primarily English language) through 2014, with some updates in 2015, were performed for each clinical question. The supplemental Appendix summarizes clinical trials regarding the treatment of cutaneous leishmaniasis, including studies analyzed in two Cochrane reviews [bib_ref] Cochrane reviews on neglected diseases: the case of cutaneous leishmaniasis. The Cochrane..., Gonzalez [/bib_ref] [bib_ref] Interventions for Old World cutaneous leishmaniasis, Gonzalez [/bib_ref]. We also included clinical trials and pivotal observational data (particularly, if they involved new therapies) identified through English-language PubMed searches using the terms leishmaniasis and treatment, starting with a 1-year overlap with the Cochrane reviews and extending through January 2015. The Appendix is organized to facilitate search by country of exposure, Leishmania species, and treatment modality; it provides transparent assessment of the quality of each study. Process Overview: The evidence evaluation process was based on the IDSA Handbook on Clinical Practice Guideline Development [fig_ref] Figure 1: Approach and implications to rating the quality of evidence and strength of... [/fig_ref]. In evaluating the evidence regarding the clinical management of leishmaniasis, the Panel followed a process developed by the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) Working Group (http:// www.gradeworkinggroup.org/). This process utilizes a systematic weighting of the quality of the evidence and an assessment of the strength of the corresponding recommendation. ## Consensus development based on evidence The Panel had several in-person meetings, and conducted most of its work though monthly teleconferences and electronically based discussion during 2011-2016. All members of the Panel participated in the preparation and review of the draft guidelines, which were reviewed by the entire Panel. Feedback via external peer review was also obtained. The content of the guidelines and the manuscript was reviewed and approved by the IDSA and ASTMH guideline steering committees and the respective Boards of Directors before dissemination. The subgroup-completed recommendations were discussed by the Panel and were finalized by electronic survey in a two-phase process in which responses and justifications for responses were anonymously summarized, revisions were made, and a final survey vote reached consensus on the GRADE assigned. In general, data from randomized controlled trials begin as "high" quality, and data from observational studies begin as "low" quality. However, the Panel may judge that particular features of the data warrant decreasing or increasing the quality-of-evidence rating; GRADE provides guidance on how various factors should be weighed [bib_ref] GRADE guidelines: a new series of articles in the Journal of Clinical..., Guyatt [/bib_ref]. The strength assigned to a recommendation chiefly reflects the Panel's confidence that the benefits of following the recommendation are likely to outweigh potential harms. Although the quality of evidence is an important factor in assessing the strength of a recommendation, it is not prescriptive. ## Guidelines and conflict of interest The Panel complied with the IDSA policy on conflicts of interest, which requires disclosure of any financial or other interest that may be construed as constituting an actual, potential, or apparent conflict. Panel members were provided IDSA's conflicts of interest disclosure statement and were asked to identify ties to companies developing products that may be affected by promulgation of the guidelines. Information was requested regarding employment, consultancies, stock ownership, honoraria, research funding, expert testimony, and membership on company advisory committees. Decisions were made by IDSA on a caseby-case basis as to whether an individual's role should be limited as a result of a conflict. Potential conflicts of interests are listed in the Acknowledgments section. ## Revision dates At annual intervals, the Standards and Practice Guidelines Committee (SPGC) will determine the need for revisions to the guidelines, on the basis of review of current literature. If necessary, a Panel will be convened (or reconvened) to discuss potential changes. ## Background information about leishmaniasis What clinical manifestations are suggestive of cutaneous leishmaniasis (CL)? CL occurs in an afebrile person with a history of residence or travel in a leishmaniasis-endemic area of the world [fig_ref] Figure 2: Maps of the Geographic Distribution of Cutaneous Leishmaniasis [/fig_ref] who has one or more chronic skin lesions. The usually painless lesions may be small or large, and nodular or ulcerative [fig_ref] Figure 4: Clinical photographs of cutaneous Leishmaniasis [/fig_ref]. Induration of the lesions is typical but purulence is not, unless lesion(s) are superinfected. Many persons do not recall being bitten by a sand fly and do not know how to distinguish sand flies from other small flying insects, but they still should be asked about potential exposures to sand flies. The morphologic characteristics and natural history of CL depend in part on the infecting Leishmania species and the host's immunoinflammatory response. Clinically compatible features of the lesions include well-defined often indurated borders, chronicity, single or clustered lesions, and occurrence in exposed skin areas. Lesions typically are painless unless secondarily infected or over a joint. There may be regional adenopathy, subcutaneous nodules in a lymphatic drainage ("sporotrichoid") pattern, and satellite papules. Single or multiple lesions may occur where the parasite was inoculated by the sand fly but also may occur distant to that site such as at the sites of trauma [bib_ref] Clinical infectious diseases : an official publication of the Infectious Diseases Society..., Wortmann [/bib_ref]. The incubation period from inoculation to clinical manifestations is usually at least several weeks [bib_ref] Epidemiologic investigation of an outbreak of cutaneous leishmaniasis in a defined geographic..., Sanchez [/bib_ref]. The lesions typically begin as papules, progress in size, and often ulcerate. Lesions may be chronic ulcers, papules, nodules, verrucous lesions, or plaques [fig_ref] Figure 4: Clinical photographs of cutaneous Leishmaniasis [/fig_ref]. Over time (months to years), the lesions usually spontaneously heal, typically with residual scarring. The clinical manifestations of CL in HIV-infected and HIVuninfected persons may be comparable, especially, but not only, in coinfected persons with minimal immunosuppression [bib_ref] Leishmania and HIV co-infection: dermatological manifestations, Puig [/bib_ref] [bib_ref] Leishmania major cutaneous leishmaniasis in HIV-positive patients does not spread to extralesional..., Foulet [/bib_ref] [bib_ref] Comparative study of cutaneous leishmaniasis in human immunodeficiency virus (HIV)-infected patients and..., Couppie [/bib_ref] [bib_ref] American tegumentary leishmaniasis and HIV-AIDS association in a tertiary care center in..., Guerra [/bib_ref]. However, in general, the likelihood of having or developing atypical, multifocal, diverse, persistent, progressive, and remitting-relapsing lesions increases in the context of progressively more severe immunosuppression [bib_ref] The relationship between leishmaniasis and AIDS: the second 10 years, Alvar [/bib_ref] [bib_ref] Unusual manifestations of tegumentary leishmaniasis in AIDS patients from the New World, Lindoso [/bib_ref]. Lesions may be unusual in interrelated respects, such as their type/appearance (e.g., pleomorphic, nonulcerative, papulonodular lesions), size, number, and distribution on the skin and mucus membranes [bib_ref] Leishmania and HIV co-infection: dermatological manifestations, Puig [/bib_ref] [bib_ref] Leishmania major cutaneous leishmaniasis in HIV-positive patients does not spread to extralesional..., Foulet [/bib_ref] [bib_ref] Comparative study of cutaneous leishmaniasis in human immunodeficiency virus (HIV)-infected patients and..., Couppie [/bib_ref] [bib_ref] Unusual manifestations of tegumentary leishmaniasis in AIDS patients from the New World, Lindoso [/bib_ref] [bib_ref] Diffuse cutaneous leishmaniasis in an HIV-positive patient in western Africa, Niamba [/bib_ref] [bib_ref] Co-Infection of Leishmania (Viannia) braziliensis and HIV: report of a case of..., Torrico [/bib_ref] [bib_ref] American cutaneous leishmaniasis associated with HIV infection: report of four cases, Mattos [/bib_ref] [bib_ref] Cutaneous Leishmaniasis Coinfection in AIDS Patients: Case Report and Literature Review. The..., Sasaki [/bib_ref]. The differential diagnosis includes cutaneous fungal and mycobacterial infections, cutaneous actinomycosis/nocardiosis, yaws, skin cancer, pyoderma gangrenosum, sarcoidosis, venous stasis ulcers, cutaneous myiasis, spider bites, tropical ulcers, prurigo nodularis, lichen simplex chronicus, fixed drug eruptions, and vasculitis. In the more acute stage, bacterial skin abscesses, infected arthropod bites, and impetigo may be considerations; in the appropriate epidemiologic and clinical context, lack of response to antibacterial therapy should prompt diagnostic testing for leishmaniasis. In addition, a chronic syndrome (skin lesion, naso-oral symptoms, or subacute febrile illness) associated with a granulomatous inflammatory reaction on histopathology may suggest leishmaniasis in persons with the appropriate history (even if remote) [bib_ref] Caseating granulomas in cutaneous leishmaniasis, Aoun [/bib_ref]. What clinical manifestations are suggestive of New World mucosal leishmaniasis (ML)? The diagnosis of ML is a consideration in the appropriate epidemiologic context [fig_ref] Figure 2: Maps of the Geographic Distribution of Cutaneous Leishmaniasis [/fig_ref] in persons with compatible naso-oropharyngeal/laryngeal symptoms or signs, especially if they have evidence or a history of active or healed NWCL. However, ML can develop in persons without a history of symptomatic cutaneous infection or any physical evidence (e.g., scars) of prior CL. The interval from onset (or clinical resolution) of CL to clinical manifestations of ML typically is several years but may range from <30 days to decades. Persistent nasal congestion/stuffiness is the most commonly reported symptom [bib_ref] Mucocutaneous leishmaniasis: an imported infection among travellers to central and South America, Ahluwalia [/bib_ref] ; associated and interrelated manifestations may include coryza, epistaxis, tissue/scab expulsion, pruritus, mass sensation, blockage/obstruction, and hyposmia [bib_ref] Mucocutaneous leishmaniasis: an imported infection among travellers to central and South America, Ahluwalia [/bib_ref] [bib_ref] Mucosal leishmaniasis ("espundia" Escomel, 1911), Marsden [/bib_ref] [bib_ref] Mucocutaneous leishmaniasis, Marsden [/bib_ref] [bib_ref] Detection of Leishmania in unaffected mucosal tissues of patients with cutaneous leishmaniasis..., Figueroa [/bib_ref] [bib_ref] Mucosal leishmaniasis: epidemiological and clinical aspects, Lessa [/bib_ref] [bib_ref] Epidemiology of American cutaneous leishmaniasis due to Leishmania braziliensis braziliensis, Jones [/bib_ref] [bib_ref] American tegumentary leishmaniasis (ATL) in Rio de Janeiro State, Brazil: main clinical..., De Oliveira-Neto [/bib_ref]. Persons with ML may have oral or pharyngeal lesions, bleeding, or pain; dysphagia/odynophagia; or dysphonia. Isolated laryngeal disease, without involvement of other mucosal sites, may occur but is relatively unusual [bib_ref] Mucosal leishmaniasis ("espundia" Escomel, 1911), Marsden [/bib_ref] [bib_ref] Epidemiology of American cutaneous leishmaniasis due to Leishmania braziliensis braziliensis, Jones [/bib_ref]. Although ML typically does not directly affect the ears, involvement of the rhinopharnyx may affect the orifice of the Eustachian tube and thereby lead to "chronic secreting otitis media," the sensation of having a blocked ear, dyacussis, and tinnitus [bib_ref] Mucosal leishmaniasis: epidemiological and clinical aspects, Lessa [/bib_ref] [bib_ref] Eustachian tube blockage with consequent middle ear infection in mucosal leishmaniasis. Revista..., Lessa [/bib_ref]. Abnormalities of the paranasal sinuses (e.g., detected via computed tomography) also have been reported. The differential diagnosis of ML includes infectious diseases (e.g., paracoccidioidomycosis, histoplasmosis, rhinosporidiosis, rhinoscleroma, leprosy, tuberculosis, syphilis, tertiary yaws), neoplastic diseases, and various other etiologies (e.g., granulomatosis with polyangiitis, sarcoidosis, intranasal cocaine use) [bib_ref] Mucocutaneous leishmaniasis: an imported infection among travellers to central and South America, Ahluwalia [/bib_ref] [bib_ref] Mucosal leishmaniasis: epidemiological and clinical aspects, Lessa [/bib_ref] [bib_ref] Non-invasive cytology brush PCR diagnostic testing in mucosal leishmaniasis: superior performance to..., Boggild [/bib_ref]. ## What clinical manifestations are suggestive of visceral leishmaniasis (vl)? VL presents in a person who has a history of residence or travel in a leishmaniasis-endemic area of the world [fig_ref] Figure 3: Maps of the Geographic Distribution of Visceral Leishmaniasis [/fig_ref] and develops a compatible clinical syndrome, which commonly includes chronic fever, weight loss, splenomegaly, pancytopenia, eosinopenia, elevated liver enzymes, hypergammaglobulinemia, and variable hepatomegaly. There is a spectrum of severity; and atypical presentations are common, especially in persons who are immunocompromised (see XXIII and XXV). The onset and course of VL are usually subacute or chronic but can be acute. Risk factors for the acquisition of VL include the bite of an infected sand fly but also needle sharing, laboratory accident, or receipt of a blood transfusion or organ transplant from an infected donor; uncommonly, congenital/perinatal (and, rarely, sexual) transmission has been reported. VL is a consideration even if the likely infection was acquired years to decades earlier (latent infection can reactivate). Immunocompromised persons with AIDS, organ transplant recipients, and persons treated with biologic immunomodulating drugs (such as tumor necrosis factor [TNF]-alpha antagonists) are at increased risk for reactivation and disseminated infection. The spectrum of infection with Leishmania donovani and L. infantum-chagasi ranges from asymptomatic to classic VL, or kala-azar, which is characterized by fever; other constitutional symptoms, including malaise, loss of appetite, and wasting; splenomegaly, which can become massive; hepatomegaly; and various laboratory abnormalities, including hypergammaglobulinemia, anemia, leukopenia, thrombocytopenia, hypoalbuminemia, elevated acute inflammatory markers, and liver enzyme abnormalities. In addition, hyperpigmentation may be observed in persons infected in India and Bangladesh. Lymphadenopathy is seen in some persons in East Africa and occasionally elsewhere. Fever may be intermittent; remittent, with twice daily temperature spikes; or, less commonly, continuous. Detailed clinical descriptions of VL are available elsewhere [bib_ref] Leishmania species, Magill [/bib_ref] [bib_ref] Leishmaniasischapter 99, Magill [/bib_ref] [bib_ref] Principles, pathogen, and practice, Jeronimo [/bib_ref]. VL may be the first opportunistic infection in persons with AIDS, and it often complicates the terminal stage of HIV infection in Leishmania-endemic areas [bib_ref] Clinical aspects of visceral leishmaniasis in HIV infection, Jarvis [/bib_ref]. The clinical manifestations of VL in HIV-infected and HIV-uninfected persons often are qualitatively similar [bib_ref] The relationship between leishmaniasis and AIDS: the second 10 years, Alvar [/bib_ref] [bib_ref] HIV/AIDSrelated visceral leishmaniasis: a clinical and epidemiological description of visceral leishmaniasis in..., Albuquerque [/bib_ref] [bib_ref] Clinical characteristics and treatment outcome of patients with visceral leishmaniasis and HIV..., Hurissa [/bib_ref] , although some common manifestations of VL (kala-azar), such as splenomegaly, may be more subtle or absent in coinfected persons . On the other hand, in coinfected persons, Leishmania parasites may be widely disseminated and found, often serendipitously, in atypical sites and cells, in essentially any organ system (e.g., the gastrointestinal tract and skin), with or without clinical manifestations or relevance [bib_ref] The relationship between leishmaniasis and AIDS: the second 10 years, Alvar [/bib_ref]. Persons with HIV-associated VL quite commonly have or develop dermatologic or mucosal involvement [bib_ref] The relationship between leishmaniasis and AIDS: the second 10 years, Alvar [/bib_ref] , which may mimic other pathologies and may be localized or diffuse. Although PKDL most commonly is associated with L. donovani infection [37], in persons with concurrent HIV/AIDS, PKDL also has been associated with L. infantum-chagasi [49-54]. VL also occurs in persons who are or become immunocompromised for reasons other than HIV/AIDS (see XXV). The onset of clinical manifestations of VL may occur years or decades after the pertinent exposure in persons who become immunocompromised. Although the clinical manifestations may be suggestive of VL in persons with exposure in a leishmaniasis-endemic area, they are not specific. The differential diagnosis is broad. When the onset is acute, it includes malaria, typhoid fever, typhus, acute Chagas disease (in Latin America), acute schistosomiasis, miliary tuberculosis, amebic liver abscess, mononucleosis, and viral hepatitis. In subacute or chronic cases, the differential diagnosis includes miliary tuberculosis, brucellosis, prolonged or recurrent Salmonella infections, subacute bacterial endocarditis, histoplasmosis or other disseminated fungal diseases, malaria with tropical splenomegaly syndrome (hyperreactive malarial splenomegaly syndrome), and hepatosplenic schistosomiasis with portal hypertension. Some noninfectious causes include lymphoma, leukemia, other myeloproliferative diseases, rheumatoid arthritis with Felty's syndrome, other autoimmune processes, and the hemophagocytic lymphohistiocytic syndrome (which is also associated with VL). ## Recommendations for the diagnosis ## Evidence summary Samples for diagnosing CL should be collected from an active appearing (vs a nearly healed) skin lesion. Commonly used approaches for collecting samples include scraping or brushing the debrided ulcer base or edges, aspirating lesions, and obtaining skin snips or punch/shave biopsy specimens from an indurated border (see V). Additional details about specimen collection and diagnostic methodologies for various presentations of CL are provided elsewhere [55-57], including on the Centers for Disease Control and Prevention (CDC) website at http://www.cdc.gov/parasites/leishmaniasis/ diagnosis.html. For collection of biopsy specimens (vs lesion aspirates or swabs), local anesthesia, such as with lidocaine plus epinephrine, typically is used (unless the lesions are on the face, genitalia, or digits, where epinephrine is not advised). Which part of the skin lesion should be sampled to optimize the likelihood of diagnosing CL? The results of several comparisons of sampling the indurated edge vs the ulcer base in NWCL (Guatemala and Colombia) have varied; although the consensus, especially with more sensitive PCR-based diagnostics, is that the base has more parasites, this may not matter clinically. Obtaining samples from under the edge of the ulcer as well as from the base of the lesion has been suggested [58-61]. The optimal sampling site(s) for CL depends upon geographic variability; lesion age, location, and other characteristics; Leishmania species; and the sensitivity of the test procedure. When initially evaluating a patient for CL, if laboratory support permits a quick assessment, it is useful to examine a scraping/aspirate/brushing or touch preparation from the lesion base, near the periphery. The best specimens are obtained from a well-cleaned, active-appearing lesion. Care should be taken to scrape without eliciting bleeding, and then to transfer the material onto a microscope slide for Giemsa staining and microscopy. The use of exudative material with minimal red blood cells on a smear makes identification of amastigotes (either extracellular or within macrophages) easier than in paraffin-fixed tissue sections. Alternatively, with the FDA clearance of the CL detect ™ immunochromatographic assay (InBios International, Inc.), the tissue brushing from an ulcerative lesion can be processed with this rapid point-of-care assay (www. accessdata.fda.gov/cdrh_docs/reviews/k141341.pdf). Molecular-based testing, such as polymerase chain reaction (PCR) analysis, is the most sensitive diagnostic approach . Improvement in the ease and standardization of molecular techniques has led to increased use of such assays. We recommend collecting tissue for PCR analysis in 100% ethyl alcohol or by using the preferred collection method of your reference laboratory; sterility is not needed. For a diagnosis using PCR methodology, almost any tissue specimen may be acceptable. The handling of the material between sampling and testing is much more crucial. PCR analysis can identify Leishmania DNA in small tissue specimens, such as in the scab overlying the lesion, as well as from deep tissue (e.g., dermal) specimens. Lesions that are not ulcerative (a setting in which scraping may be less useful) or that are in cosmetically sensitive areas, such as the face, genitalia, or digits (where biopsy is less preferred), may be sampled by needle aspiration. A needle aspirate samples 3-5 areas, using a 1-3 milliliter (mL) syringe with a small needle (23-27G); some practitioners use a small amount of preservative-free sterile saline and inject then withdraw, whereas others use a dry syringe with a back-and-forth needle incursion into the lesion, simultaneously rotating and applying suction to the syringe for collection of a small drop of tissue fluid in the syringe. This fluid can be smeared on a slide and stained, and the aspiration procedure can be repeated for culture and PCR. For Leishmania culture specimens, use sterile technique: avoid leaving residual iodine or alcohol on the lesion, which may interfere with culture yield. Full-thickness punch biopsy samples are usually obtained from the indurated edge of the skin lesion, where histology may have less degradation changes. In general, shave or punch biopsy specimens are recommended when the pre-test likelihood of leishmaniasis is lower (the differential diagnosis is broad) or when initial less-invasive sampling methods (such as brushing, scraping, or aspirating) do not identify an etiology. ## Ii. in a person with manifestations suggestive of new ## Evidence summary Many of the principles regarding specimen collection for diagnosis of CL also apply to ML; however, for ML, biopsy specimens typically should be collected by an otolaryngologist or other experienced specialist. In advance of the examination, the referring physician and otolaryngologist should discuss the differential diagnosis and the importance of assessing the anatomic extension and clinical severity of mucosal disease (if present), including the potential for respiratory obstruction. Details regarding specimen collection, handling, and testing for leishmaniasis and other potential etiologies should be discussed in advance with the pertinent laboratories. In general, ML is a pauciparasitic syndrome [bib_ref] Mucocutaneous leishmaniasis: an imported infection among travellers to central and South America, Ahluwalia [/bib_ref] , which underscores the utility of molecular amplification methods. However, obtaining mucosal specimens for Leishmania testing-even via relatively noninvasive means (e.g., via nasal swab or cytologic brush [bib_ref] Detection of Leishmania in unaffected mucosal tissues of patients with cutaneous leishmaniasis..., Figueroa [/bib_ref] [bib_ref] Non-invasive cytology brush PCR diagnostic testing in mucosal leishmaniasis: superior performance to..., Boggild [/bib_ref] -typically is not recommended for persons who do not have any macroscopic mucosal abnormalities. Because mucosal dissemination is more common than mucosal disease per se [bib_ref] Detection of Leishmania in unaffected mucosal tissues of patients with cutaneous leishmaniasis..., Figueroa [/bib_ref] , detecting the parasite/DNA in naso-oropharyngeal mucosa does not suffice to diagnose ML. The risk factors for the development of ML are poorly understood (see clinical question XII), as are the factors that affect the progression and anatomic extension of ML over time. Investigational testing for the presence of Leishmania RNA virus (a purported virulence factor) is not readily available, nor, to date, has it been found useful for identifying persons who may have or be at risk for ML . III. During the initial and subsequent evaluations of persons with CL acquired in Central or South America who may have or be at risk for mucosal leishmaniasis (ML), what should be done to assess the possibility of mucosal disease? ## Evidence summary In New World ML, the anterior nasal septum is the most commonly involved area [bib_ref] Mucosal leishmaniasis ("espundia" Escomel, 1911), Marsden [/bib_ref] [bib_ref] Mucosal leishmaniasis: epidemiological and clinical aspects, Lessa [/bib_ref] , which, in contrast to the posterior nose, may be readily accessed even by nonotolaryngologists [bib_ref] Mucocutaneous leishmaniasis: an imported infection among travellers to central and South America, Ahluwalia [/bib_ref] [bib_ref] Mucosal leishmaniasis ("espundia" Escomel, 1911), Marsden [/bib_ref]. Dried nasal secretions, if any, should be removed before beginning the examination. The external contour of the nose often is normal even in persons whose nasal septum has perforated, whereas the perforation may be palpated with the index and forefinger and may be visualized after lifting up the tip of the nose and shining a light at a diagonal angle inside the nares. The speculum examination of the nose may be facilitated by bending the nose from side to side. The oral cavity and pharynx should be inspected using a tongue depressor and a light; to visualize the entire hard palate, ask the patient to tip back his/her head [bib_ref] Mucosal leishmaniasis ("espundia" Escomel, 1911), Marsden [/bib_ref]. The potential utility of otorhinolaryngologic examination for early detection of ML in persons with NWCL was evaluated in a L. (V.) braziliensis-endemic area of Bahia State, Brazil [68]. Among 220 consecutive persons with active CL who had a "careful" otorhinolaryngologic examination (anterior rhinoscopy, oropharyngeal examination, mirror laryngoscopy, and, if indicated, fiberoptic examination), concomitant ML was diagnosed in 6 persons (2.7%). All 6 persons were immunocompetent, and none had a history of CL or a compatible cutaneous scar; their cutaneous lesions had been present for 15-30 days (in 4 persons) or for 8 months (in 2 persons). ML was diagnosed during the persons' initial evaluation. Five of the 6 persons had mucosal disease that was restricted to the nose; the other patient, who was 1 of the 2 persons with an 8-month history of CL, had "pharyngeal and laryngeal involvement and had a nasal septal perforation." The publication about the study [68] did not address whether any of the identified cases of ML would have been missed altogether if the two-step approach described above in recommendations 5-8 had been followed-i.e., if complete otorhinolaryngologic examinations had been reserved for persons who had mucosal symptoms or signs that were detected via thorough assessments by nonspecialists. The utility of a complete otorhinolaryngologic examination (anterior rhinoscopy, oropharyngeal examination, and a fiberoptic examination) for excluding ML was addressed by the same group of investigators in a study in Acre State, Brazil. Among 44 persons with a clinical diagnosis of ML-i.e., a nasal "clinical complaint" plus either a positive Leishmania skin test, a positive serologic result, or a previous diagnosis of CL-only 13 persons (29%) had evidence of active ML (10 persons) or healed/scarred mucosal disease (3 persons who already had been treated). Eight of the 10 previously untreated persons consented to having a biopsy specimen obtained; all 8 had positive Leishmania PCR results. Likely alternative diagnoses (e.g., allergic or atrophic rhinitis or chronic sinusitis) were identified for the persons who did not have evidence of ML. A complete otorhinolaryngologic examination also may be warranted in persons who have disseminated CL-a syndrome distinct from localized and diffuse CL that has been reported primarily in northern and northeastern Brazil and that is associated with an increased risk for concomitant ML, particularly in persons with head or neck lesions . [formula] IV [/formula] ## Evidence summary While there are several approaches to the diagnosis of VL, we recommend that the diagnosis be obtained by collection of tissue aspirates and/or biopsy specimens for microscopy (smears from aspirates and impression preparations from tissue), histopathology, parasite culture, and molecular testing (PCR) from venous blood and tissues . The specificity of microscopy for the diagnosis of VL is high, but its sensitivity varies among the tissues sampled, ranging from positive diagnoses in spleen (93%-99%), bone marrow (52%-85%), and lymph node aspirates (52%-58%) [bib_ref] Sensitivity of bone marrow aspirates in the diagnosis of visceral leishmaniasis, Da Silva [/bib_ref] [bib_ref] A comparison of intercostal and abdominal routes of splenic aspiration and bone..., Thakur [/bib_ref]. Splenic aspiration is not recommended as part of the diagnostic evaluation for VL for persons in North America. Aspiration of the spleen is the most likely to yield a diagnosis but encumbers risk; lifethreatening hemorrhages have been reported [bib_ref] Peripheral blood buffy coat smear: a promising tool for diagnosis of visceral..., Salam [/bib_ref]. Bone marrow aspiration is less sensitive but safer and is the preferred first source of diagnostic sample. Liver, enlarged lymph nodes, and/or even whole blood are other potential sources of tissue specimens. In immunocompromised persons with VL, samples from atypical sites (e.g., gastrointestinal tract, bronchial alveolar lavage, pleural fluid, skin) may yield a diagnosis. Serology with a rK39-based immunochromatographic test (ICT) [bib_ref] Rapid tests for the diagnosis of visceral leishmaniasis in patients with suspected..., Boelaert [/bib_ref] may provide supportive evidence for a diagnosis of VL, but it is not recommended as a stand-alone VL diagnostic test; however, it may be useful to direct more invasive testing (see VIII). A quantitative PCR is sensitive and specific when Leishmania parasitemia is above 10 parasites/mL in the venous blood (see VII) [bib_ref] Visceral leishmaniasis. Infectious disease clinics of, Van Griensven [/bib_ref] [bib_ref] Noninvasive molecular diagnosis of human visceral leishmaniasis, Vaish [/bib_ref]. Using a peripheral blood buffy coat sample for concentration before molecular testing is gaining widespread acceptance; a qualitative result can be obtained. However, because of the lack of standardization of the assay/target and undefined performance characteristics in North American reference laboratories ( ## Evidence summary There is currently no one, single "gold-standard" test for the diagnosis of leishmaniasis. Rather, a group of tests is typically performed: light-microscopic examination of tissue smears or sections (histopathology) for the presence of amastigotes, the tissue stage of the parasite; in vitro culture to isolate the parasite; DNA amplification assays; and, in VL, serologic testing. Many of these assays require reference laboratory support. It is helpful to contact the leishmaniasis laboratory in advance to optimize specimen collection and transport. Microscopy is the most widely available, but it does not allow for identification of the causative Leishmania species. Microscopy requires the visualization of Leishmania amastigotes (including cell membrane, cytoplasm, nucleus, and, in particular, the extranuclear rod-shaped kinetoplast) in tissue specimens by light microscopy with oil immersion at 1000X magnification [bib_ref] Old world leishmaniasis: an emerging infection among deployed US military and civilian..., Weina [/bib_ref]. Parasites can be seen using routine hematoxylin and eosin, Giemsa, or Wright-Giemsa stains. The morphologic identification of amastigotes is easier in smears than in tissue sections. The usual 3-5 um thickness of tissue sections makes it more difficult to confirm the presence of a kinetoplast; thin sections are sometimes helpful. Trypanosoma cruzi amastigotes may also be seen in tissue specimens. Diagnostic confusion can result, particularly in immunosuppressed organ transplant recipients with skin lesions suggestive of CL that actually are caused by T. cruzi infection. Histoplasma capsulatum is of similar size but does not have a kinetoplast . Diagnostic confusion can also result between VL and histoplasmosis in regions where histoplasmosis is endemic, a problem exacerbated by the response of both to empiric antifungal therapy (eg, with amphotericin B formulations). Although a relatively rapid method of discerning whether Leishmania parasites are present (histopathology takes 1-3 days to process, whereas smears and touch preparations take less time), microscopy requires substantial technical expertise. Biopsy quality and the usual 3-5 um thickness of tissue sections, may be factors that contribute to the relatively low sensitivity of histopathology, which has been estimated to be 50%-70% in aggregate for Old World species and 15%-30% for the New World species [bib_ref] Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis, Goto [/bib_ref]. A new point-of-care rapid diagnostic test CL Detect™ (InBios International, Inc) has been FDA cleared for use in ulcerative CL skin lesions, with sampling of early (<4 months old) lesions. This qualitative immunochromatographic assay (test strip) reportedly has limits of detection of ∼200 parasites for OWCL species and 1,000-1,440 parasites for NWCL species. In a study of OWCL in Tunisia, the sensitivity of the test was 96% and the specificity was 90.5% (www.accessdata. fda.gov/cdrh_docs/reviews/k141341.pdf). If possible, parasite isolation (by culture) should be attempted because it provides parasitologic confirmation of the diagnosis and the isolate can be used for additional testing, if indicated. Some reference laboratories provide culture and transport media. Leishmania are fastidious and it can take weeks for cultures to become positive; therefore, therapy is often initiated on the basis of other test results. Once a parasite is isolated, species identification is routinely performed at CDC (Centers for Disease Control and Prevention), Walter Reed Army Institute of Research (WRAIR), and other World Health Organization (WHO) reference laboratories by isoenzyme analysis and more recently DNA-based assays. Despite providing a definitive diagnosis of Leishmania infection, culture is not a highly sensitive diagnostic method. Many specimens contain nonviable organisms or may become contaminated during collection or transport. An estimated 44%-60% of specimens yield parasites that can be expanded in culture and maintained in the laboratory [bib_ref] Old world leishmaniasis: an emerging infection among deployed US military and civilian..., Weina [/bib_ref]. Recently, MALDI-TOF (Matrix assisted laser desorption time of flight) has been used to assist with rapid species identification of cultured promastigotes [bib_ref] Identification of Leishmania at the species level with matrix-assisted laser desorption ionization..., Cassagne [/bib_ref] [bib_ref] Easy identification of leishmania species by mass spectrometry, Mouri [/bib_ref]. PCR analysis detects Leishmania DNA in tissue specimens (see VII and. There are many Leishmania molecular assays with different targets and performance characteristics. The advantage of this approach is that it can provide diagnostic results within 24 hours (although, in practice, it takes longer), is not dependent on having viable organisms, and typically has high sensitivity and specificity . Depending on the primers and target sequence selected, one can identify the Leishmania genus, a subgenus complex, or a particular Leishmania species. Immunologic diagnostic methods include serologic and delayed-type hypersensitivity testing (Leishmania skin test). Neither can distinguish past from current infection. Serologic testing (see VIII) is recommended for persons with suspected VL in whom definitive diagnostic tests for the parasite (microscopic identification, culture, and molecular tests for parasite DNA) cannot be conducted or have negative results. Serologic tests are not reliable for the diagnosis of CL. Skin testing is not recommended or available in the United States or Canada for any form of leishmaniasis. There are no standardized, approved, or commercially available products in North America. Delayed-type cutaneous hypersensitivity responses to leishmanial antigens are typically not observed in untreated persons with kala-azar and are variably seen with L. infantum-chagasi. VI. In a person with leishmaniasis, why could it be helpful to identify the infecting Leishmania species? ## Evidence summary Although Leishmania species identification is not necessary to confirm the diagnosis of CL, ML, or VL, identifying the species can help inform clinical management decisions for individual persons. For example, species identification stratifies potential risk for associated ML, allows estimates of the natural history of the infection, and may help predict the response to a particular therapy (see XII and XIII). If the individual situation is such that none of these factors are assessed to be relevant, species identification may be foregone or treatment may be initiated before the species results are available. However, species identification should be pursued if a person has a complex residence/ travel history (if more than 1 species is found in the pertinent region[s] and infection caused by those species have clinically relevant differences that affect choice of treatment, the dose/duration of therapy, the prognosis, and posttreatment monitoring), became infected in the "mucosal belt" of South America [fig_ref] Table 1: Clinical Characteristics of Cutaneous Leishmaniasis [/fig_ref] , is immunocompromised, or has comorbidities that may affect the treatment risk-benefit assessment (e.g., young or old age, pregnancy or lactation, liver or renal disease; see XXVI and [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref]. Classically, species identification has been accomplished using multilocus enzyme electrophoresis (MLEE) with cultureadapted parasites. Molecular techniques often allow rapid species identification directly from tissue, from many different available specimen sources, with the caveat that the assays may not have been fully characterized and validated [bib_ref] Species typing in dermal leishmaniasis, Van Der Auwera [/bib_ref]. In addition, there may be irreconcilable discrepancies between the molecular and the MLEE results. These recommendations are based on clinical experience and a summary of the limited available data as outlined in a recent review article about species-directed therapy [bib_ref] Species-directed therapy for leishmaniasis in returning travellers: a comprehensive guide, Hodiamont [/bib_ref]. Decisions regarding clinical management also must take into account the availability (or lack thereof) and feasibility of particular therapeutic options. ## Evidence summary In North America, DNA-based molecular assays should be performed if direct visualization of the parasite is unsuccessful and the index of suspicion is high for any form of leishmaniasis. These assays include conventional PCR, real-time PCR, nucleic acid based amplification (NASBA), and loop-mediated isothermal amplification (LAMP). They are the preferred methodology where experienced microscopists are not readily available. They are currently the most sensitive assays for the detection of Leishmania species (spp.) and are particularly useful in situations where few parasites are present [62, [bib_ref] Predictors of visceral leishmaniasis relapse in HIV-infected patients: a systematic review, Cota [/bib_ref] [bib_ref] Molecular diagnosis of leishmaniasis, Tavares [/bib_ref] [bib_ref] Molecular tools for diagnosis of visceral leishmaniasis: systematic review and meta-analysis of..., De Ruiter [/bib_ref]. A key point is that there is no single standard Leishmania PCR assay, and many assays differ with respect to parasite targets and performance characteristics. For example, current PCR targets at North American reference laboratories vary-e.g., glucose-6-phosphate isomerase (GPI), cathepsin L-like cysteine protease B gene, and leishmanial ribosomal RNA (rRNA). Samples for PCR analysis do not have to be sterilely collected and can be inoculated onto filter paper and dried, allowing for specimen preservation and easy transport. Although the preferred sample is a fresh tissue specimen preserved in absolute alcohol, PCR assays are also useful in identifying the Leishmania species in paraffin-fixed tissue and cultured isolates. For persons with HIV/AIDS, quantitative Leishmania loads in the blood, buffy coat, and bone marrow are used in VL management [bib_ref] Molecular tools for diagnosis of visceral leishmaniasis: systematic review and meta-analysis of..., De Ruiter [/bib_ref] [bib_ref] Quantification of Leishmania infantum DNA by a real-time PCR assay with high..., Mary [/bib_ref]. Although PCR-based assays are not commercially available in North America, molecular analyses are performed at reference laboratories such as at CDC and WRAIR in the United States and at the National Reference Centre for Parasitology in Montreal, Canada, as well as at other WHO leishmaniasis collaborating centers worldwide. Quantitative PCR is not available in any North American reference laboratory as of the time of writing these guidelines; however, clinicians should contact reference laboratory directors for updated information about availability. Potential limitations of these molecular methods include the requirement for technical training and the need to avoid specimen contamination. Other issues include the infrequent validation of the assay for the geographic area where the infection was acquired and a need for contextual assurance that the assay result is consistent with the potential region of exposure [bib_ref] Universal PCR assays for the differential detection of all Old World Leishmania..., Odiwuor [/bib_ref]. Real-time PCR (RT-PCR) methodology has been developed, which uses fluorescent signal as an indicator of amplification products. This approach is an improvement over older PCR methods; it is highly specific, less labor intensive (which reduces the risk for contamination), and provides results in <1 hour (although, in practice, it takes longer). Multilocus enzyme typing (MLEE), which is technically complex and time-consuming, is a potentially more powerful methodology than molecular analysis for the identification of Leishmania spp., but it needs cultured parasites and lacks the discriminatory power of newer techniques like multilocus sequence typing [bib_ref] Is it time to revise the nomenclature of Leishmania?, Schonian [/bib_ref]. MALDI-TOF-a technology that is being widely introduced into clinical microbiology laboratories in North America-recently was reported to assist in the diagnosis of leishmaniasis and to identify the Leishmania species [bib_ref] Easy identification of leishmania species by mass spectrometry, Mouri [/bib_ref]. VIII. What is the role of serologic testing in the diagnosis of leishmaniasis? ## Evidence summary A number of assays can be used to detect antileishmanial antibodies. The sensitivity and specificity vary depending on the leishmanial antigen(s) and platform used as well as the patient populations studied. Whole or solubilized promastigotes and recombinant antigens have been used (see Background information about leishmaniasis). The best characterized is the recombinant K39 kinesin-like antigen expressed by amastigotes cloned from L. infantumchagasi [bib_ref] Rapid immunochromatographic strip test for detection of anti-K39 immunoglobulin G antibodies for..., Welch [/bib_ref] [bib_ref] Molecular characterization of a kinesin-related antigen of Leishmania chagasi that detects specific..., Burns [/bib_ref]. In the United States, the immunochromatographic dipstick (Kalazar Detect,™ InBios International, Inc., Seattle, WA) is an FDA-cleared diagnostic test. In a meta-analysis of 13 publications [bib_ref] A metaanalysis of the diagnostic performance of the direct agglutination test and..., Chappuis [/bib_ref] , the sensitivity and specificity of the rK39 dipstick for symptomatic VL in populations unlikely to have HIV/AIDS were 94% and 91%, respectively. The sensitivity was higher in studies conducted in South Asia [bib_ref] Noninvasive management of Indian visceral leishmaniasis: clinical application of diagnosis by K39..., Sundar [/bib_ref] and Latin America [bib_ref] The sensitivity and specificity of Leishmania chagasi recombinant K39 antigen in the..., Braz [/bib_ref] than in East Africa [bib_ref] Accurate Serodetection of Asymptomatic Leishmania donovani Infection by Use of Defined Antigens, Vallur [/bib_ref] [bib_ref] Comparison of point-of-care tests for the rapid diagnosis of visceral leishmaniasis in..., Bezuneh [/bib_ref] , where the sensitivity reportedly ranged from 75% to 85% and the specificity from 70% to 92% [bib_ref] Design, development and evaluation of rK28-based point-of-care tests for improving rapid diagnosis..., Pattabhi [/bib_ref] [bib_ref] Evaluation of a new recombinant K39 rapid diagnostic test for Sudanese visceral..., Ritmeijer [/bib_ref]. The specificity tends to be highest in healthy control populations [bib_ref] A metaanalysis of the diagnostic performance of the direct agglutination test and..., Chappuis [/bib_ref]. False-positive rK39 reactions have been reported in Latin America in persons with Chagas disease or CL [bib_ref] The sensitivity and specificity of Leishmania chagasi recombinant K39 antigen in the..., Braz [/bib_ref]. On occasion, the rK39 results are positive in asymptomatic persons infected with L. donovani or L. infantum-chagasi, including persons who may later progress to develop VL. Unfortunately, assays for antileishmanial antibodies are not helpful as a test of cure. In a study of 780 persons treated for VL in India, antibodies to rK39 were assessed using an ELISA format. The titers decreased rapidly during the first 12 months following treatment but then declined slowly, with 39% of patients still seropositive more than 15 years after treatment [bib_ref] Persistence of Leishmania donovani antibodies in past visceral leishmaniasis cases in India...., Gidwani [/bib_ref]. The presence of antileishmanial antibodies years after treatment for VL has been reported in cohort studies performed in India, South America, and East Africa [bib_ref] Rapid immunochromatographic strip test for detection of anti-K39 immunoglobulin G antibodies for..., Welch [/bib_ref]. Some North American laboratories perform indirect immunofluorescence assays (IFA) or enzyme-linked immunosorbent assays (ELISA) using crude promastigote or other characterized leishmanial antigens. The sensitivity and specificity vary with the platform and antigens used, as well as the threshold for considering a result positive [bib_ref] Rapid immunochromatographic strip test for detection of anti-K39 immunoglobulin G antibodies for..., Welch [/bib_ref] [bib_ref] Evaluation of direct agglutination test, rk39 Test, and ELISA for the diagnosis..., Mandal [/bib_ref]. False-positive results have been reported in persons with CL, Chagas disease, leprosy, tuberculosis, typhoid fever, malaria, and other diseases [bib_ref] Serodiagnosis of leishmaniasis, Kar [/bib_ref]. The National Reference Centre for Parasitology in Montreal, Canada, offers Leishmania IFA testing. There is also a direct agglutination test (DAT, Dutch TB Laboratory Partnership, Royal Tropical Institute, Amsterdam), using whole Leishmania promastigotes, that has been evaluated in a number of leishmaniasis-endemic areas. In a metaanalysis [bib_ref] A metaanalysis of the diagnostic performance of the direct agglutination test and..., Chappuis [/bib_ref] , the sensitivity and specificity were reported to be 95% and 86%, respectively. This assay is not available in North America. Antileishmanial antibodies may be diminished or undetectable in persons who are coinfected with HIV/AIDS. In a recent meta-analysis, the sensitivity in persons coinfected with HIV/ AIDS ranged from 51% to 84% and the specificity from 82% to 93%, depending on the assay [bib_ref] The diagnostic accuracy of serologic and molecular methods for detecting visceral leishmaniasis..., Cota [/bib_ref]. In studies in Ethiopia and Brazil [bib_ref] Field evaluation of rK39 test and direct agglutination test for diagnosis of..., Ter Horst [/bib_ref] [bib_ref] The emergence of concurrent HIV-1/AIDS and visceral leishmaniasis in Northeast Brazil, Nascimento [/bib_ref] , 77% and 82% of persons with concurrent VL and HIV/AIDS were seropositive using rK39-based assays. However, in solid organ transplant recipients [bib_ref] Noninvasive molecular diagnosis of human visceral leishmaniasis, Vaish [/bib_ref] and a few cases of persons treated with TNF-α antagonists [bib_ref] Comparison of point-of-care tests for the rapid diagnosis of visceral leishmaniasis in..., Bezuneh [/bib_ref] , serologic tests have not appeared to be of reduced sensitivity in persons with VL. Kalazar Detect™ (InBios International, Inc) test for antibodies against rK39 is known to have poor sensitivity in persons with CL. In a cohort of otherwise healthy military personnel who had CL (mainly OWCL), the sensitivity of the rK39 dipstick assay was 10.2% and of the rK39 ELISA was 28.8% [bib_ref] Positive rK39 serologic assay results in US servicemen with cutaneous leishmaniasis, Hartzell [/bib_ref]. In a study of 242 persons with confirmed CL in a L. (V.) braziliensis-endemic area in Brazil, none tested positive with the dipstick assay [bib_ref] Specificity of the rapid rK39 antigen-based immunochromatographic test Kalazar Detect(r) in patients..., Molinet [/bib_ref]. A number of other studies of serologic responses in CL have used leishmanial antigens derived from cultured promastigotes. The Leishmania spp., the methods of antigen preparation, and the platforms have varied widely, as have the reported sensitivities and specificities [bib_ref] Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis, Goto [/bib_ref]. On the basis of the available data, serologic testing is not recommended for the diagnostic evaluation of CL. ## Recommendations for the treatment of leishmaniasis Cutaneous leishmaniasis IX. In a person with a consistent travel history and compatible skin lesion(s), is it necessary to obtain parasitologic confirmation of the diagnosis of leishmaniasis before starting treatment? ## Recommendation ## After a careful diagnostic evaluation in which neither leishmaniasis nor another diagnosis is confirmed, empiric treatment may be indicated on the basis of an individualized risk-benefit assessment [Weak, very low]. Remark: This should be discussed with the patient and reevaluated periodically, taking into account the clinical evolution. ## Evidence summary This recommendation derives from opinion based on clinical experience. We strongly prefer to have a confirmed diagnosis to inform treatment and to provide prognostic information; otherwise, we manage the skin lesion(s) as a calculated riskbenefit decision. Clinical appearance (see Background) must be suggestive, although a variety of appearances are possible. Certainly, one should first ascertain that CL is endemic and plausible in the region of exposure [fig_ref] Figure 2: Maps of the Geographic Distribution of Cutaneous Leishmaniasis [/fig_ref]. Knowing what species of CL are endemic there also may be helpful [bib_ref] Species-directed therapy for leishmaniasis in returning travellers: a comprehensive guide, Hodiamont [/bib_ref]. CL may occur in clusters of exposed persons (e.g., in travelers or military groups); if efforts to make a specific diagnosis (particularly in NWCL) fail to confirm the presence of parasites, the pretest likelihood that the clinical manifestations and epidemiology are compatible with CL should be considered-e.g., if fellow travelers have confirmed cases of CL, the likelihood that a person with skin lesions has CL is higher. L. (V.) braziliensis CL and leishmaniasis recidivans (L. tropica) persisting for many months may have fewer parasites present, thus making diagnostic confirmation difficult [bib_ref] The histopathology of cutaneous leishmaniasis due to Leishmania (Leishmania) mexicana in the..., Andrade-Narvaez [/bib_ref] [bib_ref] Correlation between histopathology, immune response, clinical presentation, and evolution in Leishmania braziliensis..., Gutierrez [/bib_ref]. The availability of diagnostic molecular methods has increased the sensitivity of detection, such that negative test results are less likely (see VII). In this circumstance, obtaining a skin biopsy specimen to look for other etiologies may be helpful. The histopathologic milieu of CL may include well-formed granulomas but also lymphocytic/plasma cell infiltration; the stratum corneum may be hypertrophied and can also be ulcerated with necrosis. If the exposure was south of Nicaragua (i.e., in Costa Rica or further south), particularly in the so-called mucosal belt in South America, concern about risk for mucosal involvement may prompt empiric treatment based on clinical impression. This, as well as the potential toxicities associated with particular medications [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref] , should be considered in individualized treatment decisions. Oral miltefosine, which recently became available in the United States, may have a role in this circumstance, although it also can be associated with adverse effects. OWCL skin lesions can often be treated with nonspecific local measures, which also could be indicated for other similarly appearing conditions and are associated with less toxicity than available systemic agents. X. Is treatment of clinically manifest cutaneous infection (CL) always indicated? ## Recommendations ## Evidence summary These guidelines assume a setting with ready access to medical resources and availability of most relevant treatment modalities. Persons with CL will be involved in the assessment of risks and benefits associated with treatment, and potential legal liabilities for adverse outcomes will require consideration as well. These factors may lead to recommendations that differ from those in some leishmaniasis-endemic areas. When deciding whether to treat a case of CL, one must consider the goals of treatment. CL can lead to morbidity but does not directly cause mortality. The primary goal is to accelerate healing of the lesion(s) and, thereby, to minimize tissue damage, scarring, and disfigurement; appropriate treatment is also thought to reduce the risk for subsequent therapeutic failure, including ML. In some instances, at the time of diagnosis, lesions already will show evidence of spontaneous healing. Some lesions may also be considered "simple," in the sense that they are uncomplicated [fig_ref] Table 1: Clinical Characteristics of Cutaneous Leishmaniasis [/fig_ref] and seem unlikely to lead to substantial morbidity. In particular, the lesions are small in size, are few in number, and are not localized on parts of the body with the potential for cosmetic or functional consequences. When assessing whether treatment may be indicated, there are several patient categories to consider: 1) Known species, low ML risk, clinically benign lesions: The infection was acquired in the Old World or it was acquired in the New World but is known to be caused by a species not in the Viannia subgenus or is caused by a Viannia species from a region north of Costa Rica. In addition, the lesions are clinically benign or reportedly are spontaneously healing, and the patient is not immunocompromised. In these cases, the risks for ML and other complications are low and observation is a reasonable approach. However, persons with lesions that are not shown to heal subsequently may be offered treatment. 2) Region of acquisition known, low ML risk, clinically benign lesions: The infecting species is unknown, but infection was acquired in a region where ML is rare. In addition, the lesions are clinically benign or reportedly are spontaneously healing, and the patient is not immunocompromised. In these cases, the risks for ML or other complications are low, and observation is a reasonable approach. However, persons with lesions that do not subsequently heal should be offered treatment. 3) Increased ML risk: The infection is caused by a Viannia species from Costa Rica or further south or the species is not known but infection was acquired in a region where ML is endemic. Treatment should be offered even if the lesions are spontaneously or recently healed. The natural history of CL has received limited study, although the placebo groups of clinical trials provide some information. There is a variable tendency for lesions to spontaneously heal within approximately 2-6 months (e.g., L. major), 3-9 months (e.g., L. mexicana), or 6-15 months (e.g., L. tropica, L. [V.] braziliensis, or L. [V.] panamensis) of disease onset. On the basis of this knowledge, observation alone may be considered for lesions expected to heal in a short time (e.g., 1-3 months) and that are clinically simple as defined in [fig_ref] Table 1: Clinical Characteristics of Cutaneous Leishmaniasis [/fig_ref]. Observation may also be preferred when therapy, especially systemic therapy, would ideally be delayed, such as during pregnancy (see XXVI) or during treatment for other conditions that may interfere or interact with the antileishmanial agents. Anecdotally, observation is poorly accepted by many persons as a management approach. Unfortunately, there are no reliable clinical predictors of delayed healing or therapeutic failure, other than the demonstration that both phenomena are complex and are related to variability in the host immune response as well as strain factors [bib_ref] Natural history, clinical evolution, and the host-parasite interaction in New World cutaneous..., Weigle [/bib_ref] [bib_ref] Advances in leishmaniasis, Murray [/bib_ref]. Some factors associated with slower healing are discussed in section XV. Whether lesions have healed spontaneously or after treatment, risk for therapeutic failure remains and it is difficult to quantify for an individual immunocompetent person. The primary concern related to observation of CL without treatment is that, despite apparent spontaneous healing, metastatic infection in the form of mucosal involvement may occur. Mucosal disease may cause destructive lesions that are difficult to treat and may lead to severe sequelae (see II). A careful nasal-oropharyngeal examination should always be performed (see III). An additional concern is that apparently healing cutaneous disease may persist for long periods or relapse. Treatment can mitigate both of these potential complications. The risks for ML in leishmaniasis-endemic areas have been summarized [bib_ref] Local or systemic treatment for New World cutaneous leishmaniasis? Re-evaluating the evidence..., Blum [/bib_ref]. L. (V.) braziliensis is the New World species most often associated with ML, which can occur years, even decades, after acquisition of infection. The incidence of mucosal involvement associated with CL seems to vary with geography and species/strain. Generally, it is highest in the Amazonian basin and adjacent lower altitudes of Andean South America, particularly Bolivia, Peru, and Brazil, and lower in Colombia, Venezuela, Argentina, and Central America. Systemic treatment should be offered for L. (V.) braziliensis infections and other cases in category 3, above. The ML risk is lower outside of South America and the Central American countries from Costa Rica southward. Importantly, case reports of disease imported into North America and Europe by travelers have suggested limited imported mucosal disease from outside these regions [bib_ref] New World cutaneous leishmaniasis imported into Australia, Maguire [/bib_ref] [bib_ref] Leishmania braziliensis presenting as a granulomatous lesion of the nasal septum mucosa, Lohuis [/bib_ref] [bib_ref] Imported mucosal leishmaniasis in a traveler. Clinical infectious diseases : an official..., Scope [/bib_ref] [bib_ref] New world mucosal and cutaneous leishmaniasis: an emerging health problem among British..., Lawn [/bib_ref] [bib_ref] Clinical complexity of Leishmania (Viannia) braziliensis infections amongst travelers, Eichner [/bib_ref] [bib_ref] Successful treatment of imported mucosal leishmania infantum leishmaniasis with miltefosine after severe..., Neumayr [/bib_ref] [bib_ref] New World cutaneous leishmaniasis in returned travellers: treatment failures using intravenous sodium..., Lawn [/bib_ref] [bib_ref] New world cutaneous leishmaniasis in travellers, Schwartz [/bib_ref]. NWCL caused by non-Viannia species and OWCL are very rarely associated with ML, although cases have been reported in immunocompromised and some immuncompetent hosts [bib_ref] Clinical picture of cutaneous leishmaniases due to Leishmania (Leishmania) mexicana in the..., Andrade-Narvaez [/bib_ref] [bib_ref] Mucosal Leishmania infantum infection, Richter [/bib_ref]. Patient education regarding this possibility should be a standard component of care. The evidence for the effectiveness of systemic treatment in preventing ML is summarized in clinical question XII. Another point of consideration in selecting a treatment plan includes that, although often considered a clinically less virulent pathogen, L. mexicana has rarely been associated with a more severe condition known as diffuse cutaneous leishmaniasis (DCL). DCL has been reported as caused by other species, including L. amazonensis, L. venezuelensis, and L. pifanoi [42, [bib_ref] Diffuse cutaneous leishmaniasis with mucosal involvement in Colombia, caused by an enzymatic..., Velez [/bib_ref] [bib_ref] Disseminated American cutaneous leishmaniasis, Bonfante-Garrido [/bib_ref] [bib_ref] Clinical and immunopathological spectrum of American cutaneous leishmaniasis with special reference to..., Silveira [/bib_ref]. This syndrome appears to be a type of anergic, severe, and chronic nonulcerative, plaquelike form of CL, thought to be related to a host immunologic defect. Treatment is often unsatisfactory. Systemic treatment is usually given, but relapse is typical when treatment is stopped. Miltefosine may yield a better initial response rate than antimonials, but some type of chronic or intermittent therapy may be required [bib_ref] Diffuse cutaneous leishmaniasis responds to miltefosine but then relapses, Zerpa [/bib_ref]. Regardless of whether antileishmanial therapy is administered, standard wound care should be applied to ulcerative skin lesions until they have fully reepithelialized. Although there are few trials of particular interventions, clinical experience supports the importance of these common measures. They include control of secondary infection, gentle debridement of necrotic tissue if present, and moisturizing to promote tissue regeneration. Daily ulcer cleansing with mild soap and allowing water in the shower to run over the lesions is advised. A thin layer of a petroleum-based ointment (e.g., Aquaphor®, petroleum jelly, Vaseline®) should be applied after bathing; other moisturizing creams used in leishmaniasis include Aquaphilic® or Eucerin® products. Occlusion does not seem to be needed but can be used when wound drainage is present. XI. In a person with CL, what could be the consequences of no treatment or suboptimal therapy, and how should persons who received no or suboptimal therapy be monitored? ## Evidence summary When considering whether to treat CL in persons who have not been previously treated or who have received suboptimal treatment, the potential consequences of the infection should be considered. The most common morbidity relates to scarring of the lesions, which can be extensive. Scars and pigmentary changes, especially if on the face, can have substantial aesthetic consequences. Scars that are over joints, such as those in the fingers, can impair function. In the short term, optimal treatment accelerates healing and may reduce tissue destruction. Faster healing presumably also reduces the opportunity for bacterial superinfection and the associated complications. These benefits have been confirmed by clinical experience, although rigorous assessments of benefits are lacking. In the midterm, treatment reduces the likelihood of persisting lesions or relapse, whether local, regional (e.g., lymphatic spread), or more distant. In the long term, although the evidence is indirect, the probability of developing ML appears to be reduced, and there may be a reduction in late reactivation (e.g., in the context of immunosuppression). Regardless of whether treatment is administered, careful objective documentation of the evolution of the skin lesions is important for guiding clinical management. Photographic records of lesions are often helpful; even photographs taken by patients using their own cameras or smart phones can be helpful. Observations should be made approximately every 2-4 weeks until lesions have reepithelialized and less frequently thereafter. The surface area and induration should be recorded, as well as the proportion of the ulcer base that has reepithelialized. The lesion(s) size, location, and associated subcutaneous nodules or adenopathy should be noted, especially new findings around the original lesions and along lymphatic drainage pathways. Evidence of secondary infection of any lesion and adjacent tissues should be described, including pain, purulence, and fluctuance. Superinfection may require debridement of eschar. The time course of healing is further discussed in XV. Careful examination of the mouth and nose should be included in all follow-up evaluations (see III); the indications for referral to a specialist for a complete otorhinolaryngologic examination are discussed in III. The likelihood of therapeutic success and failure has proven very difficult to predict in the individual patient. Healing rates appear to be influenced by host genetics and immune responses, the Leishmania strain, and even the strain of the vector sand fly. There are few long-term studies monitoring defined cohorts of infected patients for therapeutic failure. Reappearance of lesions at the same site is generally presumed to represent relapse. Clinically manifest reinfection is rare with L. major and has not been well studied for other species. The extent to which infection with one species/ strain protects against infection (or disease) with another is also poorly understood [bib_ref] Therapeutic vaccines for leishmaniasis, Khamesipour [/bib_ref]. Most relapses of cutaneous lesions occur within 1 year, although much longer intervals have been reported with extended follow-up periods [bib_ref] Recurrent lesions in human Leishmania braziliensis infection-reactivation or reinfection?, Saravia [/bib_ref] [bib_ref] Long-term follow-up of patients with Leishmania (Viannia) braziliensis infection and treated with..., Netto [/bib_ref] ; and viable parasites have been isolated from healed scars years later [bib_ref] Persistence of leishmania parasites in scars after clinical cure of American cutaneous..., Mendonca [/bib_ref]. There are many case reports of later recurrence associated with acquired immunosuppression [bib_ref] Advances in leishmaniasis, Murray [/bib_ref]. Similar to CL recurrence, the risk for ML following NWCL is highest within 2 years of the onset of the initial skin lesion (see III) [bib_ref] Mucosal leishmaniasis ("espundia" Escomel, 1911), Marsden [/bib_ref]. Persons should be informed that even after routine follow-up has ended, they may still be at risk of developing ML. Severe sequelae from ML include destructive lesions causing nasal, oral, pharyngeal, and airway complications (see II and III); treatment of advanced ML is often difficult and unsatisfactory (see XVII). When planning patient follow-up, it can be challenging to balance the relatively low risk for late ML against the costs and discomfort of long-term surveillance for ML symptoms and signs. The risks associated with laryngoscopy and biopsy are minimal but should nonetheless be considered when discussing such surveillance [bib_ref] Morbidity and patient perception of flexible laryngoscopy, Paul [/bib_ref]. Patient values and preferences are important when developing follow-up plans. ## Xii. in a person with cl, what factors should prompt consideration of use of a systemic (oral or parenteral) agent for initial therapy? Recommendations 32. Systemic treatment is recommended for persons with complex CL as defined in [fig_ref] Table 1: Clinical Characteristics of Cutaneous Leishmaniasis [/fig_ref] ## Evidence summary The most important reason for giving systemic therapy is the treatment of local or distant dissemination. Systemic (vs local) therapy involves the reliable and sustained delivery of the therapeutic agent to the infected tissues, including distant sites of potential spread. For this reason, systemic therapy has become the standard of care for all disseminated infection, and such cases are generally excluded from studies of local therapy. This principle also relates to prevention of ML, presumably by treating organisms that already have seeded the naso-oropharynx and, perhaps, by accelerating healing and thereby reducing the opportunity for metastatic spread. Other infections defined as complex [fig_ref] Table 1: Clinical Characteristics of Cutaneous Leishmaniasis [/fig_ref] may also benefit from systemic therapy. These include large, multiple, or difficult-to-access lesions that make local treatment (see XIV) technically difficult or impossible. Data from compar-ative studies regarding simple [fig_ref] Table 1: Clinical Characteristics of Cutaneous Leishmaniasis [/fig_ref] leishmaniasis do not suggest that systemic therapy is superior to local therapy for uncomplicated infection (see XIV). Some experts think that systemic therapy may lead to more rapid healing of lesions compared with local treatment, with possible associated benefits in terms of scarring and superinfection, although we did not identify published data to support this impression. Systemic treatment options include parenteral and oral therapies [fig_ref] Table 3: Approach to Syndromic Treatment of Leishmaniasis in North America 1,2 [/fig_ref]. Choosing the optimal therapy for a particular case is difficult, given the limited information available from comparative clinical trials and the substantial methodologic or other limitations of many studies. The majority of treated CL persons in South America are treated with parenteral pentavalent antimonials (Sb V ). In several recent clinical trials, miltefosine and parenteral Sb V therapy were compared, yielding results that supported FDA approval of miltefosine for this indication. There are limited published data regarding other systemic agents, such as amphotericin B deoxycholate, liposomal amphotericin B (L-AmB), and the oral "azoles." Data from published clinical trials are summarized in Appendix 1. It remains unclear how the results of individual studies can be extrapolated to other species, geographic areas, and patient populations where data are unavailable. Systemic therapy of NWCL (compared with no or suboptimal therapy) appears to reduce the risk for subsequent ML. If ML is considered to be a risk, treatment selection should be based on predicted efficacy, patient tolerance of risk for therapeutic failure, toxicity, practicality, availability, and cost (see XIII). ML can cause disfigurement and disabilities, especially if the diagnosis and treatment are delayed (see XVII). No controlled clinical trials have compared the incidence of ML after treatment of NWCL with systemic versus local therapy (see XIV). Observational studies have generally found incidence rates of ML following CL caused by L. (V.) braziliensis to be 2%-10% [bib_ref] Local or systemic treatment for New World cutaneous leishmaniasis? Re-evaluating the evidence..., Blum [/bib_ref] and close to 30% in some reports [bib_ref] Epidemiological, clinical and biological features of mucocutaneous leishmaniasis in Bolivia after a..., Dimier-David [/bib_ref]. On the basis of retrospective estimates in an actively surveyed population of >3,000 CL persons in a L. (V.) braziliensis focus in Peru, the lifetime risk for ML was 12.8% [bib_ref] The epidemiology and control of leishmaniasis in Andean countries, Davies [/bib_ref]. Unfortunately, study methods have been highly variable and often poorly described. It is difficult to use individual studies to assess variations in risk associated with different geographic regions, Leishmania species/strains, and host factors; of note, the proportion of patients treated and the types of treatment used in the study population have not always been described, further complicating interpretation of the findings. The evidence that systemic therapy (compared with no or suboptimal therapy) may reduce the risk of developing ML derives from 3 types of studies: 1) treatment trials of NWCL (presumed or proven L. [V.] braziliensis) with long-term followup showing rates of ML that appear to be substantially lower than those described above; 2) case series that suggest that most of the persons with ML had not received adequate treatment for their prior CL; and 3) clinical trials of NWCL in which subjects were observed over extended periods, such that the incidence of ML could be compared between treated subjects and those who received incomplete, ineffective, or no therapy. There have been several studies of the first type. Among 658 persons with presumed L. (V.) braziliensis CL in Brazil (Rio de Janeiro State), only 0.4% of patients who received various dosage regimens of parenteral Sb V treatment went on to develop ML after follow-up for 1 to 11 years [bib_ref] Intralesional therapy of American cutaneous leishmaniasis with pentavalent antimony in Rio de..., Oliveira-Neto [/bib_ref]. In a study in which a low-dose regimen of parenteral Sb V was used and the follow-up period was 5-10 years, no cases of ML were identified among 120 patients whose cases of CL were successfully treated; and no cases of ML were reported among 59 patients treated with intralesional Sb V [bib_ref] Intralesional therapy of American cutaneous leishmaniasis with pentavalent antimony in Rio de..., Oliveira-Neto [/bib_ref] [bib_ref] A low-dose antimony treatment in 159 patients with American cutaneous leishmaniasis: extensive..., Oliveira-Neto [/bib_ref]. In a study in Brazil, a 3.2% rate (2/62 persons) of development of ML posttreatment was reported [bib_ref] Long-term follow-up of patients with Leishmania (Viannia) braziliensis infection and treated with..., Netto [/bib_ref]. The second type of study suggests that the majority of cases of ML occur in persons who did not receive optimal therapy for their prior cutaneous lesions. This type of study includes a series of 78 Brazilian patients with ML, only 7 of whom reported having a history of treatment of CL [bib_ref] American tegumentary leishmaniasis (ATL) in Rio de Janeiro State, Brazil: main clinical..., De Oliveira-Neto [/bib_ref] ; and a series of 12 Brazilian patients, 4 of whom had been treated previously (3 with parenteral Sb V and 1 with pentamidine). However, among imported ML cases in travelers, there are reports of some who had received prior systemic treatment [bib_ref] New world cutaneous leishmaniasis in travellers, Schwartz [/bib_ref]. There have been a few small studies of the third type. In a study in Colombia (L. [V.] panamensis and L. [V.] braziliensis), none of 66 subjects with CL treated with parenteral Sb V , 2 of 55 treated with allopurinol (generally not effective for CL), and 1 of 46 who received placebo developed ML within 1 year [bib_ref] Inefficacy of allopurinol as monotherapy for Colombian cutaneous leishmaniasis. A randomized, controlled..., Velez [/bib_ref]. In a study in Salvador, Brazil, 2 of 18 patients treated with allopurinol developed ML within 1 year, compared with none of 16 who received parenteral Sb V [bib_ref] Evaluating the efficacy of allopurinol for the treatment of cutaneous leishmaniasis, Junior [/bib_ref]. In aggregate, these observations suggest that effective systemic treatment of NWCL caused by Viannia species can decrease the risk for ML but may not prevent all cases of ML. ## Xiii. what systemic treatment options are available in ## Evidence summary The options for systemic treatment of CL in North America are partially limited by availability issues [fig_ref] Table 3: Approach to Syndromic Treatment of Leishmaniasis in North America 1,2 [/fig_ref] , which are discussed for each individual agent below. In the United States, using those drugs that are available only under Investigational New Drug (IND) protocols implies somewhat reduced flexibility in treatment administration and the need for IND-associated record keeping and review. In Canada, agents not approved for use are available through the Special Access Program from Health Canada; but physicians must make their own arrangements for importation, and permission is usually given only if other approved agents can be clearly shown to be ineffective, inferior, or not tolerated. Associated costs may not be covered by public or private insurance. There is no ideal systemic treatment, in the sense of being uniformly and highly effective, regardless of the parasite species or the patient's immunologic status; safe, regardless of the patient's age, pregnancy status, or comorbidities; and inexpensive, short-course oral therapy. Each available regimen lacks several of these desirable features. Individual persons and physicians will weigh these factors differently. No therapy has been shown to eradicate all parasites, and the risk for relapse cannot be entirely eliminated. The choice of systemic agents will depend on several factors. Species-directed therapy has received much attention. The relevant data have been reviewed [bib_ref] Species-directed therapy for leishmaniasis in returning travellers: a comprehensive guide, Hodiamont [/bib_ref] , and most available clinical trials are summarized in the Appendix. In general, the mainstay for systemic treatment has been the pentavalent antimonials (Sb V ), the majority of the data on treatment relates to the use of these agents, and these agents have been the reference against which other agents have been compared. The antimonials have issues with toxicity and availability, which provide the motivation for using alternative regimens and agents. The reasons for choosing systemic therapy are discussed in XII. Modification of the risk for ML is often an important consideration, but the only available data involve use of Sb V ; other agents may be considered when the risk for ML is thought to be low or if geographically restricted therapeutic failure with Sb V has been reported. It is difficult to accurately determine whether an infection is truly localized or who is at risk for dissemination. When systemic treatment is chosen for cosmetic or practical reasons, factors related to toxicity, cost, and convenience become more relevant. Factors in addition to the Leishmania species and the geographic region in which the infection was acquired may negatively affect response rates and may account for some of the heterogeneity in the results of clinical trials. Factors that may adversely affect outcome include markers of severity, such as higher number of skin lesions and coinfection with Leishmania RNA virus 1 [bib_ref] Presence of Leishmania RNA Virus 1 in Leishmania guyanensis Increases the Risk..., Bourreau [/bib_ref] [bib_ref] Association of the Endobiont Double-Stranded RNA Virus LRV1 With Treatment Failure for..., Adaui [/bib_ref] Factors that, paradoxically, may increase the risk for poor outcome include shorter duration of exposure in a CL-endemic region (<72 months), earlier initiation of therapy for CL, and younger patient age [bib_ref] Association of the Endobiont Double-Stranded RNA Virus LRV1 With Treatment Failure for..., Adaui [/bib_ref]. Treatment early in the course of the disease, including treatment of adenitis before skin ulceration is evident, appears to be a risk factor for poor response [bib_ref] Failure of early treatment of cutaneous leishmaniasis in preventing the development of..., Machado [/bib_ref]. One hypothesis is that some or all of these factors may be proxies for a less-effective immune response [bib_ref] Clinical and parasite species risk factors for pentavalent antimonial treatment failure in..., Llanos-Cuentas [/bib_ref]. Therapeutic failure with particular antileishmanial agents has not been well studied in CL. Unusually high antimonial therapeutic failure rates have been noted in tourists returning from Amazonian Bolivia, generally L. (V.) braziliensis acquired in the frequently visited Madidi National Park [bib_ref] Liposomal amphotericin B in comparison to sodium stibogluconate for Leishmania braziliensis cutaneous..., Solomon [/bib_ref]. Anecdotally, this observation has also been associated with L. (V.) braziliensis acquired in Manu National Park and Puerto Maldonado in southeastern Peru. Miltefosine appeared to perform less well against L. (V.) braziliensis in Guatemala compared with other countries [bib_ref] Clinical infectious diseases : an official publication of the Infectious Diseases Society..., Soto [/bib_ref]. Research techniques for monitoring drug resistance in vitro have been described; and surveillance of response rates in specific regions, together with monitoring of clinical risk factors associated with treatment success or failure, may become available in the future. It is possible that some therapeutic failures are related to our limited understanding of drug pharmacodynamics and weight-based dosing. On the basis of pharmacokinetic considerations, we assume that amphotericin B deoxycholate doses should be based on total body weight, whereas pentavalent antimonial dosing is more complex and, in some cases, might be better guided by ideal body weight (see XXVI). Anecdotal experience with miltefosine suggests that gastrointestinal toxicity tends to limit the ability to give daily doses above 150 mg. As mentioned above, drug toxicities as listed in [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref] become more important considerations among those with relevant comorbidities and in the elderly in general. Some antileishmanial drugs are not recommended during pregnancy or breastfeeding (see XXVI and [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref]. Convenience and adherence are important in some cases. For example, amphotericin compounds are typically given with saline loading and premedication, and the entire process may take 4 hours for each dose. Antimonials can be infused over a shorter time but may require more doses. Use of oral agents presumes adherence, in contrast to parenteral doses administered by a health worker. In some settings, services for giving IV infusions may not be available on weekends; and some home care services will not administer IND agents. The systemic antileishmanial agents available in North America are discussed below and in [fig_ref] Table 3: Approach to Syndromic Treatment of Leishmaniasis in North America 1,2 [/fig_ref] Sb V compounds have been the mainstay of systemic antileishmanial treatment for ∼7 decades. They have shown reasonably good efficacy against almost all Leishmania species in most geographic regions. However, no Sb V drug is approved for commercial use in the United States or Canada. In the United States, the Sb V compound sodium stibogluconate (SSG; Pentostam®; GlaxoSmithKline; 100 mg Sb V /mL) is available to U.S.-licensed physicians under IND protocols-for civilians, through the CDC Drug Service; and, for military beneficiaries, through the U.S. Army Medical Materiel Development Activity. At the time of this writing, the IND protocols cover intravenous (IV) and intramuscular (IM) but not intralesional administration. In North America, the most common route of administration is IV (vs IM), in part because the volume per dose is high (e.g., 14 mL for a 70-kg patient treated with SSG). The traditional regimen for CL is 20 mg of Sb V per kg daily for 20 days; 10 days may suffice in some settings. In Canada, both meglumine antimoniate (Glucantime®; Sanofi; 81 mg Sb V /mL) and SSG are available to licensed physicians through the Special Access Program from Health Canada, generally free of charge [fig_ref] Table 3: Approach to Syndromic Treatment of Leishmaniasis in North America 1,2 [/fig_ref] [bib_ref] Clinical infectious diseases : an official publication of the Infectious Diseases Society..., Soto [/bib_ref]. The FDA-approved regimen of miltefosine is 2.5 mg/kg per day (maximum, 150 mg, in 3 divided doses), for 28 days. The upper limit of 150 mg per day was established because of poor gastrointestinal tolerability and applies to all persons who weigh ≥45 kg. Limited information is available about the use of miltefosine in heavier persons, particularly in those who weigh ≥75 kg (see XXVI). However, some data suggest that doses <2 mg/kg per day are associated with lower response rates [bib_ref] Pharmacokinetics of miltefosine in Old World cutaneous leishmaniasis patients, Dorlo [/bib_ref]. Miltefosine is not approved for use in Canada, and permission to import the drug is not always granted. Conventional amphotericin B deoxycholate traditionally has been used as rescue therapy for CL. Some data suggest that amphotericin B is likely to be highly and broadly effective against a wide range of species. Lipid formulations of amphotericin B generally are better tolerated than conventional amphotericin B and may be better tolerated than Sb V (especially in HIV-coinfected persons). Essentially no controlled clinical trials of amphotericin B formulations have been successfully completed for CL; standard dosage regimens have not been established. The anecdotal experience using lipid formulations of amphotericin B, which are targeted to the reticuloendothelial system, has been mixed. Reasonably good response rates in the range of ∼83%-85% have been reported for IV liposomal amphotericin B (L-AmB) in several case series: for Bolivian L. (V.) braziliensis CL in 34 Israeli tourists who were treated with a total L-AmB dose of 18 mg/kg (6 doses of 3 mg/kg/day); for L. tropica CL in 13 Israeli patients who also were treated with a total of 18 mg/kg; and for CL caused by various Old and New World species among 19 U.S. military health care beneficiaries whose initial L-AmB course (for purposes of the efficacy analyses) entailed a median total dose of 21 mg/kg (maximum of 30 mg/kg) [bib_ref] Liposomal amphotericin B in comparison to sodium stibogluconate for Leishmania braziliensis cutaneous..., Solomon [/bib_ref] [bib_ref] Liposomal amphotericin B treatment of cutaneous leishmaniasis due to Leishmania tropica, Solomon [/bib_ref] [bib_ref] Lipsosomal amphotericin B for treatment of cutaneous leishmaniasis, Wortmann [/bib_ref]. Despite the lack of randomized controlled clinical data, off-label use of L-AmB is appealing to some clinicians because the drug is readily available in North America and they may be familiar with its use. Pentamidine has had a unique niche in the treatment of L. (V.) guyanensis infection, largely on the basis of studies of individuals with high response rates, although most are retrospective observations. A single randomized controlled trial showed outcomes similar to parenteral antimony [bib_ref] A randomized clinical trial comparing meglumine antimoniate, pentamidine and amphotericin B for..., Neves [/bib_ref]. Two clinical trials have been conducted for L. (V.) braziliensis infection: the first showed inferiority to antimony, and the second showed outcomes similar to antimony [bib_ref] Comparative study of meglumine antimoniate, pentamidine isethionate and aminosidine sulfate in the..., Correia [/bib_ref] [bib_ref] Comparison of meglumine antimoniate and pentamidine for peruvian cutaneous leishmaniasis, Andersen [/bib_ref]. A more recent study from Surinam showed a lower therapeutic success rate than in previous studies, leading to the question of whether resistance to pentamidine could be emerging; however, this study was of low quality due to a high loss to follow-up rate [bib_ref] Evaluation of treatment with pentamidine for cutaneous leishmaniasis in Suriname, Van Der Meide [/bib_ref]. Pentamidine showed some efficacy in treatment of L. (V.) panamensis infection in Colombia [bib_ref] Clinical infectious diseases : an official publication of the Infectious Diseases Society..., Soto-Mancipe [/bib_ref]. Pentamidine, which is available as an isethionate salt, has been used in doses lower than those used to treat Pneumocystis pneumonia (its most common indication in North America) and, consequently, with less associated toxicity [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref]. The "azoles" ketoconazole and fluconazole have been used with mixed results, in various settings. For example: ketoconazole (adult regimen: 600 mg daily for 28 days) showed modest activity against L. mexicana and L. (V.) panamensis infection in small studies in Guatemala and Panama, respectively [bib_ref] Placebo-controlled clinical trial of sodium stibogluconate (Pentostam) versus ketoconazole for treating cutaneous..., Navin [/bib_ref]. Use of fluconazole (adult regimen: 200 mg daily for 6 weeks) for treatment of L. major infection in various countries in the Old World has been associated with mixed results [bib_ref] Fluconazole for the treatment of cutaneous leishmaniasis caused by Leishmania major, Alrajhi [/bib_ref]. Preliminary data from Iran suggest that a higher daily dose (400 vs 200 mg) for 6 weeks might be more effective against L. major infection [bib_ref] Superior efficacy of oral fluconazole 400 mg daily versus oral fluconazole 200..., Emad [/bib_ref]. Preliminary, uncontrolled data from northeastern Brazil suggest that a regimen of 8 mg/kg daily for 4-6 weeks might be effective against L. (V.) braziliensis infection in that region, at least in the short term [bib_ref] High-dose oral fluconazole therapy effective for cutaneous leishmaniasis due to Leishmania (Vianna)..., Sousa [/bib_ref]. There is little evidence for the efficacy of itraconazole, essentially no clinical data are available for posaconazole or voriconazole, and data comparing the "azole" agents with each other are not available. Thus, while ketoconazole is relatively toxic [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref] , it is unknown whether other agents in this class have similar antileishmanial efficacy. Additionally, although substantial toxicity issues with ketoconazole have been described, such as serious hepatotoxicity in persons without apparent risk factors and QT prolongation that can result in life-threatening ventricular arrhythmias, these risks should be weighed against the toxicity of other commonly used antileishmanial agents, such as amphotericin and antimonial drugs. Comparative and some recent selected noncomparative clinical trials of various available therapies are summarized in the Appendix, together with a general assessment of the methodology and conduct of each study. Studies are classified according to species and geographic region. The reader can use the Appendix to extract the studies relevant to a particular species and region of acquisition, and to obtain information about the quality of the treatment data. The marked heterogeneity among the studies suggests that data from one species/ region cannot be extrapolated to other species or regions. ## Xiv. in which clinical settings can local therapy be used effectively in a person with cl? Recommendations 38. Local therapy is preferred for treatment of OWCL lesions defined as clinically simple ( ## Evidence summary The overarching concept is that localized and limited CL (simple CL) should, in general, be treated initially with local therapies, which typically can suffice for healing, and are less toxic and less expensive than systemic therapies. See [fig_ref] Table 1: Clinical Characteristics of Cutaneous Leishmaniasis [/fig_ref] for a definition of complex CL, which usually is not treated solely with local therapy. A current constraint in North America is access to and experience with local therapies, which are more in the practice scope of dermatologists than infectious disease clinicians. Types of local therapy include physical treatments (e.g., heat, liquid nitrogen, photodynamic therapy, CO 2 laser), intralesional injection (pentavalent antimony), and topical ointments/creams (paromomycin preparations). Most of the published experience using local therapies has been with OWCL, particularly in L. major/L. tropica-endemic regions, with limited published experience with CL caused by L. infantum or L. aethiopica. In the New World, local thera- Patients for whom local therapy may be a good option include those who have small, few lesions of localized CL that do not involve the nose, ears, eyelids, lips, or genitalia; patients who are pregnant for whom systemic therapy may be contraindicated because of potential toxicity; and patients who may benefit from mop-up treatment after an incomplete response to systemic therapy. Combination therapy (e.g., local therapy plus an "azole" or cryotherapy plus intralesional Sb V ) may be considered for some patients. Therapeutic failure of initial local treatment can be managed with oral or parenteral systemic therapy. Local therapy usually is not recommended for treatment of CL if the risk for mucosal dissemination is considered substantial. This includes infection acquired south of Nicaragua with species in the Viannia subgenus. Local therapy is also not usually recommended for treatment of CL lesions with associated nodular lymphangitis or in immunocompromised hosts [fig_ref] Table 1: Clinical Characteristics of Cutaneous Leishmaniasis [/fig_ref]. Before initiating local therapy, lesions with overlying eschar should be debrided down to a clean ulcer base; and secondary bacterial infection (e.g., manifest by suppuration or surrounding cellulitis), if present, should be treated. ## Physical methods for cl treatment Heat treatment: Dermatotropic species, such as L. major, L. tropica, and L. mexicana, are thermosensitive [bib_ref] New World cutaneous strains of Leishmania growing within mouse peritoneal macrophages in..., Sacks [/bib_ref]. The therapeutic effect of heat generated in tissue using radiofrequency waves has been studied in randomized controlled trials with efficacy rates ranging from 54%-81% (see Appendix) [bib_ref] Efficacy of thermotherapy to treat cutaneous leishmaniasis caused by Leishmania tropica in..., Reithinger [/bib_ref] [bib_ref] Evaluation of thermotherapy for the treatment of cutaneous leishmaniasis in Kabul, Safi [/bib_ref] [bib_ref] A randomized controlled trial of local heat therapy versus intravenous sodium stibogluconate..., Aronson [/bib_ref] [bib_ref] Efficacy of local heat therapy by radiofrequency in the treatment of cutaneous..., Sadeghian [/bib_ref] [bib_ref] Placebo-controlled clinical trial of meglumine antimonate (glucantime) vs. localized controlled heat in..., Navin [/bib_ref] [bib_ref] An alternative for the treatment of American cutaneous leishmaniasis, Lopez [/bib_ref]. Efficacy rates with two devices have been reported: the Ellman RF device (Ellman International, Inc., Hicksville NY); and, more commonly, with the ThermoMed™ device (Thermosurgery Technologies Inc, Phoenix AZ), which is FDA-cleared for treatment of CL. In brief, the protocol is to initially disinfect the lesion and surrounding skin (such as with an iodine preparation), provide local anesthesia with lidocaine, moisten with sterile saline, and apply the heat at 50°C for 30-second doses using the device prongs to cover the lesion in a grid-like pattern extending 1-2 mm into surrounding normal-appearing skin. A second-degree burn can be anticipated. The cosmetic outcome with heat therapy generally has been good, although with repeated treatment sessions more scarring may be seen. Most recipients report mild pain afterwards for a day, redness, oozing, and an eventual crusted eschar. Secondary bacterial infection can occur; use of topical antibiotics and dressing(s) for several days after a heat treatment is recommended. Good candidates for heat therapy include persons with uncomplicated CL, with smaller (≤25 mm width) and fewer lesions, not directly over superficial veins, nerves, or cartilaginous tissue. Areas where scarring is an issue, such as eyelids, nose, and the lips, should be avoided. Heat therapy can be used during pregnancy/breastfeeding and may also have a role as follow-up management for residual lesions not healing after systemic treatment. Cryotherapy (or cryosurgery) may be more readily available than heat therapy. Various regimens of cryotherapy have been published. An example of an approach is to apply liquid nitrogen with a cotton-tipped applicator for 15-20 seconds, until 1-2 mm of the circumferential skin around the lesion appears frozen; then thaw for 20-60 seconds; then repeat the freeze step; and repeat the entire process at 3-week intervals until healing occurs [bib_ref] A 2-year study of liquid nitrogen therapy in cutaneous leishmaniasis, Al-Majali [/bib_ref]. In some studies, more frequent applications were administered. No anesthesia is used, which reportedly is not helpful. Combination therapy with cryotherapy, immediately followed by intralesional antimony, seems to have the best efficacy. In two controlled clinical trials in Iran, persons with CL were randomized to receive intralesional (IL) Sb V , cryotherapy, or a combination of both therapies, which were administered every 1-2 weeks for 6-8 weeks [bib_ref] Comparison of intralesional meglumine antimoniate, cryotherapy and their combination in the treatment..., Salmanpour [/bib_ref] [bib_ref] Treatment response of cutaneous leishmaniasis due to Leishmania aethiopica to cryotherapy and..., Negera [/bib_ref]. In these studies, the therapeutic success rates for the combined treatment arms were higher, 89% and 91%. The most responsive lesions tended to be those that were small (<30 mm width), on the face or neck, dry, and present for <3 months. When cryotherapy is combined with IL Sb V , a shorter application of liquid nitrogen is used (e.g., no second freeze step), and the whitened skin is allowed to normalize in color before injection of the Sb V a few seconds later. On the basis of limited data, cryotherapy has been effective for infection caused by L. aethiopica in Ethiopia, L. donovani in Sri Lanka, and L. infantum in the Mediterranean region [bib_ref] Treatment response of cutaneous leishmaniasis due to Leishmania aethiopica to cryotherapy and..., Negera [/bib_ref] [bib_ref] Liquid nitrogen cryotherapy on Leishmania donovani cutaneous leishmaniasis, Ranawaka [/bib_ref]. Data from several large (thousands of persons), noncomparative case series provide perspective about the toxicity that can be associated with cryotherapy. Immediate reactions that can be seen in and near the treated skin include vesicle formation, erythema, swelling, and burning pain. Both hypoand hyperpigmentation result; they typically are worse and more persistent in patients with darkly pigmented skin but generally have improved by 6-12 months of follow-up. Overall in the series, the scar has been described as acceptable, although keloids may form [bib_ref] Cryosurgery in old world cutaneous leishmaniasis, Al-Gindan [/bib_ref] [bib_ref] Cutaneous leishmaniasis in Sanliurfa: epidemiologic and clinical features of the last four..., Gurel [/bib_ref] [bib_ref] Cutaneous leishmaniasis: evaluation of 3,074 cases in the Cukurova region of Turkey, Uzun [/bib_ref]. Cryotherapy should be considered in smaller, recent onset, uncomplicated CL lesions, including nonulcerative forms. It has been well tolerated on the face but avoidance of eyelids, lips, nose, and ears is recommended. It can be used during pregnancy and breastfeeding. It also may be an option for treatment of small residual lesions that persist after systemic therapy. The success of both heat and cryotherapy is highly dependent on the skill of the operator and complete, careful appli-cation. It is important to treat into normal-appearing tissue around the lesions. Persons who have evidence of potential dissemination (e.g., subcutaneous nodules or regional adenopathy) and are infected with NWCL Leishmania species that can cause ML should not be treated solely with physical methods, which may not control the infection. Experience in OWCL suggests that small subcutaneous nodules may respond to local therapy of the primary lesion alone. ## Other Photodynamic therapy and carbon dioxide laser treatment have been studied in randomized clinical trials with some promising early results [bib_ref] Comparison between the efficacy of photodynamic therapy and topical paromomycin in the..., Asilian [/bib_ref] [bib_ref] Cutaneous leishmaniasis responds to daylight-activated photodynamic therapy: proof of concept for a..., Enk [/bib_ref]. ## Intralesional pentavalent antimonial treatment The Sb V compounds sodium stibogluconate and meglumine antimoniate have been used for intralesional treatment of CL (see above, the Appendix, and [fig_ref] Table 3: Approach to Syndromic Treatment of Leishmaniasis in North America 1,2 [/fig_ref]. Most of the published clinical trials have involved OWCL, although recently a few studies of NWCL have been performed. The intralesional method uses the undiluted parenteral formulation of these drugs but at much smaller doses (see below), which results in fewer systemic adverse effects and less expense. Laboratory monitoring is not needed. The procedure is painful: local anesthesia should be given in advance (such as with EMLA cream, i.e., lidocaine plus prilocaine), and young children may need general anesthesia. Intralesional Sb V injections should not be used on fingers, nose, ears, eyelids, near the lips, or anywhere vascular compromise could be of concern. In addition to pain, adverse effects can include local allergic reactions, pruritus, edema, and transient erythema. In general, referral of patients to practitioners who have experience with intralesional administration is suggested when this treatment approach is considered. The aim is to inject the Sb V into the dermis, using a small gauge needle (25-27G); subcutaneous injection would be innocuous but ineffective. The volume injected is determined as a function of lesion size and varies from 0.2-5 mL in up to 4-5 injection sites, with a total estimated dose of about 0.1 mL per cm 2 . The WHO recommends repeating injections every 3-7 days until healing occurs . First cleanse the lesion and surrounding skin (e.g., with betadine or soap and water), then approach the lesion with the needle at a right angle initially and infiltrate in a V-shaped pattern, injecting drug under pressure as the needle is advanced [bib_ref] LeishMan recommendations for treatment of cutaneous and mucosal leishmaniasis in travelers, Blum [/bib_ref]. Initially, the dermal injection may be met with resistance; this tends to decrease with subsequent sessions. The entire lesion and 1-2 mm of surrounding normal-appearing skin must be infiltrated until blanching is seen. When combination therapy with cryotherapy is used, the Sb V should be injected after liquid nitrogen (no preanesthesia is used) until blanching of lesion borders and swelling of the entire base are noted. As with the physical methods, the skill of the operator and careful controlled application are key to a successful outcome. Most of the clinical trials of intralesional Sb V therapy have been conducted in the Old World, in Iran/Afghanistan, in studies in which the infecting species was not identified but the possibilities (depending on the region) included primarily L. major and L. tropica. Many regimens have been used, ranging from one injection 2 to 3 times per week to one injection every other week for 5-8 weeks; response rates have ranged from 25% to 100% [bib_ref] Evaluation of thermotherapy for the treatment of cutaneous leishmaniasis in Kabul, Safi [/bib_ref] [bib_ref] Social impact of leishmaniasis, Reithinger [/bib_ref] [bib_ref] Randomized, double-blind, comparative clinical trial on the efficacy and safety of intralesional..., Ranawaka [/bib_ref] [bib_ref] Treatment of cutaneous leishmaniasis with antimony: intramuscular versus intralesional administration, Alkhawajah [/bib_ref] [bib_ref] A randomized trial comparing a pentavalent antimonial drug and recombinant interferon-gamma in..., Harms [/bib_ref]. Only a few studies of intralesional Sb V therapy for NWCL have been reported, generally because the risk for metastatic infection associated with L. (V.) braziliensis and other Viannia species has dissuaded use of local therapy. In a randomized clinical trial of single ulcer (≤30 mm largest diameter) Bolivian CL (predominantly L. [V.] braziliensis), intralesional Sb V dosed on days 1, 3, and 5 was compared with two doses of cryotherapy and with placebo cream. The reported efficacies of treatments at 3 months (with only 6 months of follow-up) were 70%, 20%, and 17% [bib_ref] Clinical infectious diseases : an official publication of the Infectious Diseases Society..., Soto [/bib_ref]. As per the prior cryotherapy section, studies combining cryotherapy with intralesional antimony showed an improved response in OWCL compared with each method individually [bib_ref] Comparison of intralesional meglumine antimoniate, cryotherapy and their combination in the treatment..., Salmanpour [/bib_ref] [bib_ref] Comparative study of the efficacy of combined cryotherapy and intralesional meglumine antimoniate..., Asilian [/bib_ref]. This synergistic response has also been noted for L. infantum, L. mexicana, L. amazonensis, and L. (V.) naiffi infection [bib_ref] Species-directed therapy for leishmaniasis in returning travellers: a comprehensive guide, Hodiamont [/bib_ref]. ## Topical paromomycin preparations The only topical preparation with good supportive evidence for use in the treatment of CL is topical paromomycin. This aminoglycoside has been studied primarily in ulcerative infections caused by L. major in the Old World and by L. (V.) panamensis (small studies with other NWCL spp.) in Colombia and Panama [bib_ref] Topical treatment of cutaneous leishmaniasis, El-On [/bib_ref] [bib_ref] Treatment of cutaneous leishmaniasis with a topical antileishmanial drug (WR279396): phase 2..., Soto [/bib_ref] [bib_ref] Randomized, doubleblinded, phase 2 trial of WR 279,396 (paromomycin and gentamicin) for..., Sosa [/bib_ref]. Note that the vehicle seems cardinally important for efficacy, and different formulations cannot be considered equivalent. In a recent meta-analysis [bib_ref] Is paromomycin an effective and safe treatment against cutaneous leishmaniasis? A meta-analysis..., Kim [/bib_ref] , the response to topical paromomycin therapy was higher if the formulation included methylbenzethonium chloride (MBCL), which itself induces a local inflammatory response. For L. major infection, the efficacy was equivalent to that for intralesional Sb V ; but, in NWCL, it was inferior to parenteral Sb V therapy. Topical agents may have better absorption in ulcerative (vs nodular) skin lesions, which may partially explain why the reported efficacy for L. tropica and L. aethiopica infection has been poor; L. tropica seems inherently less responsive (39% cure rate) than L. major to paromomycin/MBCL [bib_ref] Leishmania tropica in northern Israel: a clinical overview of an emerging focus, Shani-Adir [/bib_ref]. More recently, a third-generation topical paromomycin and gentamicin cream WR 279,396 (without MBCL) has been found in several phase II studies and a phase III clinical trial (n = 375 patients) to be associated with response rates of 81%-94% (compared with 58%-71% for vehicle placebo) using a 20-day course; twice and once daily applications have been associated with comparable response rates for treatment of L. major infection [bib_ref] Topical paromomycin with or without gentamicin for cutaneous leishmaniasis, Salah [/bib_ref]. None of these preparations are commercially available or FDA approved in the United States. WR279,396 is available under an expanded-access treatment protocol for U.S. military health care beneficiaries; contact usarmy.detrick. medcom-usammda.list.leishmania-tx-protocol@mail.mil for details. Leshcutan™ ointment, Teva Pharmaceuticals Israel, similar to the El On topical paromomycin formulation [bib_ref] Treatment of cutaneous leishmaniasis with antimony: intramuscular versus intralesional administration, Alkhawajah [/bib_ref] , has been available on international mail order sites such as www.pharmacyworld.com, although there may be FDA restrictions for U.S. physicians prescribing it. Oral paromomycin capsules are available, and a compounding pharmacy can provide a topical preparation (with unknown performance characteristics) using 15% paromomycin and 12% MBCL in soft white paraffin [bib_ref] Topical treatment of cutaneous leishmaniasis, El-On [/bib_ref]. ## Evidence summary The responses of individual persons to treatment of CL are assessed clinically by the physical appearance of their lesion(s). Therapeutic success is usually defined as complete epithelialization of ulcerative lesions and lack of inflammatory findings/induration for nonulcerative lesions. Scarring is common but can improve with remodeling over months to years. Parasitologic assessment is used in the context of clinical trials; but it does not correlate well with clinical healing, which is the patient-relevant outcome [bib_ref] Cutaneous scars in American tegumentary leishmaniasis patients: a site of Leishmania (Viannia)..., Schubach [/bib_ref] [bib_ref] American cutaneous leishmaniasis: a comparison of three sodium stibogluconate treatment schedules, Oster [/bib_ref] [bib_ref] The natural history of cutaneous leishmaniasis in Guatemala, Herwaldt [/bib_ref]. During the first 2 weeks of therapy, there can be a paradoxical increase in the perilesional inflammatory response, including new satellite lesions and more erythema/induration especially around the border [bib_ref] Clinical manifestations and classification of Old World cutaneous leishmaniasis, Akilov [/bib_ref]. This exacerbation does not portend a poor treatment response but may be concerning to the patient and physician; with adequate treatment, it will usually resolve within 3-4 weeks. Treatment response can vary based on many factors. CL caused by some Leishmania spp. often spontaneously heals within months (e.g., L. mexicana, L. major), whereas CL caused by L. tropica and Viannia spp. may be very slow to resolve. Other parameters that affect the response to treatment include host factors (e.g., age, immune status); lesion appearance (e.g., ulcerative vs not), location (e.g., lesions on the lower legs or on cartilaginous areas, such as ears or nose, may be slow to heal), and severity; bacterial superinfection (may interfere with healing); and the treatment and route of administration used [bib_ref] Methodology of clinical trials aimed at assessing interventions for cutaneous leishmaniasis, Olliaro [/bib_ref]. Clinical trials show that tissue repair will take weeks after the parasite is killed; therefore, typically, healing is seen by 6-9 weeks after the start of treatment (faster with L. major and L. mexicana; slower with Viannia spp.). Especially for large ulcerative lesions, the healing process may continue after the treatment course has been completed. Five clinical parameters of healing have been suggested for assessing endpoints in treatment trials: the size of the area of ulceration (using the two largest diameter measurements), the size of the area of induration (consider using the ball-point pen method to determine), an estimate of the thickness of the induration, the color of the lesion border, and the extent of scarring [bib_ref] Methodology of clinical trials aimed at assessing interventions for cutaneous leishmaniasis, Olliaro [/bib_ref] [bib_ref] Palpation vs pen method for the measurement of skin tuberculin reaction (Mantoux..., Bouros [/bib_ref]. A general timeline for assessing the adequacy of the treatment response was developed by a WHO expert consensus group [bib_ref] Methodology of clinical trials aimed at assessing interventions for cutaneous leishmaniasis, Olliaro [/bib_ref]. Usually one should expect some degree of improvement by 42-63 days after the start of treatment and clinical "cure" by 3 months [bib_ref] Designing and reporting clinical trials on treatments for cutaneous leishmaniasis. Clinical infectious..., Gonzalez [/bib_ref]. Patients should be monitored for 6-12 months to assess for longer-term therapeutic failure or relapse (most occur within the first 3 months posttreatment). The first sign of healing is usually flattening (decreasing induration) of the skin lesion. Other physical findings associated with progressive healing include increasing reepithelialization of ulcerative lesions, decreasing lesion size, the presence of more granulation tissue, and decreasing erythema. In contrast, enlarging lesions or new lesions (e.g., satellite lesions) or subcutaneous nodules along the draining lymphatics may be indicators of a lack of response. Therapeutic failure often starts with breakdown along the border of previously epithelialized ulcers; increasing size, induration, and erythema are also suggestive of reactivation. XVI. What are the recommended approaches for additional management in a person with CL that does not respond to therapy? ## Evidence summary Limited published data are available that can inform clinical management decisions when CL therapeutic failure occurs. The factors considered with the initial therapy decision continue to be important, and the treatment history may influence the retreatment choices. Drug availability, as well as the experience of the treating provider and the wishes of the patient, will influence the approach taken. When therapeutic failure has occurred, confirmation of the diagnosis and species identification of the parasite (by culture and molecular diagnostic testing), if not previously done, are recommended. When scraping or aspiration of the lesion does not yield sufficient diagnostic information, obtaining a full-thickness biopsy specimen should be considered. Local wound care should be continued and bacterial superinfection, if any, should be treated since it has been associated with lower response rates to Sb V therapy [bib_ref] Decreased effect of glucantime in cutaneous leishmaniasis complicated with secondary bacterial infection, Sadeghian [/bib_ref]. Changing the treatment should be considered, such as selecting a different local therapy, a different systemic ther-apy, or a systemic instead of a local therapy. To mitigate adverse effects, a washout period between therapies may be required (e.g., between Sb V and amphotericin B formulations). Retreatment with more of the same drug may also work. If CL progresses during therapy or if there is no response at all by 4-6 weeks posttreatment, retreating with the same drug may not be the best option. For some patients, combination therapy may be an option-e.g., with two antiparasitic agents, an antiparasitic plus a physical modality (such as with IL Sb V plus cryotherapy), or an antiparasitic plus an immune modulator. Sometimes, discontinuation of therapy and observation may be the optimal approach. Despite relatively high therapeutic failure rates even in immunocompetent persons (∼10%-25%), the possibility of immune deficiency should be considered if CL is rapidly progressive, unresponsive to various therapeutic modalities, or highly atypical in clinical manifestations. If the patient is immunocompromised or if the Leishmania species/strain is associated with ML, systemic therapy should be continued either alone or in combination with another agent/modality unless associated with substantial toxicity. Predictors of therapeutic failure include host as well as parasite factors. The host's general immunologic status (especially regarding cell-mediated immunity) plays an important role in treatment response [bib_ref] Leishmaniasis in immunosuppressed individuals, Van Griensven [/bib_ref] [bib_ref] Mucosal leishmaniasis: description of case management approaches and analysis of risk factors..., Amato [/bib_ref]. Corticosteroids, both topical and systemic [bib_ref] Cutaneous leishmaniasis reactivation 2 years after treatment caused by systemic corticosteroids -first..., Tuon [/bib_ref] [bib_ref] Leishmaniasis recidivans recurrence after 43 years: a clinical and immunologic report after..., Marovich [/bib_ref] [bib_ref] Cutaneous leishmaniasis: an unusual case with atypical recurrence, Kanj [/bib_ref] [bib_ref] Recurrent American cutaneous leishmaniasis, Gangneux [/bib_ref] , have been associated with recurrence of CL; similarly, immune modulators, especially TNF-α antagonists (e.g., infliximab), have also been implicated in therapeutic failure (see XXV) [bib_ref] Relapsing cutaneous leishmaniasis in a patient with ankylosing spondylitis treated with infliximab, Mueller [/bib_ref]. Several case-control studies in Peru assessed risk factors associated with CL Sb V therapeutic failure. Depending on the report, these included concomitant distant lesions, the species L. (V.) braziliensis, young patient age, short duration of skin lesions, prior treatment, incomplete treatment, and weight >68 kg [bib_ref] Failure of early treatment of cutaneous leishmaniasis in preventing the development of..., Machado [/bib_ref] [bib_ref] Clinical and parasite species risk factors for pentavalent antimonial treatment failure in..., Llanos-Cuentas [/bib_ref] [bib_ref] Prediction score for antimony treatment failure in patients with ulcerative leishmaniasis lesions, Valencia [/bib_ref] [bib_ref] Association of treatment of American cutaneous leishmaniasis prior to ulcer development with..., Unger [/bib_ref]. Local trauma was also associated with CL recurrence [bib_ref] Clinical infectious diseases : an official publication of the Infectious Diseases Society..., Wortmann [/bib_ref] [bib_ref] Recurrent American cutaneous leishmaniasis, Gangneux [/bib_ref]. In addition to host factors described above, intrinsic and acquired parasite resistance to antileishmanials has been described with Sb V [bib_ref] Efficacy of glucantime for treatment of cutaneous leishmaniasis in Central Iran, Mohammadzadeh [/bib_ref] [bib_ref] Assessment of drug resistance related genes as candidate markers for treatment outcome..., Torres [/bib_ref] [bib_ref] Leishmania antimony resistance: what we know what we can learn from the..., Ait-Oudhia [/bib_ref] [bib_ref] Role of imiquimod and parenteral meglumine antimoniate in the initial treatment of..., Arevalo [/bib_ref] [bib_ref] Oral pentoxifylline combined with pentavalent antimony: a randomized trial for mucosal leishmaniasis, Machado [/bib_ref] [bib_ref] Successful treatment of refractory mucosal leishmaniasis with pentoxifylline plus antimony, Lessa [/bib_ref] [bib_ref] An alternative antimonial schedule to be used in cutaneous leishmaniasis when high..., De Oliveira-Neto [/bib_ref] [bib_ref] Old world Leishmania infantum cutaneous leishmaniasis unresponsive to liposomal amphotericin B treated..., Hervas [/bib_ref] , miltefosine [bib_ref] Treatment failure and miltefosine susceptibility in dermal leishmaniasis caused by leishmania subgenus..., Obonaga [/bib_ref] , amphotericin B (deoxycholate or liposomal) [bib_ref] Leishmaniasis recidivans recurrence after 43 years: a clinical and immunologic report after..., Marovich [/bib_ref] [bib_ref] An alternative antimonial schedule to be used in cutaneous leishmaniasis when high..., De Oliveira-Neto [/bib_ref] [bib_ref] Old world Leishmania infantum cutaneous leishmaniasis unresponsive to liposomal amphotericin B treated..., Hervas [/bib_ref] [bib_ref] Recidivans cutaneous leishmaniasis unresponsive to liposomal amphotericin B (AmBisome), Gunduz [/bib_ref] [bib_ref] Up-regulation of silent information regulator 2 (Sir2) is associated with amphotericin B..., Purkait [/bib_ref] , and pentamidine [bib_ref] An alternative antimonial schedule to be used in cutaneous leishmaniasis when high..., De Oliveira-Neto [/bib_ref] in treatment of Old and New World CL. Therapeutic failure has been associated with CL caused by the following species: L. (V.) braziliensis [bib_ref] Role of imiquimod and parenteral meglumine antimoniate in the initial treatment of..., Arevalo [/bib_ref] [bib_ref] Treatment failure and miltefosine susceptibility in dermal leishmaniasis caused by leishmania subgenus..., Obonaga [/bib_ref] [bib_ref] American cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis resistant to meglumine antimoniate,..., Pimentel [/bib_ref] [bib_ref] Influence of Leishmania (Viannia) species on the response to antimonial treatment in..., Arevalo [/bib_ref] , L. (V.) panamensis [bib_ref] Treatment failure and miltefosine susceptibility in dermal leishmaniasis caused by leishmania subgenus..., Obonaga [/bib_ref] , L. tropica, L. major [bib_ref] Unresponsiveness to Glucantime treatment in Iranian cutaneous leishmaniasis due to drug-resistant Leishmania..., Hadighi [/bib_ref] , and L. aethiopica [bib_ref] Susceptibility of clinical isolates of Leishmania aethiopica to miltefosine, paromomycin, amphotericin B..., Utaile [/bib_ref]. Therapeutic failure with local physical or other non-drug modalities (e.g., cryotherapy, heat therapy, photodynamic therapy) has been reported [bib_ref] Old world Leishmania infantum cutaneous leishmaniasis unresponsive to liposomal amphotericin B treated..., Hervas [/bib_ref] , but this cannot strictly be considered parasite resistance or even a hostdriven therapeutic failure. Success or failure with some of these modalities may also depend, in part, on operator expertise. Therapeutic decision-making for persons with relapsed CL or CL treatment failure, including leishmaniasis recidivans, can be challenging and frustrating. We recommend consultation with a leishmaniasis treatment expert regarding management options. The evidence for these recommendations derives from case reports and modest-sized case series. Therapeutic choices are often driven by the availability of particular treatment modalities and the practitioner's experience. The published reports must be interpreted in the context that CL is a self-resolving disease in immunocompetent hosts, in whom the course and prognosis vary greatly by species/strain, geographic location, and various host factors. Summarized below are treatments that have been reported as successful for CL with therapeutic failure. In NWCL, repeating a course of antimonials [bib_ref] Cutaneous leishmaniasis reactivation 2 years after treatment caused by systemic corticosteroids -first..., Tuon [/bib_ref] ; and treating with immunomodulators, such as imiquimod, pentoxifylline, or granulocyte macrophage colony stimulating factor (GmCSF), together with repeat courses of antimonial drugs or alone, have been associated with efficacy [bib_ref] Old world Leishmania infantum cutaneous leishmaniasis unresponsive to liposomal amphotericin B treated..., Hervas [/bib_ref] [bib_ref] American cutaneous leishmaniasis unresponsive to antimonial drugs: successful treatment using combination of..., Bafica [/bib_ref] [bib_ref] Successful treatment of drug-resistant cutaneous leishmaniasis in humans by use of imiquimod,..., Arevalo [/bib_ref]. Amphotericin/liposomal amphotericin B are regularly used in lieu of Sb V , including in retreatment for therapeutic failure [bib_ref] Lipsosomal amphotericin B for treatment of cutaneous leishmaniasis, Wortmann [/bib_ref] [bib_ref] Prediction score for antimony treatment failure in patients with ulcerative leishmaniasis lesions, Valencia [/bib_ref]. L. (V.) guyanensis infection can be treated with a repeat course of pentamidine [bib_ref] Recurrent American cutaneous leishmaniasis, Gangneux [/bib_ref]. For therapeutic failure of OWCL, repeating antimonial therapy IL or systemically, adding or using imiquimod [bib_ref] Relapsing cutaneous leishmaniasis in a patient with ankylosing spondylitis treated with infliximab, Mueller [/bib_ref] , changing to liposomal amphotericin B [bib_ref] Liposomal amphotericin B treatment of cutaneous leishmaniasis due to Leishmania tropica, Solomon [/bib_ref] , using combination treatments such as allopurinol and Sb V [bib_ref] Successful treatment of cutaneous leishmaniasis with allopurinol after failure of treatment with..., Baum [/bib_ref] , or extending the duration of/ repeating a liposomal amphotericin course [bib_ref] Lipsosomal amphotericin B for treatment of cutaneous leishmaniasis, Wortmann [/bib_ref] have been reported anecdotally as successful therapeutic strategies. ## Mucosal leishmaniasis XVII. What are the treatment options for American (New World) mucosal leishmaniasis (ML)? Recommendations 45. All persons with clinically manifest, metastatic, American ML should receive systemic antileishmanial therapy, with the goals of preventing morbidity (e.g., disfigurement) and mortality (e.g., from aspiration pneumonia or respiratory obstruction) [Strong, low]. 46. Before treatment is initiated, a complete examination of the naso-oropharyngeal/laryngeal mucosa should be conducted by a specialist to assess the anatomic extension and clinical severity of the mucosal disease, which have prognostic implications [Strong, moderate]. 47. We recommend inpatient monitoring and prophylactic corticosteroid therapy for persons with laryngeal/ pharyngeal disease and increased risk for respiratory obstruction,asindicatedbysymptomsandotolaryngologic/ radiologic examinations, because of the potential for inflammatory reactions after initiation of antileishmanial therapy [Strong, low]. 48. The choice of antileishmanial agent, dose, and duration of therapy for persons with ML should be individualized ( ## Evidence summary Many of the principles regarding treatment of NWCL caused by L. (V.) braziliensis and related species in the Viannia subgenus are applicable to persons with ML. However, in comparison with CL, the stakes are higher for ML (because of the risks for substantial morbidity and for mortality); the management issues are more complex, compounded by immunologic and anatomic factors; fewer prospective clinical trials have been conducted and even fewer randomized clinical trials [bib_ref] Interventions for American cutaneous and mucocutaneous leishmaniasis. The Cochrane database of systematic, Gonzalez [/bib_ref] ; and the trials that have been conducted have, of necessity, been comparatively small [bib_ref] Reply to Ojha et al, Machado [/bib_ref]. Response rates-even with the same drug regimen-vary widely, depending in part on interrelated factors such as the Leishmania species/strain; the geographic region in which infection was acquired [bib_ref] Mucosal leishmaniasis. Current scenario and prospects for treatment, Amato [/bib_ref] [bib_ref] Mucosal leishmaniasis ("espundia") responsive to low dose of N-methyl glucamine (Glucantime) in..., Oliveira-Neto [/bib_ref] ; the particular, as well as the number of, anatomic locations involved (e.g., nasal mucosa, palate, pharynx, larynx/epiglottis/vocal cords) [bib_ref] Efficacy of sodium stibogluconate alone and in combination with allopurinol for treatment..., Llanos-Cuentas [/bib_ref] ; the severity of the site-specific symptoms and signs; the duration of the mucosal involvement; and poorly understood immunologic and other variables. As broad generalizations, ML, compared with CL caused by the same species/strain in the same setting, is less responsive to antileishmanial treatment and posttreatment relapse is more common. However, if ML is detected early and is confined to the nasal (or oral) mucosa, the response rates for ML may approach those for CL. The lowest cure rates generally have been associated with laryngeal disease, especially if the vocal cords are involved [bib_ref] Efficacy of sodium stibogluconate alone and in combination with allopurinol for treatment..., Llanos-Cuentas [/bib_ref]. Persons with laryngeal/pharyngeal disease also may be at risk for respiratory obstruction, including after initiation of antileishmanial therapy, which may trigger a Jarisch Herxheimertype reaction [bib_ref] Mucosal leishmaniasis ("espundia" Escomel, 1911), Marsden [/bib_ref] [bib_ref] Mucocutaneous leishmaniasis, Marsden [/bib_ref] [bib_ref] New world mucosal and cutaneous leishmaniasis: an emerging health problem among British..., Lawn [/bib_ref] [bib_ref] Acute airway obstruction due to oedema of the larynx following antimony therapy..., Costa [/bib_ref] [bib_ref] Apparent Glucantime failure in five patients with mucocutaneous leishmaniasis, Rocha [/bib_ref]. At-risk persons should be closely monitored; and prophylactic corticosteroid therapy should be considered [bib_ref] Mucosal leishmaniasis ("espundia" Escomel, 1911), Marsden [/bib_ref] [bib_ref] New world mucosal and cutaneous leishmaniasis: an emerging health problem among British..., Lawn [/bib_ref] , taking into account potential benefits and risks [bib_ref] Reducing the risk of infection in a 74-year-old man who is to..., Shafran [/bib_ref]. The potential need for corticosteroid therapy and the dose and duration thereof (before and during antileishmanial therapy) to prevent or treat laryngeal/ pharyngeal edema/obstruction need to be individualized in consultation with the otolaryngologist who performed the ENT examination. For example, even short courses of corticosteroid therapy can be associated with development of life-threatening strongyloidiasis [bib_ref] Strongyloides stercoralis septicaemia following steroid therapy for eosinophilia: report of three cases...., Ghosh [/bib_ref] ; therefore, laboratory screening for asymptomatic Strongyloides stercoralis infection (and, potentially, empiric ivermectin therapy) may be warranted [bib_ref] Screening, prevention, and treatment for hyperinfection syndrome and disseminated infections caused by..., Mejia [/bib_ref]. In Latin America, Sb V compounds and amphotericin B deoxycholate generally are the most readily available and commonly used drugs for treatment of ML [bib_ref] Mucosal leishmaniasis. Current scenario and prospects for treatment, Amato [/bib_ref]. Selected information and perspective about these and other options are provided below; the drugs are not necessarily discussed in order of preference for persons in North America. In a L. (V.) panamensis-endemic area of Panama, a 28-day course of therapy with IV sodium stibogluconate (SSG; 20 mg Sb V /kg/day) was evaluated in a prospective, noncomparative clinical trial among 16 persons with disease confined to the nasal mucosa. At the last follow-up examination, up to 1 year posttherapy, 10 persons (63%) were classified as cured, all of whom had received a 28-day treatment course. In a prospective clinical trial in Peru (L. [V.] braziliensis infection), using the same 28-day SSG regimen, six (75%) of eight persons whose ulcerative/infiltrative disease was confined to the nasal mucosa had sustained clinical cures, without relapse during the 12-month posttreatment follow-up period [bib_ref] Efficacy and toxicity of sodium stibogluconate for mucosal leishmaniasis, Franke [/bib_ref]. However, in the same study, only two (10%) of 21 persons whose disease involved at least one additional anatomic location (e.g., pharynx or larynx) were classified as cured. To assess whether a longer course of Sb V therapy would increase the cure rate for Peruvian persons with "multi-anatomic" ML, the same group of investigators randomized such persons to receive either 28 or 40 days of IV SSG (20 mg Sb V /kg/day) [bib_ref] Efficacy of 28-day and 40-day regimens of sodium stibogluconate (Pentostam) in the..., Franke [/bib_ref]. The per-protocol cure rate was 63% in both treatment groups-i.e., 10 (63%) of 16 persons treated for 28 days and 12 (63%) of 19 persons treated for 40 days had sustained clinical cures, without relapse during the 12-month follow-up period. The investigators did not have an explanation for the much higher cure rate in the second compared with the first study (63% vs 10%) among persons with multi-anatomic disease. Adjunctive therapy with pentoxifylline, which inhibits the production of TNF-α by mononuclear cells and modulates the immune response [bib_ref] Clinical and immunological outcome in cutaneous leishmaniasis patients treated with pentoxifylline, Brito [/bib_ref] , has looked promising in clinical trials in Brazil [bib_ref] Oral pentoxifylline combined with pentavalent antimony: a randomized trial for mucosal leishmaniasis, Machado [/bib_ref] [bib_ref] Successful treatment of refractory mucosal leishmaniasis with pentoxifylline plus antimony, Lessa [/bib_ref] [bib_ref] Reply to Ojha et al, Machado [/bib_ref]. In a double-blind, placebocontrolled clinical trial, conducted in a L. (V.) braziliensisendemic area (Bahia State) among persons with nasal ML, all 11 persons who received a 30-day course of combination therapy with parenteral Sb V (20 mg/kg/day) plus oral pentoxifylline (400 mg thrice daily) were classified as cured, without relapse during ∼2 years of follow-up, compared with seven (58%) of 12 persons who received Sb V therapy plus placebo [bib_ref] Oral pentoxifylline combined with pentavalent antimony: a randomized trial for mucosal leishmaniasis, Machado [/bib_ref]. The investigators previously had conducted an openlabel study among persons with Sb V -refractory ML [bib_ref] Successful treatment of refractory mucosal leishmaniasis with pentoxifylline plus antimony, Lessa [/bib_ref] ; nine of the 10 enrolled persons treated with Sb V plus pentoxifylline fulfilled the criteria for cure after 1 year of follow-up. Amphotericin B deoxycholate has been the traditional alternative to Sb V therapy [bib_ref] Treatment of mucocutaneous (American) leishmaniasis with amphotericin B: report of 70 cases, Sampaio [/bib_ref] ; because it generally is considered more toxic (with a higher risk for irreversible toxicity), in some settings in Latin America, it has been used primarily for persons who did not respond to Sb V therapy [bib_ref] Mucosal leishmaniasis ("espundia" Escomel, 1911), Marsden [/bib_ref]. In a randomized clinical trial in Bolivia and Peru, combination therapy with amphotericin B deoxycholate plus itraconazole was not better than monotherapy with amphotericin B [bib_ref] A randomized trial of amphotericin B alone or in combination with itraconazole..., Rodriguez [/bib_ref]. In a prospective case series among Bolivian persons with ML of variable severity treated with amphotericin B deoxycholate (1 mg/kg every other day for a total of 45 doses), seven (50%) of 14 evaluable subjects and seven (37%) of 19 total persons were classified as cured [bib_ref] Clinical infectious diseases : an official publication of the Infectious Diseases Society..., Soto [/bib_ref]. Limited, uncontrolled data from case reports/series have been published regarding therapy with lipid formulations of amphotericin B, most often with L-AmB [bib_ref] New world mucosal and cutaneous leishmaniasis: an emerging health problem among British..., Lawn [/bib_ref] [bib_ref] Clinical complexity of Leishmania (Viannia) braziliensis infections amongst travelers, Eichner [/bib_ref] [bib_ref] New World cutaneous leishmaniasis in returned travellers: treatment failures using intravenous sodium..., Lawn [/bib_ref] [bib_ref] Mucosal leishmaniasis: description of case management approaches and analysis of risk factors..., Amato [/bib_ref] [bib_ref] Liposomal formulation of amphotericin B for the treatment of mucosal leishmaniasis in..., Rocio [/bib_ref] [bib_ref] Treatment of mucosal leishmaniasis with a lipid formulation of amphotericin B. Clinical..., Amato [/bib_ref] [bib_ref] Mucocutaneous leishmaniasis treated with liposomal amphotericin B. Revista da Sociedade Brasileira de, Lambertucci [/bib_ref] [bib_ref] Efficacy and Safety of Liposomal Amphotericin B for the Treatment of Mucosal..., Cunha [/bib_ref]. In two relatively large retrospective studies (16 and 29 patients, respectively) conducted by different groups of investigators in São Paulo, Brazil [bib_ref] Liposomal formulation of amphotericin B for the treatment of mucosal leishmaniasis in..., Rocio [/bib_ref] [bib_ref] Efficacy and Safety of Liposomal Amphotericin B for the Treatment of Mucosal..., Cunha [/bib_ref] , the results regarding L-AmB treatment of ML were promising, with the caveat that the studies were subject to the many limitations inherent to uncontrolled studies in which data are obtained by retrospective review of medical records. Limited data regarding miltefosine therapy for ML have been published [bib_ref] Clinical infectious diseases : an official publication of the Infectious Diseases Society..., Soto [/bib_ref] [bib_ref] Efficacy of extended (six weeks) treatment with miltefosine for mucosal leishmaniasis in..., Soto [/bib_ref] , the bulk of which are from two nonrandomized clinical trials conducted in a L. (V.) braziliensis-endemic region of Bolivia [bib_ref] Clinical infectious diseases : an official publication of the Infectious Diseases Society..., Soto [/bib_ref] [bib_ref] Efficacy of extended (six weeks) treatment with miltefosine for mucosal leishmaniasis in..., Soto [/bib_ref]. In the studies in Bolivia, the enrolled adult subjects received a daily dose of either 100 or 150 mg. The mean weights of the persons in both studies were <60 kg, whereas North American adults typically are much heavier (see XXVI). In the first study [bib_ref] Clinical infectious diseases : an official publication of the Infectious Diseases Society..., Soto [/bib_ref] , the duration of miltefosine therapy was 28 days. According to the published report [bib_ref] Clinical infectious diseases : an official publication of the Infectious Diseases Society..., Soto [/bib_ref] , 78 persons were enrolled and 51 (71%) of the 72 persons considered evaluable were classified as cured after 12 months of followup, including 21 (58%) of 36 persons with palatal, pharyn-geal, or laryngeal disease. In modified analyses, the intention-to-treat cure rate was 62% (49 of 79) and the perprotocol cure rate was 64.5% (49 of 76). In the second study [bib_ref] Efficacy of extended (six weeks) treatment with miltefosine for mucosal leishmaniasis in..., Soto [/bib_ref] , 21 persons not previously treated with miltefosine were treated for 6 weeks. Compared with persons in the first study, these 21 persons had had mucosal disease for a much shorter period (means of 5 years vs 14 months, respectively). Fifteen persons (71% of 21) fulfilled the criteria for cure. In addition, 17 of the persons from the first study who had been treated for 4 weeks and had not been classified as cured were located and retreated for 6 weeks, 11 (65%) of whom were considered cured thereafter. The investigators also assessed whether a longer follow-up period (i.e., 24 vs 12 months) could increase the relapse rate. Among the 45 persons classified as cured during the first study who were located and reevaluated, three (7%) definite or probable relapses were identified. Limited published data are available regarding treatment of ML with pentamidine isethionate [bib_ref] Mucosal leishmaniasis: description of case management approaches and analysis of risk factors..., Amato [/bib_ref] , an alternative, second-line agent . Monotherapy with the parenteral formulation of paromomycin (not available in North America) is not recommended, on the basis of clinical trials in Peru and Brazil. Response to antileishmanial treatment of ML typically is assessed by clinical criteria. The majority of relapses occur within the first year, but they may occur later [bib_ref] Mucosal leishmaniasis ("espundia" Escomel, 1911), Marsden [/bib_ref] [bib_ref] Long-term follow-up of patients with Leishmania (Viannia) braziliensis infection and treated with..., Netto [/bib_ref] [bib_ref] Efficacy of extended (six weeks) treatment with miltefosine for mucosal leishmaniasis in..., Soto [/bib_ref]. The risk factors for relapse are poorly understood [bib_ref] Mucosal leishmaniasis ("espundia" Escomel, 1911), Marsden [/bib_ref] [bib_ref] Local immunological factors associated with recurrence of mucosal leishmaniasis, Tuon [/bib_ref]. In persons whose mucosal disease improved or healed during or after the initial treatment course, relapses do not necessarily mean drug failure (drug resistance). In some settings, reinduction therapy with the agent initially used may be justified. Alternatives to consider for some persons/settings include monotherapy with a different medication or, potentially, combination therapy, such as with pentoxifylline. ## Visceral leishmaniasis XVIII. In what circumstances should a person with visceral Leishmania infection be treated? Recommendations 49. We recommend that persons with clinical abnormalities compatible with VL and laboratory evidence of VL be treated ( ## Evidence summary All persons with symptomatic visceral infection (i.e., VL) should be treated with antileishmanial drugs and ancillary measures. If untreated, advanced cases of VL can result in death, in association with progressive wasting, superinfection, or hemorrhage. Ancillary care includes nutritional support, treatment of other infectious diseases (e.g., tuberculosis, malaria, or bacterial or parasitic dysentery), and blood transfusions as needed. Persons newly diagnosed with VL should also be assessed for concurrent HIV/AIDS or other causes of cell-mediated immunosuppression. The majority of asymptomatic L. donovani and L. infantumchagasi infections in immunocompetent persons in VLendemic areas are self-resolving, but prospective studies are lacking on how to manage them. Among a cohort of 32,529 persons monitored in L. donovani-endemic areas of India and Nepal, risk for progression to VL disease was associated with high serologic titer values and seroconversion during the study period [bib_ref] Strong association between serological status and probability of progression to clinical visceral..., Hasker [/bib_ref]. If the person can be monitored closely, understands the situation, and is comfortable with delaying therapy, it is reasonable to follow and initiate therapy if signs and symptoms of VL develop. Quantitative measures of parasite load (e.g., qPCR) may eventually prove useful in predicting who will progress to symptomatic VL, but qPCR has not been adequately studied in immunocompetent asymptomatic persons and a standardized qPCR assay is not currently available in North America (see VII). XIX. What is the optimal treatment for VL in a symptomatic immunocompetent person (person without an identified immune defect) in North America? Recommendations 51. For an immunocompetent person with VL, treatment with liposomal amphotericin B (L-AmB) is recommended. The FDA-approved dosage regimen is 3 mg/ kg/day IV on days 1-5, 14, and 21 (total dose, 21 mg/ kg) [fig_ref] Table 3: Approach to Syndromic Treatment of Leishmaniasis in North America 1,2 [/fig_ref] [Strong, high]. Remarks: Multiple regimens in which the total L-AmB dose is 18-21 mg/kg have been used effectively in regions other than East Africa. Doses of 40 mg/kg or more may be necessary in persons with VL acquired in East Africa. Other lipid-associated formulations of amphotericin B, such as amphotericin B lipid complex and amphotericin B colloidal dispersion, are not generally recommended: they have not been approved by FDA for treatment of VL; and they have been less well studied in VL treatment trials (i.e., bioequivalence has not been established). 52. For an immunocompetent person with VL caused by L. donovani, acquired in the Indian subcontinent (South Asia), who is >12 years of age, weighs >30 kg, and is not pregnant or breastfeeding, treatment with the oral agent miltefosine, 2.5 mg/kg per day (maximum, 150 mg, in 3 divided doses) for 28 days, is a possible alternative to L-AmB, particularly in persons weighing <75 kg (see XXVI and [fig_ref] Table 3: Approach to Syndromic Treatment of Leishmaniasis in North America 1,2 [/fig_ref] [formula] [Strong, moderate]. [/formula] ## Evidence summary The studies that served as the basis for the group's treatment recommendations have been summarized in review articles [bib_ref] Therapeutic options for visceral leishmaniasis, Monge-Maillo [/bib_ref] and in the FDA Briefing Document for the Anti-Infective Drugs Advisory Committee Meeting on the use of Miltefosine (Impavido®) for the Treatment of Visceral, Mucosal and Cutaneous Leishmaniasis. For persons with no identifiable immune defect who have VL caused by either L. donovani or L. infantumchagasi, we recommend treatment with L-AmB using the FDA-approved regimen. For many years, prolonged courses of amphotericin B deoxycholate were known to be effective VL treatment in India and elsewhere, but the drug's use was associated with substantial nephrotoxicity and other untoward effects [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref]. Amphotericin B interacts with ergosterol precursors in Leishmania, disrupting the parasite plasma membrane [bib_ref] Mechanism of action of amphotericin B on Leishmania donovani promastigotes, Saha [/bib_ref]. Lipid formulations of amphotericin B couple liposome protection against renal and other toxic effects of amphotericin with deep tissue penetration into Leishmania-infected macrophages [bib_ref] Liposomal and lipid formulations of amphotericin B. Clinical pharmacokinetics, Janknegt [/bib_ref]. Therapeutic levels of L-AmB persist for ≥2 weeks in the liver/spleen after loading doses [bib_ref] Effect of tissue penetration on AmBisome efficacy, Adler-Moore [/bib_ref] [bib_ref] Therapy of visceral leishmaniasis due to Leishmania infantum: experimental assessment of efficacy..., Gangneux [/bib_ref] [bib_ref] Activity of liposomal amphotericin B (AmBisome) against Leishmania infantum and tissue distribution..., Gradoni [/bib_ref]. Liposomal amphotericin B (AmBisome®) was approved by FDA in 1997 for treatment of VL, on the basis of review of Mediterranean L. infantum dose-ranging, open-label treatment studies and case series, comprising 65% pediatric cases [bib_ref] Liposomal amphotericin B (AmBisome) in Mediterranean visceral leishmaniasis: a multi-centre trial, Davidson [/bib_ref] [bib_ref] Food and Drug Administration approval of AmBisome (liposomal amphotericin B) for treatment..., Meyerhoff [/bib_ref]. The FDA analysis found that the response rates among persons who received a total dose of >21 mg/kg or of 18 mg/kg were 100% and 97%, respectively. Data from a large case series of L. donovani-infected persons treated in a very rudimentary Sudanese field setting were also provided [bib_ref] Liposomal amphotericin B (AmBisome) in the treatment of complicated kala-azar under field..., Seaman [/bib_ref]. The regimen of L-AmB that the FDA approved for treatment of VL in immunocompetent persons (3 mg/kg/day on days 1-5, 14, and 21; total dose of 21 mg/kg) does not appear to have been used in any of the studies that were reviewed, but it has been shown to be effective in subsequent studies [bib_ref] Therapeutic options for visceral leishmaniasis, Monge-Maillo [/bib_ref]. A number of different dosage regimens have been studied, including regimens with shorter durations of therapy (e.g., even just a single infusion) and various total L-AmB doses; the FDAapproved regimen is recommended for persons treated in North America [fig_ref] Table 3: Approach to Syndromic Treatment of Leishmaniasis in North America 1,2 [/fig_ref]. There are geographic differences in VL treatment responses to L-AmB. In India, susceptibility to L-AmB has been observed in large, well-conducted randomized clinical trials demonstrating high therapeutic success rates among persons with parasitologically confirmed VL (L. donovani). A total L-AmB dose of 10 mg/kg administered over 5 days or given as a single infusion has been associated with an efficacy rate of 96%. In a large cohort study in Bihar, India, L-AmB 5 mg/kg daily for 4 doses over 4-10 days resulted in a therapeutic success rate of 98% [bib_ref] Post Kala-Azar Dermal Leishmaniasis following Treatment with 20 mg/kg Liposomal Amphotericin B..., Burza [/bib_ref]. In the case of Mediterranean VL caused by L. infantum, L-AmB in a total dose of 18 mg/kg, administered in 6 doses over 10 days, also had an efficacy of 98% [bib_ref] Clinical infectious diseases : an official publication of the Infectious Diseases Society..., Davidson [/bib_ref]. In another study, a pediatric regimen of L-AmB 10 mg/kg/day for 2 days was compared with a historical control group treated with meglumine antimoniate (20 mg Sb V /kg/day for 30 days). The short course of L-AmB was at least as effective as Sb V treatment (97.6% vs 90%) [bib_ref] Two doses of a lipid formulation of amphotericin B for the treatment..., Syriopoulou [/bib_ref]. L-AmB has also been used successfully to treat VL caused by L. infantum-chagasi in Latin America, but the published data are limited [bib_ref] Efficacy and Tolerability of Liposomal Amphotericin B (Ambisome) in the Treatment of..., Freire [/bib_ref]. These results contrast with the treatment of VL caused by L. donovani in East Africa in which the therapeutic success rate at 6 months was 85% using the FDA-recommended 7-dose regimen (total dose 21 mg/kg) of L-AmB, but significantly lower with single-dose therapy of either 7.5 mg/kg (40%) or 10 mg/kg (58%) [bib_ref] Safety and Efficacy of Single Dose versus Multiple Doses of AmBisome (registered..., Khalil [/bib_ref]. Furthermore, in eastern Sudan, L-AmB at a total dose of 30 mg/kg over 10 days resulted in an initial therapeutic success rate of 94% with 7% therapeutic failure [bib_ref] Liposomal amphotericin B for complicated visceral leishmaniasis (kala-azar) in eastern Sudan: How..., Salih [/bib_ref]. In Uganda and Kenya, therapeutic failure was reported to be more common in persons with VL who received a total dose of L-AmB of 20 mg/kg (13%) than in those treated with a total dose of 30 mg/kg (3.9%) [bib_ref] Clinical epidemiology, diagnosis and treatment of visceral leishmaniasis in the Pokot endemic..., Mueller [/bib_ref]. Finally, in an open trial of L-AmB to treat persons in Sudan who previously had an incomplete parasitologic response or had relapsed after treatment with pentavalent antimony and aminosidine or had severe disease, a treatment regimen of 3-5 mg/kg on days 0, 3, and 10 cured 50% of 16 persons and 6 doses of 3-5 mg/kg on days 0, 3, 6, 8, 10, and 13 cured 88% of 16 persons [bib_ref] Liposomal amphotericin B (AmBisome) in the treatment of complicated kala-azar under field..., Seaman [/bib_ref]. Other lipid-associated formulations of amphotericin B, such as amphotericin B lipid complex (ABLC) and amphotericin B colloidal dispersion (ABCD), have different pharmacokinetic and toxicity profiles than L-AmB and have been less well-studied in VL treatment trials [bib_ref] Treatment of Brazilian kala-azar with a short course of amphocil (amphotericin B..., Dietze [/bib_ref] [bib_ref] Short-course, low-dose amphotericin B lipid complex therapy for visceral leishmaniasis unresponsive to..., Sundar [/bib_ref] [bib_ref] Efficacy of amphotericin B colloidal dispersion in the treatment of Mediterranean visceral..., Gaeta [/bib_ref] [bib_ref] Treatment of kala-azar in Brazil with Amphocil (amphotericin B cholesterol dispersion) for..., Dietze [/bib_ref] [bib_ref] Amphotericin B lipid complex in the management of antimony unresponsive Indian visceral..., Sundar [/bib_ref] [bib_ref] Treatment of antimony-unresponsive Indian visceral leishmaniasis with ultra-short courses of amphotericin-B-lipid complex, Sundar [/bib_ref] [bib_ref] Amphotericin B colloidal dispersion for the treatment of Indian visceral leishmaniasis. Clinical..., Sundar [/bib_ref]. In a randomized clinical trial among 153 persons with Indian VL, the therapeutic success rates with amphotericin B deoxycholate (1 mg/kg every other day for 15 doses), L-AmB (2 mg/kg/day for 5 days), and ABLC (2 mg/kg/day for 5 days) were 96%, 96%, and 92%, respectively; the study was not powered to show differences in efficacy. L-AmB was associated with the fewest adverse reactions per person (mean 0.6 ± 0.1): there were 14-fold more with amphotericin B deoxycholate, and >2 fold more in the ABLC group [bib_ref] Amphotericin B treatment for Indian visceral leishmaniasis: conventional versus lipid formula-tions, Sundar [/bib_ref]. Finally, amphotericin B deoxycholate at 1 mg/kg dosing either every other day for 30 days or 15 days consecutively was 95%-100% effective for treatment of Indian VL; but there is substantially more renal toxicity, hypokalemia, and infusion-related toxicity than with L-AmB [bib_ref] Amphotericin B treatment for Indian visceral leishmaniasis: conventional versus lipid formula-tions, Sundar [/bib_ref] [bib_ref] A comparative evaluation of amphotericin B and sodium antimony gluconate, as first-line..., Thakur [/bib_ref] [bib_ref] Daily versus alternate-day regimen of amphotericin B in the treatment of kala-azar:..., Thakur [/bib_ref] [bib_ref] Treatment options for visceral leishmaniasis: a systematic review of clinical studies done..., Olliaro [/bib_ref] [bib_ref] Amphotericin versus sodium stibogluconate in first-line treatment of Indian kala-azar, Mishra [/bib_ref] [bib_ref] Amphotericin B treatment for Indian visceral leishmaniasis: response to 15 daily versus..., Sundar [/bib_ref] [bib_ref] Injectable paromomycin for Visceral leishmaniasis in India, Sundar [/bib_ref] [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref]. L-AmB has associated adverse events that may prompt selection of alternative therapy. CARPA (complement activation related pseudoallergy), caused by C3a/C5a anaphylaxitoxins triggering mast cells and basophils, yields hypersensitivity reactions that are not mediated by IgE [bib_ref] Complement activation-related pseudoallergy: a new class of drug-induced acute immune toxicity, Szebeni [/bib_ref]. Acute infusion reactions (occurring in the first 5 minutes and responsive to diphenhydramine) can include chest pain; hypoxia; dyspnea; severe leg, flank, or abdominal pain; and flushing with urticaria [bib_ref] Triad of acute infusion-related reactions associated with liposomal amphotericin B: analysis of..., Roden [/bib_ref]. ABLC was used to treat fungal infections without severe adverse reactions in 34 of 40 persons who previously had experienced severe intolerance of L-AmB [bib_ref] The safety of amphotericin B lipid complex in patients with prior severe..., Farmakiotis [/bib_ref]. Although ABLC may be useful for treatment of selected cases of VL, its use in this setting is less well documented than that of L-AmB; a rough conversion factor is that 3 mg/kg L-AmB is similar to 5 mg/kg of ABLC. Even though, in comparison with amphotericin B deoxycholate, L-AmB is associated with less nephrotoxicity, 15% of persons treated with L-AmB have a two-fold increase in their baseline serum creatinine levels (AmBisome® package insert) [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref]. For persons with VL caused by L. donovani acquired in the Indian subcontinent who are at least 12 years of age, weigh at least 30 kg, and are not pregnant or breastfeeding, treatment with the oral agent miltefosine is an option (see XXVI and [fig_ref] Table 3: Approach to Syndromic Treatment of Leishmaniasis in North America 1,2 [/fig_ref]. Large randomized clinical trials in India suggest that miltefosine is effective against L. donovani infection, with cure rates of 82%-97% [bib_ref] Phase 4 trial of miltefosine for the treatment of Indian visceral leishmaniasis, Bhattacharya [/bib_ref] [bib_ref] Miltefosine in children with visceral leishmaniasis: a prospective, multicentric, cross-sectional study, Singh [/bib_ref] [bib_ref] Oral miltefosine treatment in children with mild to moderate Indian visceral leishmaniasis, Sundar [/bib_ref] [bib_ref] Miltefosine for visceral and cutaneous leishmaniasis: drug characteristics and evidencebased treatment recommendations...., Monge-Maillo [/bib_ref] [bib_ref] Oral miltefosine for Indian visceral leishmaniasis, Sundar [/bib_ref] [bib_ref] Trial of oral miltefosine for visceral leishmaniasis, Sundar [/bib_ref] [bib_ref] Failure of pentavalent antimony in visceral leishmaniasis in India: report from the..., Sundar [/bib_ref] [bib_ref] Conflict and kala-azar: determinants of adverse outcomes of kala-azar among patients in..., Collin [/bib_ref] [bib_ref] Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis, Jha [/bib_ref]. The response rate may be lower for VL caused by L. donovani infection acquired in East Africa. In a clinical trial in Ethiopia among HIV-uninfected persons with VL, the 6-month therapeutic success rate was 75.6% [bib_ref] A comparison of miltefosine and sodium stibogluconate for treatment of visceral leishmaniasis..., Ritmeijer [/bib_ref]. Evidence is sparse to support the use of miltefosine for VL caused by L. infantum-chagasi [bib_ref] Proteomic analysis of the soluble proteomes of miltefosine-sensitive and -resistant Leishmania infantum..., Carnielli [/bib_ref]. Miltefosine has frequent gastrointestinal side effects including transient vomiting and diarrhea; it is also teratogenic and requires birth control measures in women of child-bearing age, and it is associated with hepatotoxicity and rarely nephrotoxicity (see XXVI and [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref]. Development of miltefosine resistance has been a concern in India. The miltefosine IC 90 has been reported to be significantly higher in geographic areas where it had been used extensively in comparison with areas where its use had been limited [bib_ref] In vitro antileishmanial drug susceptibility of clinical isolates from patients with Indian..., Prajapati [/bib_ref]. In addition, the posttreatment IC 50 has been significantly higher than the pretreatment IC 50 in persons who have had a relapse [bib_ref] Drug susceptibility in Leishmania isolates following miltefosine treatment in cases of visceral..., Bhandari [/bib_ref]. Finally, decreased therapeutic success rates and increased failure rates have been observed in India after a decade of miltefosine use and increasing rates of therapeutic failure have been reported in Nepal [bib_ref] Increasing failure of miltefosine in the treatment of kala-azar in nepal and..., Rijal [/bib_ref] [bib_ref] Efficacy of miltefosine in the treatment of visceral leishmaniasis in India after..., Sundar [/bib_ref]. XX. What alternative agent(s) can be used for a person with VL who cannot tolerate liposomal amphotericin B or miltefosine or in whom these agents otherwise are contraindicated? ## Recommendations ## Evidence summary The availability, use, and toxicities of the pentavalent antimonials sodium stibogluconate and meglumine antimoniate are discussed in reference to the treatment of CL in clinical question XIII and summarized in [fig_ref] Table 3: Approach to Syndromic Treatment of Leishmaniasis in North America 1,2 [/fig_ref]. Sodium stibogluconate 20 mg Sb V /kg/day IV or IM for 30 consecutive days (28 days in some L. infantum-chagasi studies) or meglumine antimoniate 20 mg Sb V /kg/day were the first-line drugs for the treatment of VL for many decades. Reports of therapeutic failures (especially in Northeast India, Bangladesh, Nepal, and Bhutan) [bib_ref] Failure of pentavalent antimony in visceral leishmaniasis in India: report from the..., Sundar [/bib_ref] [bib_ref] Treatment of visceral leishmaniasis in south-eastern Nepal: decreasing efficacy of sodium stibogluconate..., Rijal [/bib_ref] and concerns about toxicity have led to the emergence of L-AmB and miltefosine as first-line drugs for VL, but Sb V remains an option in some areas. Studies in East Africa, Brazil, and Greece suggest that the efficacy with Sb V remains in excess of 90%-95% for both L. infantum-chagasi and L. donovani infection [bib_ref] Two doses of a lipid formulation of amphotericin B for the treatment..., Syriopoulou [/bib_ref] [bib_ref] Sodium stibogluconate (ssg) & paromomycin combination compared to ssg for visceral leishmaniasis..., Musa [/bib_ref] [bib_ref] Treatment of visceral leishmaniasis in children in the Central-West Region of Brazil, Brustoloni [/bib_ref] [bib_ref] Challenges in the therapy of visceral leishmaniasis in Brazil: a public health..., De Melo [/bib_ref]. Pentamidine isethionate has been used to treat VL: in one study, 4 mg/kg IM given for 20 alternate day doses had an efficacy of 77% compared with 98% for amphotericin B deoxycholate [bib_ref] Amphotericin versus pentamidine in antimony-unresponsive kala-azar, Mishra [/bib_ref]. Pentamidine toxicity has been substantial and has included sudden death (because of QT-prolongation effect), delayed symptomatic hypoglycemia, hypotension, allergic reactions, and insulin-dependent diabetes [bib_ref] Comparison of regimes of treatment of antimony-resistant kala-azar patients: a randomized study, Thakur [/bib_ref] [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref]. On the basis of experience in the treatment of fungal infections, we do not recommend switching to amphotericin B deoxycholate for persons with contraindications to or substantial toxicity with L-AmB. Amphotericin B deoxycholate is almost always associated with more toxicity. Other drugs have been used for the treatment of VL, at times in multidrug regimens. There are published case reports and a small clinical series with imidazole antifungals (fluconazole or itraconazole) with/without allopurinol in persons with VL: the available data are insufficient to recommend their use [bib_ref] Treatment of kala-azar with oral fluconazole, Sundar [/bib_ref]. Parenteral paromomycin has looked promising in clinical trials in India, but it is not available in North America. ## Xxi ## Evidence summary Clinical parameters correlate well with parasitologic responses to VL treatment. Normalization of temperature; decreased liver and spleen size; rises in leukocytes, hemoglobin, and platelet values; and increasing appetite and weight suggest a clinical response [bib_ref] Clinical and laboratory features and treatment of visceral leishmaniasis in hospitalized patients..., Maru [/bib_ref] [bib_ref] Clinical, haematological and parasitological response to treatment of visceral leishmaniasis in Kenya...., Kager [/bib_ref]. With effective treatment, fever typically abates in <1 week [bib_ref] Two doses of a lipid formulation of amphotericin B for the treatment..., Syriopoulou [/bib_ref] [bib_ref] The treatment of kala-azar: old and new options, Zijlstra [/bib_ref] [bib_ref] Are there differences in clinical and laboratory parameters between children and adults..., Caldas [/bib_ref]. Organomegaly is slower to resolve (∼3-6 months), but some decrease may be seen by 10 days after initiation of treatment, depending in part on whether physical examination or ultrasonography is used for assessment [bib_ref] Two doses of a lipid formulation of amphotericin B for the treatment..., Syriopoulou [/bib_ref] [bib_ref] A 6 day course of liposomal amphotericin B in the treatment of..., Cascio [/bib_ref]. Leukopenia and thrombocytopenia generally normalize within a month, but resolution of anemia may be slower . Therapeutic failure (return of clinical signs/symptoms in concert with parasitologic confirmation) can occur at least up to 12 months after treatment (often the longest duration of follow-up in clinical trials), but most therapeutic failure occurs within the first 6 months [bib_ref] Clinical infectious diseases : an official publication of the Infectious Diseases Society..., Davidson [/bib_ref] [bib_ref] Efficacy and Tolerability of Liposomal Amphotericin B (Ambisome) in the Treatment of..., Freire [/bib_ref] [bib_ref] A 6 day course of liposomal amphotericin B in the treatment of..., Cascio [/bib_ref] [bib_ref] Single-dose liposomal amphotericin B for visceral leishmaniasis in India, Sundar [/bib_ref] [bib_ref] Treatment of visceral leishmaniasis in children with liposomal amphotericin B, Di Martino [/bib_ref] [bib_ref] Is one year follow-up justified in kala-azar post-treatment?, Nyakundi [/bib_ref] [bib_ref] Treatment of Indian visceral leishmaniasis with single or daily infusions of low..., Sundar [/bib_ref] [bib_ref] New treatment approach in Indian visceral leishmaniasis: single-dose liposomal amphotericin B followed..., Sundar [/bib_ref]. Risk factors associated with death (often studied in VL populations with substantial comorbidities quite different than in North America) include severe anemia, prolonged illness, jaundice, malnutrition, age <1 year, concomitant infection, mucosal bleeding, gastrointestinal symptoms, neutrophils <500 cells/uL, and platelets <50,000 cells/uL [bib_ref] Conflict and kala-azar: determinants of adverse outcomes of kala-azar among patients in..., Collin [/bib_ref] [bib_ref] Prognostic factors for death from visceral leishmaniasis in Teresina, Werneck [/bib_ref] [bib_ref] Epidemic visceral leishmaniasis in southern Sudan: treatment of severely debilitated patients under..., Seaman [/bib_ref] [bib_ref] Risk factors for in-hospital mortality of visceral leishmaniasis patients in eastern Uganda...., Mueller [/bib_ref] [bib_ref] Risk factors for death in children with visceral leishmaniasis, Sampaio [/bib_ref]. A prognostic scoring system for children with VL has shown a sensitivity of 88.7% and a specificity of 78.5% [bib_ref] Risk factors for death in children with visceral leishmaniasis, Sampaio [/bib_ref]. Parasitologic reassessment (such as by repeat bone marrow aspiration) typically is not needed in persons who have a timely clinical response and usually is reserved for subjects in clinical trials for definitive outcome information and for individual persons who remain symptomatic. Molecular analyses using semi-quantitative and real-time PCR assays show rapid clearance of Leishmania DNA from the peripheral blood during effective VL treatment of immunocompetent persons; but these tests are not standardized (various techniques, parasite targets, sensitivities), are not routinely available for clinical use in North America, and are not FDA approved [bib_ref] Quantification of Leishmania infantum DNA by a real-time PCR assay with high..., Mary [/bib_ref] [bib_ref] Post-kala-azar dermal leishmaniasis as an immune reconstitution inflammatory syndrome in a patient..., Antinori [/bib_ref] [bib_ref] Evaluation of PCR for diagnosis of Indian kala-azar and assessment of cure, Maurya [/bib_ref] [bib_ref] Polymerase chain reaction in the diagnosis and prognosis of Mediterranean visceral leishmaniasis..., Cascio [/bib_ref] [bib_ref] A nested polymerase chain reaction for diagnosis and follow-up of human visceral..., Fisa [/bib_ref] [bib_ref] Rapid clearance of circulating Leishmania kinetoplast DNA after treatment of visceral leishmaniasis, Disch [/bib_ref] [bib_ref] Diagnosis of symptomatic visceral leishmaniasis by use of the polymerase chain reaction..., Nuzum [/bib_ref]. The results of serologic testing using the rK39 immunochromatographic assay (Kalazar Detect™, InBios) may remain reactive for >1 year after successful treatment, although early studies suggested that the ELISA (vs dipstick) format showed declining rK39 levels after treatment [bib_ref] A cloned antigen (recombinant K39) of Leishmania chagasi diagnostic for visceral leishmaniasis..., Houghton [/bib_ref] [bib_ref] Use of the recombinant K39 dipstick test and the direct agglutination test..., Bern [/bib_ref] [bib_ref] Immunologic tests in patients after clinical cure of visceral leishmaniasis, De Almeida Silva [/bib_ref]. Post kala-azar dermal leishmaniasis (PKDL) has been identified during or after treatment of L. donovani VL in up to 10%-27.5% of patients in India and 1.5%-60% VL in Sudan; it uncommonly has been associated with L. infantum-chagasi VL in otherwise immunocompetent patients [bib_ref] Post-kala-azar dermal leishmaniasis, Zijlstra [/bib_ref] [bib_ref] Burden of visceral leishmaniasis in villages of eastern Gedaref State, Sudan: an..., Mueller [/bib_ref] [bib_ref] Clinicoepidemiological analysis of Post kala-azar dermal leishmaniasis (PKDL) cases in India over..., Ramesh [/bib_ref] [bib_ref] PKDL-A Silent Parasite Pool for Transmission of Leishmaniasis in Kala-azar Endemic Areas..., Ganguly [/bib_ref]. The skin lesions can include papules, nodules, and sometimes hypopigmented macules, which may coalesce into irregular patches. There is a predilection for the face, around the nose and mouth; but PKDL can extend to the trunk, arms, and legs. The skin of biopsied papular lesions is infiltrated with amastigotes, and persons with PKDL are a likely reservoir for VL infection and a source for sand fly infection in VL-endemic regions, perpetuating transmission. XXII. How should a person with VL be treated who does not respond to initial therapy as assessed by these parameters [or who has a relapse]? Recommendations 57. Immunocompetent persons with VL who do not respond to therapy with L-AmB should be treated with an alternative drug or with a higher dose or a longer course of L-AmB [Strong, low]. 58. Immunocompetent persons with VL who do not respond to initial therapy with miltefosine or a pentavalent antimonial compound should be treated with L-AmB or an alternative drug if L-AmB is unavailable [Strong, low]. 59. Immunocompetent persons with VL who respond to initial therapy but subsequently have a relapse should be treated with an alternative drug or with another, potentially longer, course of therapy with the initial drug. If L-AmB was the drug used for initial therapy, use of a higher dose can be considered . 60. Combination therapies may be considered but have not been well studied after therapeutic failure in persons with VL [Weak, low]. ## Evidence summary There are insufficient data to formulate an evidencebased recommendation for a therapeutic regimen for those who initially fail to respond. They can be treated with an alternative drug, the same drug at higher doses or for longer periods, or a combination of drugs. The choice of drug (s) is based on the infecting Leishmania species, the prevalence of therapeutic failure in the geographic area of acquisition, the immune status of the host, and potential untoward effects of the regimen. Therapeutic failure can occur in persons without documented immunodeficiency, most are within 6 to 12 months, but it is more likely in those with AIDS or compromised cell-mediated immunity for other reasons and often represent an immunologic failure rather than a drug failure (see XXIII and XXV). ## Evidence summary Nonsterile cure of Leishmania infection is considered the norm, even for immunocompetent persons. Residual parasites may be present indefinitely in tissue macrophages, typically held in check by T cell (predominantly, CD4 cell)dependent immunoinflammatory responses, including Th1type cytokine-mediated activation of macrophages [bib_ref] Leishmaniasis in the United States: treatment in 2012, Murray [/bib_ref]. However, HIV infection increases the risk for development and recurrence of clinically manifest VL; even visceral infection that was quiescent for years to decades may (re)activate in the context of immunosuppression. In HIV-infected persons, the first diagnosed episode of VL typically repre-sents (re)activation of latent infection and subsequent episodes usually constitute posttreatment relapses. However, in leishmaniasis-endemic areas, newly acquired (re)infections may account for some VL episodes [bib_ref] Parasite susceptibility to amphotericin B in failures of treatment for visceral leishmaniasis..., Lachaud [/bib_ref]. When VL initially is diagnosed in HIV-infected persons, the CD4 cell count typically is <200 cells/mm 3 (often, <100 cells/mm 3 ) [bib_ref] Clinical aspects of visceral leishmaniasis in HIV infection, Jarvis [/bib_ref] [bib_ref] Clinical characteristics and treatment outcome of patients with visceral leishmaniasis and HIV..., Hurissa [/bib_ref] [bib_ref] HIV/AIDS-associated visceral leishmaniasis in patients from an endemic area in Central-west Brazil, Alexandrino-De-Oliveira [/bib_ref]. The presence of other coinfections/ comorbidities may complicate clinical management. Many of the principles regarding treatment of VL in immuncompetent persons are applicable to persons with concurrent HIV/AIDS. However, the management issues are more complex, the evidence base is weaker, and the response to antileishmanial therapy (and ART) is suboptimal. Coinfected (vs HIV-uninfected) persons are less apt to respond to the initial treatment course, and posttreatment relapses are much more common. L-AmB generally is the drug of choice for treatment of VL in North America, regardless of whether the patient is immunocompetent or immunocompromised. However, the FDA-approved dosage regimen of L-AmB for immunocompromised persons entails a higher daily dose (4 vs 3 mg/kg), number of doses (10 vs 7), and total dose (40 vs 21 mg/kg) [bib_ref] Food and Drug Administration approval of AmBisome (liposomal amphotericin B) for treatment..., Meyerhoff [/bib_ref]. The optimal L-AmB regimen for inducing clinical remission has not been established and undoubtedly varies by host as well as parasite factors, such as in different geographic regions [bib_ref] Limited effectiveness of high-dose liposomal amphotericin B (AmBisome) for treatment of visceral..., Ritmeijer [/bib_ref] [bib_ref] Liposomal amphotericin B for visceral leishmaniasis in human immunodeficiency virus-coinfected patients: 2-year..., Sinha [/bib_ref] [bib_ref] Five-Year Field Results and Long-Term Effectiveness of 20 mg/kg Liposomal Amphotericin B..., Burza [/bib_ref] [bib_ref] Visceral leishmaniasis and HIV co-infection in Bihar, India: long-term effectiveness and treatment..., Burza [/bib_ref]. Regimens including L-AmB (or, less commonly, other lipid formulations of amphotericin B)-on consecutive days or in an interrupted schedule (such as in the FDA-approved regimen)-to achieve a total cumulative dose of ∼40 mg/ kg (range, 20-60 mg/kg) have been used with variable response rates [bib_ref] Leishmaniasis in the United States: treatment in 2012, Murray [/bib_ref] [bib_ref] Limited effectiveness of high-dose liposomal amphotericin B (AmBisome) for treatment of visceral..., Ritmeijer [/bib_ref] [bib_ref] Liposomal amphotericin B for visceral leishmaniasis in human immunodeficiency virus-coinfected patients: 2-year..., Sinha [/bib_ref] [bib_ref] Five-Year Field Results and Long-Term Effectiveness of 20 mg/kg Liposomal Amphotericin B..., Burza [/bib_ref] [bib_ref] Visceral leishmaniasis and HIV co-infection in Bihar, India: long-term effectiveness and treatment..., Burza [/bib_ref] [bib_ref] Efficacy of intermittent liposomal amphotericin B in the treatment of visceral leishmaniasis..., Laguna [/bib_ref] [bib_ref] Visceral leishmaniasis in HIV infected patients: treatment with high dose liposomal amphotericin..., Russo [/bib_ref] [bib_ref] Treatment of leishmaniasis in HIV-positive patients, Laguna [/bib_ref] [bib_ref] Clinical infectious diseases : an official publication of the Infectious Diseases Society..., Bern [/bib_ref]. The particular L-AmB regimen that FDA approved in 1997 for immunosuppressed persons was selected on the basis of analysis of limited, pooled data from three nonrandomized clinical studies conducted in Europe during the pre-ART era [bib_ref] Liposomal amphotericin B (AmBisome) in Mediterranean visceral leishmaniasis: a multi-centre trial, Davidson [/bib_ref] [bib_ref] Clinical infectious diseases : an official publication of the Infectious Diseases Society..., Davidson [/bib_ref] [bib_ref] Visceral leishmaniasis in HIV infected patients: treatment with high dose liposomal amphotericin..., Russo [/bib_ref]. The studies included 21 immunosuppressed persons, 17 of whom were infected with HIV. The first 10 of the 19 immunosuppressed persons who fulfilled FDA's inclusionary criteria [bib_ref] Food and Drug Administration approval of AmBisome (liposomal amphotericin B) for treatment..., Meyerhoff [/bib_ref] were treated with 100 mg of L-AmB daily for 21 days (total dose, 2.1 grams; 29-38.9 mg/kg). All 10 persons had clinical and parasitologic responses to therapy; however, eight persons (80%) experienced relapses during the follow-up period. The other nine evaluable persons [bib_ref] Visceral leishmaniasis in HIV infected patients: treatment with high dose liposomal amphotericin..., Russo [/bib_ref] , all of whom were infected with HIV, were treated with the dosing schedule that FDA ultimately approved (total dose, 40 mg/kg, with intermittent rather than daily dosing). All nine persons clinically improved, eight of whom had parasitologic responses (no parasites evident by light-microscopic examination or culture of bone marrow aspirates), one of whom defaulted during the follow-up period, and all of the other seven persons experienced relapses 2-7 months posttreatment. Only one patient was still alive 26 months posttreatment. Among the other six persons, the mean interval from the initial diagnosis of VL to death was 19 months (range, 5-40 months). Evidence from a systematic review of data regarding therapy of HIV-associated VL-which were analyzed with indirect comparisons, constrained by the limitations and heterogeneity of the available data, including the paucity of randomized clinical trials-has underscored that treatment with a amphotericin B formulation (e.g., L-AmB) is "superior" to pentavalent antimonial (Sb V ) therapy [bib_ref] Efficacy of anti-leishmania therapy in visceral leishmaniasis among HIV infected patients: a..., Cota [/bib_ref] , in part because of the safety issues associated with Sb V treatment in coinfected persons (e.g., potentially life-threatening clinical pancreatitis and cardiotoxicity [bib_ref] A comparison of miltefosine and sodium stibogluconate for treatment of visceral leishmaniasis..., Ritmeijer [/bib_ref] [bib_ref] Treatment of leishmaniasis in HIV-positive patients, Laguna [/bib_ref] [bib_ref] High parasitological failure rate of visceral leishmaniasis to sodium stibogluconate among HIV..., Diro [/bib_ref] [bib_ref] Treatment of visceral leishmaniasis in HIV-infected patients: a randomized trial comparing meglumine..., Laguna [/bib_ref] [bib_ref] Amphotericin B lipid complex ver-sus meglumine antimoniate in the treatment of visceral..., Laguna [/bib_ref]. Amphotericin B deoxycholate also generally is relegated to second-line status, in the context of L-AmB's better safety profile. If a coinfected patient in North America needed to be treated with amphotericin B deoxycholate or a Sb V compound, standard dosage regimens for VL generally would be used; data regarding optimal regimens for coinfected persons are not available. Limited data regarding treatment of HIV-associated VL with the oral agent miltefosine have been published [bib_ref] A comparison of miltefosine and sodium stibogluconate for treatment of visceral leishmaniasis..., Ritmeijer [/bib_ref] [bib_ref] Oral miltefosine for leishmaniasis in immunocompromised patients: compassionate use in 39 patients..., Sindermann [/bib_ref] [bib_ref] Long term failure of miltefosine in the treatment of refractory visceral leishmaniasis..., Troya [/bib_ref] [bib_ref] Miltefosine for visceral leishmaniasis relapse treatment and secondary prophylaxis in HIV-infected patients, Marques [/bib_ref]. In a randomized clinical trial in a population in Ethiopia with a high prevalence of HIV infection, miltefosine (100 mg daily for 28 days) was safer but less effective than treatment with parenteral sodium stibogluconate (SSG; 20 mg Sb V /kg daily for 30 days) [bib_ref] A comparison of miltefosine and sodium stibogluconate for treatment of visceral leishmaniasis..., Ritmeijer [/bib_ref]. Preliminary, uncontrolled data from Ethiopia suggest that the combination of L-AmB and miltefosine might be more effective than monotherapy for VL in HIV-infected persons in that setting [bib_ref] Visceral Leishmaniasis and HIV coinfection in East Africa, Diro [/bib_ref] ; retrospective data regarding L-AmB-miltefosine combination therapy for VL in coinfected persons in India also have been published [bib_ref] Combination Treatment for Visceral Leishmaniasis Patients Coinfected with Human Immunodeficiency Virus in..., Mahajan [/bib_ref]. In southern Europe, the incidence of VL (i.e., of symptomatic visceral infection) markedly decreased in the late 1990s, after the introduction and widespread use of ART [bib_ref] The relationship between leishmaniasis and AIDS: the second 10 years, Alvar [/bib_ref] [bib_ref] The impact of highly active antiretroviral therapy (HAART) on visceral leishmaniasis in..., Lopez-Velez [/bib_ref] [bib_ref] Visceral leishmaniasis in those infected with HIV: clinical aspects and other opportunistic..., Russo [/bib_ref] [bib_ref] Impact of highly active antiretroviral therapy on the incidence of visceral leishmaniasis..., Del Giudice [/bib_ref] [bib_ref] Influence of highly active antiretroviral therapy on the outcome of subclinical visceral..., De La Rosa [/bib_ref] [bib_ref] Incidence of and risk factors for symptomatic visceral leishmaniasis among human immunodeficiency..., De La Rosa [/bib_ref] [bib_ref] Highly active antiretroviral therapy (HAART) modifies the incidence and outcome of visceral..., Tortajada [/bib_ref]. In addition, ART has been associated with improved survival among coinfected persons in southern Europe, as well as with longer intervals between induction therapy and relapse of VL [bib_ref] Highly active antiretroviral therapy (HAART) modifies the incidence and outcome of visceral..., Tortajada [/bib_ref]. However, benefits regarding treatment outcomes per se have not been clearly shown [bib_ref] Clinical aspects of visceral leishmaniasis in HIV infection, Jarvis [/bib_ref]. Standard regimens of ART should be used, pending identification or development of regimens optimized for persons with leishmaniasis. Although in vitro data suggest that certain HIV-1 protease inhibitors-particularly, if present at high concentrations-might have direct inhibitory effects against Leishmania, the potential clinical relevance of such data is not yet known [bib_ref] HIV-1 protease inhibitors for treatment of visceral leishmaniasis in HIVco-infected individuals, Van Griensven [/bib_ref]. Although the benefits of ART generally outweigh the risks, treated persons should be monitored for adverse reactions. Increased toxicity may be noted if particular antiretroviral agents are used in conjunction with Sb V or miltefosine therapy; for example, coadministration of SSG and zidovudine could potentiate bone-marrow toxicity, and ritonavir-containing protease inhibitors could potentiate gastrointestinal symptoms in patients treated with miltefosine. Leishmaniasis-associated IRIS appears to be relatively uncommon [bib_ref] Immune reconstitution disease associated with parasitic infections following initiation of antiretroviral therapy, Lawn [/bib_ref] [bib_ref] Leishmaniasis as a Manifestation of Immune Reconstitution Inflammatory Syndrome (IRIS) in HIV-Infected..., Badaro [/bib_ref]. In a case series in southern Europe, none of 11 HIV-coinfected persons with documented subclinical visceral infection developed active VL after starting ART [bib_ref] Influence of highly active antiretroviral therapy on the outcome of subclinical visceral..., De La Rosa [/bib_ref]. Case reports have described development of symptomatic VL in association with ART [bib_ref] Leishmaniosis-new perspectives on an underappreciated opportunistic infection, Albrecht [/bib_ref] [bib_ref] Visceral leishmaniasis in HIV-infected patients with nondetectable HIV-1 viral load after highly..., Jimenez-Exposito [/bib_ref] [bib_ref] Two case reports of symptomatic visceral leishmaniasis in AIDS patients concomitant with..., Berry [/bib_ref]. Other case reports have described predominantly dermatologic (or mucosal/uveal) manifestations, often in a diffuse pattern, resembling PKDL or disseminated/diffuse CL [bib_ref] Post-kala-azar dermal leishmaniasis as an immune reconstitution inflammatory syndrome in a patient..., Antinori [/bib_ref] [bib_ref] Leishmaniasis as a Manifestation of Immune Reconstitution Inflammatory Syndrome (IRIS) in HIV-Infected..., Badaro [/bib_ref] [bib_ref] Successful miltefosine treatment of post-kala-azar dermal leishmaniasis occurring during antiretroviral therapy, Belay [/bib_ref] [bib_ref] Post-kala-azar dermal leishmaniasis manifesting after initiation of highly active anti-retroviral therapy in..., Gilad [/bib_ref]. In a systematic review, the identified risk factors for relapse of VL in coinfected persons included a CD4 cell count <100 cells/mm 3 when VL initially was diagnosed, a poor incremental increase in the CD4 cell count in response to ART, lack of secondary prophylaxis, and history of a pre-vious relapse [bib_ref] Predictors of visceral leishmaniasis relapse in HIV-infected patients: a systematic review, Cota [/bib_ref]. Relapse within 1 year posttreatment is the norm, even among persons who were treated with L-AmB and who receive ART and secondary prophylaxis, which provide only partial protection against relapses [bib_ref] Predictors of visceral leishmaniasis relapse in HIV-infected patients: a systematic review, Cota [/bib_ref]. Patients should be monitored indefinitely (until immune reconstitution) for clinical evidence of relapse. If possible, the diagnosis should be parasitologically confirmed. A positive PCR result with a nonquantitative method would not confirm that the person is experiencing a relapse, and a negative result would not exclude relapse. Although testing serial blood specimens with a quantitative Leishmania PCR (qPCR) assay may help identify persons at risk for clinical relapse (i.e., persons with increasing parasitemia levels), such assays are not generally available for clinical use in North America. Antileishmanial treatment is indicated for persons who have a documented recurrence of VL. At least for amphotericin formulations, relapses typically represent immunologic rather than drug failure (drug resistance) [bib_ref] Parasite susceptibility to amphotericin B in failures of treatment for visceral leishmaniasis..., Lachaud [/bib_ref]. Therefore, reinduction therapy with L-AmB typically is justified. Alternatives to consider for some persons/settings include monotherapy with a different medication or, potentially, combination therapy (e.g., L-AmB plus miltefosine). Even if a clinical response is noted, coinfected persons may have serial relapses at progressively shorter intervals and may develop chronic refractory VL [bib_ref] Active chronic visceral leishmaniasis' in HIV-1-infected patients demonstrated by biological and clinical..., Bourgeois [/bib_ref]. Secondary prophylaxis with an effective antileishmanial drug should be initiated after the end of the initial treatment course (i.e., to persons who respond to the induction therapy) and administered at periodic intervals thereafter. The optimal agent and regimen (e.g., dose and dosing interval) have not been defined, and comparative data regarding different regimens are not available [bib_ref] Predictors of visceral leishmaniasis relapse in HIV-infected patients: a systematic review, Cota [/bib_ref]. The results of one small, randomized clinical trial of secondary prophylaxis have been published. Among the eight persons who received amphotericin B lipid complex (3 mg/kg IV) every 3 weeks, the 1-year relapse rate was 50%, compared with 78% among the nine persons who did not receive secondary prophylaxis [bib_ref] Amphotericin B lipid complex versus no treatment in the secondary prophylaxis of..., Lopez-Velez [/bib_ref]. In nonrandomized studies and case series, periodic doses of parenteral L-AmB (e.g., 3-5 mg/kg every 3-4 weeks) [bib_ref] Efficacy of liposomal amphotericin B for secondary prophylaxis of visceral leishmaniasis in..., Molina [/bib_ref] , pentamidine isethionate (e.g., 4 mg salt/kg [up to 300 mg per dose] every 2-4 weeks) [bib_ref] Pentamidine isethionate as secondary prophylaxis against visceral leishmaniasis in HIV-positive patients, Perez-Molina [/bib_ref] [bib_ref] Pentamidine as secondary prophylaxis for visceral leishmaniasis in the immunocompromised host: report..., Patel [/bib_ref] [bib_ref] Use of Pentamidine As Secondary Prophylaxis to Prevent Visceral Leishmaniasis Relapse in..., Diro [/bib_ref] , and SSG (e.g., 20 mg Sb V /kg every 3-4 weeks) [bib_ref] Prophylaxis of visceral leishmaniasis in human immunodeficiency virus-infected patients, Ribera [/bib_ref] have been associated with decreased relapse rates. Experience using miltefosine for secondary prophylaxis is limited [bib_ref] Long term failure of miltefosine in the treatment of refractory visceral leishmaniasis..., Troya [/bib_ref] [bib_ref] Miltefosine for visceral leishmaniasis relapse treatment and secondary prophylaxis in HIV-infected patients, Marques [/bib_ref] [bib_ref] Leishmania resistance to miltefosine associated with genetic marker, Cojean [/bib_ref]. Discontinuation of secondary prophylaxis can be considered in persons without evidence of active Leishmania infection whose CD4 cell counts on ART have been >200-350 cells/mm 3 for ≥6 months [bib_ref] The relationship between leishmaniasis and AIDS: the second 10 years, Alvar [/bib_ref] [bib_ref] Discontinuation of secondary anti-leishmania prophylaxis in HIVinfected patients who have responded to..., Berenguer [/bib_ref]. However, relapses of VL have been reported in coinfected persons with CD4 cell counts >200 cells/mm [bib_ref] Interventions for Old World cutaneous leishmaniasis, Gonzalez [/bib_ref] ## Evidence summary In HIV-coinfected persons, cutaneous, mucosal, and visceral dissemination can be caused by essentially any of the Leishmania species that infect humans [bib_ref] Leishmania major cutaneous leishmaniasis in HIV-positive patients does not spread to extralesional..., Foulet [/bib_ref] [bib_ref] The relationship between leishmaniasis and AIDS: the second 10 years, Alvar [/bib_ref] [bib_ref] Diffuse cutaneous leishmaniasis in an HIV-positive patient in western Africa, Niamba [/bib_ref] , not just by species stereotypically associated with diffuse CL, disseminated CL, American ML, or VL, although the risks, pathophysiology, and clinical manifestations may differ (e.g., from those for classic New World ML [bib_ref] Mucosal Leishmania infantum leishmaniasis: specific pattern in a multicentre survey and historical..., Faucher [/bib_ref] [bib_ref] Localized mucosal leishmaniasis due to Leishmania (Leishmania) infantum: clinical and microbiologic findings..., Aliaga [/bib_ref] [bib_ref] Oral leishmaniasis in an HIV-infected patient. European journal of clinical microbiology &..., Cascio [/bib_ref] [bib_ref] Mucocutaneous leishmaniasis as presentation of HIV infection in Sardinia, insular Italy, Madeddu [/bib_ref] [bib_ref] Mucocutaneous leishmaniasis and HIV, Miralles [/bib_ref]. Even in some coinfected persons in the Americas, clinically manifest ML has been the first identified leishmanial form, which sometimes has been followed by the development of cutaneous lesions [bib_ref] The relationship between leishmaniasis and AIDS: the second 10 years, Alvar [/bib_ref] [bib_ref] Unusual manifestations of tegumentary leishmaniasis in AIDS patients from the New World, Lindoso [/bib_ref] [bib_ref] Disseminated American muco-cutaneous leishmaniasis caused by Leishmania braziliensis braziliensis in a patient..., Machado [/bib_ref]. Not surprisingly, the clinical management issues are more complex for persons with HIV/AIDS-associated CL/ML than they are for CL/ML in general. In coinfected persons, the spectrum of clinical manifestations is even broader and the evidence base is even weaker-constrained by the absence of data from randomized, controlled treatment trials and by the heterogeneity of the limited anecdotal data regarding the use of various antileishmanial agents in persons with HIV/AIDS-associated CL/ML . In general, CL/ML-coinfected (vs HIV-uninfected) persons, particularly if severely immunosuppressed (CD4 cell count <200 cells/mm 3 ), may be less apt to respond to the initial treatment course or to have a durable, relapsefree response [bib_ref] The relationship between leishmaniasis and AIDS: the second 10 years, Alvar [/bib_ref] and may be more likely to have drugassociated toxicity. In addition, in part because of the nonquantified risk for dissemination in such persons, use of systemic therapy generally is considered prudent, even for treatment of seemingly focal CL. Whether the systemic regimens used for the initial treatment of CL/ML in HIVuninfected persons should be modified for coinfected persons is not yet clear [bib_ref] Leishmania major cutaneous leishmaniasis in HIV-positive patients does not spread to extralesional..., Foulet [/bib_ref] [bib_ref] The relationship between leishmaniasis and AIDS: the second 10 years, Alvar [/bib_ref] [bib_ref] Leishmaniasis in the United States: treatment in 2012, Murray [/bib_ref]. On principle, ART should be initiated or optimized in accordance with standard practice for HIV/AIDS; relatively limited data regarding use of ART in persons who have CL/ML without VL have been published. Clinicians should be aware of the potential for increased toxicity if particular antiretroviral agents are used in conjunction with Sb V or miltefosine therapy, as well as the potential for inter-actions between antiretroviral agents and azole/triazole drugs (including ketoconazole, itraconazole, and fluconazole). Occasional cases of presentation or worsening of CL or mucosal/uveal involvement that might have represented IRIS reactions have been reported in the New and Old Worlds in persons without current or past evidence of VL [bib_ref] Leishmaniasis as a Manifestation of Immune Reconstitution Inflammatory Syndrome (IRIS) in HIV-Infected..., Badaro [/bib_ref] [bib_ref] Tegumentary leishmaniasis as the cause of immune reconstitution inflammatory syndrome in a..., Chrusciak-Talhari [/bib_ref] [bib_ref] Dermatologic manifestations associated with immune reconstitution syndrome in HIV+ patients starting HAART:..., Sarazin [/bib_ref] [bib_ref] Diffuse cutaneous leishmaniasis associated with the immune reconstitution inflammatory syndrome, Sinha [/bib_ref] [bib_ref] First case of cutaneous reconstitution inflammatory syndrome associated with HIV infection and..., Kerob [/bib_ref] [bib_ref] Uveitis due to Leishmania major as part of HAARTinduced immune restitution syndrome..., Blanche [/bib_ref] [bib_ref] Immune response to Leishmania antigens in an AIDS patient with mucocutaneous leishmaniasis..., Gois [/bib_ref]. Leishmania infection that becomes manifest or worsens after initiation of ART should be treated with antileishmanial (and, if indicated, corticosteroid) therapy. XXV. What is the preferred treatment of visceral/cutaneous leishmaniasis in immunocompromised hosts with solid organ transplant, persons with lymphatichematologic malignancies, or persons receiving immunosuppressive therapy for other reasons? ## Evidence summary With the number of immunosuppressed persons increasing globally and travel to and from leishmaniasis-endemic regions becoming more common, imported cases in countries where leishmaniasis is not endemic may increase [bib_ref] Leishmaniasis, an emerging infection in travelers, Pavli [/bib_ref] [bib_ref] Euro surveillance : bulletin Europeen sur les maladies transmissibles, Gautret [/bib_ref] [bib_ref] Patterns of illness in travelers visiting Mexico and Central America: the GeoSentinel..., Flores-Figueroa [/bib_ref] [bib_ref] Imported leishmaniasis: a heterogeneous group of diseases, Perez-Ayala [/bib_ref] [bib_ref] Holiday souvenirs from the Mediterranean: three instructive cases of visceral leishmaniasis, Buonomano [/bib_ref]. In the context of immunosuppression, VL can result from reactivation of dormant infection or from de novo infection if the person lives or travels in a VL-endemic area. Therefore, protective measures to prevent exposure to sand fly bites are recommended, particularly for immunocompromised travelers going to leishmaniasisendemic regions [bib_ref] Transmission of tropical and geographically restricted infections during solid-organ transplantation, Martin-Davila [/bib_ref] [bib_ref] Parasitic infections in solid organ transplant recipients, Coster [/bib_ref]. During a 2009-2012 L. infantum outbreak in Madrid, Spain, many of the detected VL cases were in patients who were immunocompromised for reasons other than HIV infection [bib_ref] Euro surveillance : bulletin Europeen sur les maladies transmissibles, Arce [/bib_ref]. Most of the cases in this setting are VL, but CL and ML have also been observed [bib_ref] Leishmaniasis in immunosuppressed individuals, Van Griensven [/bib_ref]. Among transplant recipients, VL has been most commonly reported in recipients of renal transplants (the most common type of solid organ transplant) but also has been reported in recipients of other types of solid organs, including heart, liver, and lung [bib_ref] Leishmaniasis in immunosuppressed individuals, Van Griensven [/bib_ref] [bib_ref] Visceral leishmaniasis in an Italian heart recipient: first case report, Larocca [/bib_ref] [bib_ref] Fatal visceral leishmaniasis in a heart transplant recipient, Frapier [/bib_ref] [bib_ref] Leishmaniasis in a heart transplant patient, Golino [/bib_ref] [bib_ref] Visceral leishmaniasis in lung transplantation, Morales [/bib_ref] , as well as in hematopoietic stem cell/bone marrow recipients [bib_ref] Leishmaniasis in immunosuppressed individuals, Van Griensven [/bib_ref]. In VL-organ transplant cases, the median onset time was in the first year post transplant, and high-dose corticosteroid use during the previous 6-month period was a risk factor for development of VL [bib_ref] Risk factors, clinical features and outcomes of visceral leishmaniasis in solid-organ transplant..., Clemente [/bib_ref]. Cases of VL and CL have been associated with the use of various immunosuppressive drugs, such as azathioprine, methotrexate, corticosteroids, cyclosporine, and cyclophosphamide [bib_ref] Leishmaniasis in immunosuppressed individuals, Van Griensven [/bib_ref] [bib_ref] Leishmania infantum leishmaniasis in corticosteroid-treated patients, Pittalis [/bib_ref] [bib_ref] Visceral leishmaniasis and immunocompromise as a risk factor for the development of..., Fletcher [/bib_ref] [bib_ref] Visceral leishmaniasis in immunocompromised hosts, Fernandez-Guerrero [/bib_ref]. Reports of leishmaniasis manifesting after several months of treatment with a TNF-α antagonist suggest a higher risk in patients receiving infliximab or adalimumab than etanercept [bib_ref] Tumor necrosis factor alpha antagonist drugs and leishmaniasis in Europe. Clinical microbiology..., Zanger [/bib_ref]. Several cancer-associated (mainly hematologic malignancies) cases of VL have been reported, in the context of the use of various chemotherapeutic agents or monoclonal antibodies [bib_ref] Leishmaniasis in immunosuppressed individuals, Van Griensven [/bib_ref]. Leishmaniasis rarely has been described in patients with primary immunodeficiency conditions [bib_ref] Leishmaniasis in immunosuppressed individuals, Van Griensven [/bib_ref]. During the 2009-2012 outbreak of leishmaniasis in a region of Madrid, Spain, in which 446 cases of leishmaniasis (286 CL and 160 VL) were identified (421 [94%] of which were defined as confirmed), 68 cases (18 CL and 50 VL) were in persons with at least one identified "intrinsic risk factor" [bib_ref] Euro surveillance : bulletin Europeen sur les maladies transmissibles, Arce [/bib_ref] ; only 18 (26%) of these 68 case-patients were infected with HIV, including 2 (11%) of the 18 who had CL and 16 (32%) of the 50 with VL. In hospitalized persons in Madrid with confirmed VL, 1% had associated solid tumors and 2.5% had hematopoietic malignancies [bib_ref] Epidemiological changes in leishmaniasis in Spain according to hospitalization-based records, 1997-2011: raising..., Herrador [/bib_ref]. Among 54 persons with CL in a retrospective study for the period 1992-2012 at a tertiary care hospital in Barcelona, Spain, 16 persons were classified as immunocompromised: 7 were infected with HIV, 4 had an autoimmune disease, 3 had a lymphoproliferative disorder, 9 received immunosuppressive therapy, and 2 received biologic immunomodulating therapy [bib_ref] Cutaneous leishmaniasis: 20 years' experience in a Spanish tertiary care hospital, Giavedoni [/bib_ref]. In an evidence base mainly comprised of case reports, the most common leishmaniasis-malignancy association has been between VL and acute lymphocytic leukemia (ALL); other malignancies reportedly associated with VL include acute myelogenous leukemia (AML), chronic lymphocytic leukemia, primary cutaneous T-cell lymphoma (Sezary syndrome), Hodgkins and Non-Hodgkins lymphoma, and multiple myeloma [bib_ref] Leishmaniasis in immunosuppressed individuals, Van Griensven [/bib_ref] [bib_ref] Visceral leishmaniasis and immunocompromise as a risk factor for the development of..., Fletcher [/bib_ref] [bib_ref] Aspects of the association between leishmaniasis and malignant disorders, Kopterides [/bib_ref] [bib_ref] Visceral leishmaniasis in immunocompromised patients with and without AIDS: a comparison of..., Fernandez-Guerrero [/bib_ref]. VL is usually diagnosed months to years after initiation of chemotherapy, often with a prolonged regimen of multiple courses/complicated clinical course implying longer periods of immunosuppression. The agents associated with VL include corticosteroids, rituximab, and fludarabine; bortezomib has been mentioned in several case reports and bevacizumab in one report. In patients with leukemia, potential confounding factors include increased ascertainment of VL because of the increased frequency of obtaining bone marrow biopsy specimens (in the context of fever and cytopenias), frequent blood transfusions (which, in leishmaniasis-endemic regions, could be an additional risk factor for Leishmania infection), and common early use of amphotericin B for empiric therapy of fever in neutropenic patients (which could partially treat VL, depending on the dosage regimen). In general, chemotherapy was held or interrupted briefly during the course of antileishmanial therapy (usually with L-AmB) but then resumed because of the life-threatening malignancy; in some cases, this was associated with therapeutic failure. Decisions about the use of subsequent secondary prophylaxis for leishmaniasis should be individualized, depending in part on the level and the anticipated duration of the underlying immunosuppression. The clinical presentation of VL in immunosuppressed patients who are not infected with HIV often resembles the syndrome described in immunocompetent patients (see Background information about leishmaniasis) [bib_ref] Leishmania infantum leishmaniasis in corticosteroid-treated patients, Pittalis [/bib_ref]. However, as with HIV/AIDS-associated VL (see XXIII), atypical parasite dissemination (see below) and severe clinical forms have been reported in persons with advanced immunosuppression. Severely immunosuppressed patients with VL also may have or develop dermatologic manifestations suggestive of diffuse/disseminated CL or mucosal involvement, which can be caused Leishmania species not typically associated with dermatologic or mucosal dissemination [bib_ref] Mucosal Leishmania infantum leishmaniasis: specific pattern in a multicentre survey and historical..., Faucher [/bib_ref]. VL can mimic systemic lupus erythematosus, rheumatoid arthritis, or hematologic malignancy, which can lead to diagnostic errors. The evidence base regarding treatment of VL in patients who are immunocompromised for reasons other than HIV/ AIDS consists of case reports and small case series. Response rates to initial treatment usually are higher and recurrence rates lower than in HIV-infected patients, although response rates typically are lower than those in immunocompetent patients. We suggest that VL treatment be similar to what is recommended for induction therapy (ie, L-AmB) for persons with HIV/AIDS-associated VL (see and that decisions about the patient's immunosuppressive therapy (if applicable) be individualized, taking into account the level and anticipated duration of immunosuppression. Despite a lack of systematic comparisons, L-AmB is recommended because of its safety profile and generally good efficacy [bib_ref] Leishmaniasis in the United States: treatment in 2012, Murray [/bib_ref] [bib_ref] Parasitic infections in solid organ transplantation, Schwartz [/bib_ref]. If an immunocompromised person with L. infantum-chagasi infection does not have therapeutic success with L-AmB, the administration of pentavalent antimonials can be effective [bib_ref] Antimony to Cure Visceral Leishmaniasis Unresponsive to Liposomal Amphotericin B, Morizot [/bib_ref]. As with HIV/AIDS-associated CL, in persons in whom cellmediated immune responses are seriously compromised for other reasons, the response to treatment of CL can be suboptimal; we recommend systemic instead of local therapy for CL [bib_ref] Leishmaniasis in the United States: treatment in 2012, Murray [/bib_ref]. Species identification is important when treating CL in immunocompromised persons because the treatment recommendations or prognosis may vary (see VI) [bib_ref] Clinical aspects and management of cutaneous leishmaniasis in rheumatoid patients treated with..., Neumayr [/bib_ref]. If the immunosuppression is drug induced (e.g., associated with treatment with corticosteroids, TNF-α antagonists, or methotrexate), we recommend decreasing the dose of the drug, if feasible, or, if pertinent, withdrawing TNF-α antagonists [bib_ref] Clinical aspects and management of cutaneous leishmaniasis in rheumatoid patients treated with..., Neumayr [/bib_ref]. The evidence base for treatment of ML in immunocompromised persons is limited [bib_ref] Localized mucosal leishmaniasis due to Leishmania (Leishmania) infantum: clinical and microbiologic findings..., Aliaga [/bib_ref]. In general, we recommend that CL and ML be treated as per the recommendations for HIV-coinfected patients. Screening transplant donors for evidence of Leishmania infection typically is not recommended. However, serologic screening of transplant recipients who have a history of potential exposure to Leishmania may be considered before transplantation. Iatrogenic transmission of VL via organ transplantation may occur [bib_ref] Visceral leishmaniasis in the early post-transplant period after kidney transplantation: clinical features..., Veroux [/bib_ref]. Immunosuppressed persons known to have asymptomatic infection or to have a history of VL warrant close clinical monitoring [bib_ref] Transmission of tropical and geographically restricted infections during solid-organ transplantation, Martin-Davila [/bib_ref]. Primary prophylaxis is not recommended at present. When blood quantitative real-time PCR (qPCR) testing is available in North America, it may be helpful to detect early reactivation (see VII) [bib_ref] Recurrent leishmaniasis in kidney transplant recipients: report of 2 cases and systematic..., Simon [/bib_ref]. In a Brazilian study, none of the liver recipients who had positive Leishmania PCR results at the time of transplantation and none of the recipients of a PCR-positive organ developed VL during a median follow-up period of 2 years; no prophylaxis was given [bib_ref] Visceral leishmaniasis in the early post-transplant period after kidney transplantation: clinical features..., Veroux [/bib_ref] [bib_ref] High prevalence of asymptomatic Leishmania spp. infection among liver transplant recipients and..., Clemente [/bib_ref]. Secondary prophylaxis has been administered to patients with non-HIV-related immunosuppression only in exceptional cases, because many patients have therapeutic success without maintenance therapy regardless of the continued use of immunosuppressive medication. However, in a recent case-control study of solid organ transplant recipients (n = 36 cases) with VL, 26% had therapeutic failure, often in the first year post transplantation, raising the issue of whether secondary prophylaxis should be considered [bib_ref] Risk factors, clinical features and outcomes of visceral leishmaniasis in solid-organ transplant..., Clemente [/bib_ref]. ## Special populations and leishmaniasis XXVI. How should the treatment of leishmaniasis be modified in persons who are pregnant or lactating; are young children or older adults; or have comorbidities such as renal, hepatic, or cardiac dysfunction? ## Recommendations 78. In general, clinically manifest cases of VL and ML should be treated even in these special populations of persons because the benefits of treatment typically outweigh the risks. However, patient-specific factors, including the presence of comorbid conditions, should be considered in the selection of the antileishmanial therapy, dosage regimen, and monitoring approach ( ## Evidence summary Basic principles applicable to all persons with leishmaniasis -including the needs to ensure that the diagnosis is correct and thereafter to individualize all treatment decisions (e.g., whether, when, and how to treat)-are particularly important for persons who have special characteristics or comorbid conditions [bib_ref] Treatment of American tegumentary leishmaniasis in special populations: A summary of evidence, Silva [/bib_ref]. However, the published information regarding special patient populations is even more limited than it is for leishmaniasis in general, which compounds the challenges inherent to individualizing patient care, such as assessing the probability and magnitude of the potential risks and benefits of various treatment and monitoring approaches. The heterogeneity encompassed not only by leishmaniasis but also by each of the special populations (e.g., children, older adults, persons with comorbidities) compounds the complexities; expert consultation and clinical judgment typically are needed. The discussion below focuses on selected topics, principles, and cautionary notes. In [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref] , additional pertinent details and perspective about antileishmanial medications are provided. Considerations applicable to HIV-coinfected persons and to persons who are immunocompromised for other reasons are addressed in clinical questions XXIII-XXV. Pregnant women VL during pregnancy: Among the special populations discussed in this section, the stakes are highest for persons who have clinically manifest VL during pregnancy-which, in case reports/series, has been associated with maternal deaths, abortions/miscarriages, preterm deliveries, smallfor-gestational-age infants, and congenital transmission [42, [bib_ref] Visceral leishmaniasis (kala-azar) and pregnancy, Figueiro-Filho [/bib_ref] [bib_ref] Visceral leishmaniasis and pregnancy: analysis of cases reported in a central-western region..., Figueiro-Filho [/bib_ref] [bib_ref] A comparison of liposomal amphotericin B with sodium stibogluconate for the treatment..., Mueller [/bib_ref] [bib_ref] Maternal and perinatal outcomes of visceral leishmaniasis (kala-azar) treated with sodium stibogluconate..., Adam [/bib_ref]. In this context, the benefits of antileishmanial therapy during pregnancy typically outweigh the potential risks to the fetus-particularly if persons are treated with liposomal amphotericin B (L-AmB), which is classified in pregnancy category B. Although relatively limited data have been published regarding L-AmB therapy for VL in pregnant women [bib_ref] Liposomal amphotericin B for complicated visceral leishmaniasis (kala-azar) in eastern Sudan: How..., Salih [/bib_ref] [bib_ref] Visceral leishmaniasis and pregnancy: analysis of cases reported in a central-western region..., Figueiro-Filho [/bib_ref] [bib_ref] A comparison of liposomal amphotericin B with sodium stibogluconate for the treatment..., Mueller [/bib_ref] [bib_ref] Visceral leishmaniasis in pregnancy: a case series and a systematic review of..., Pagliano [/bib_ref] [bib_ref] Visceral leishmaniasis in pregnancy: a case report, Caldas [/bib_ref] [bib_ref] Visceral leishmaniasis in pregnancy -the role of amphotericin B, Topno [/bib_ref] [bib_ref] The treatment of kala-azar during pregnancy. The National medical journal of, Thakur [/bib_ref] , good maternal/fetal outcomes typically have been reported; amphotericin B compounds also have been safely used for treatment of systemic fungal infections in pregnant women. However, as always, treated persons should be closely monitored for adverse events [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref]. Case reports and retrospective analyses of uncontrolled data suggest that Sb V therapy, especially during the first (or second) trimester, may increase the risks for abortions/ miscarriages and preterm deliveries [42, [bib_ref] A comparison of liposomal amphotericin B with sodium stibogluconate for the treatment..., Mueller [/bib_ref] [bib_ref] Maternal and perinatal outcomes of visceral leishmaniasis (kala-azar) treated with sodium stibogluconate..., Adam [/bib_ref]. Additional cautionary notes include the observations of embryotoxicity in laboratory animals [bib_ref] Visceral leishmaniasis (kala-azar) and pregnancy, Figueiro-Filho [/bib_ref] [bib_ref] Embryotoxicity of meglumine antimoniate in the rat, Paumgartten [/bib_ref] and of genotoxicity in a murine model although not in vitro [bib_ref] Genotoxic effects of the antileishmanial drug Glucantime, Lima [/bib_ref]. Miltefosine is contraindicated during pregnancy. Although human risk data are lacking, embryo-fetal toxicity (in rats and rabbits) and teratogenicity (in rats) have been observed in animals exposed to doses lower than those recommended for human persons [bib_ref] Development of miltefosine as an oral treatment for leishmaniasis, Sindermann [/bib_ref] [bib_ref] Highlights of prescribing information, Fda [/bib_ref]. According to the FDA-approved product label [bib_ref] Highlights of prescribing information, Fda [/bib_ref] , women with reproductive potential should have a negative pregnancy test before starting therapy and should use effective contraception both during the treatment course and for 5 months thereafter. Although the optimal duration of posttreatment contraception is not yet known [bib_ref] Pharmacokinetics of miltefosine in Old World cutaneous leishmaniasis patients, Dorlo [/bib_ref] [bib_ref] Translational pharmacokinetic modelling and simulation for the assessment of duration of contraceptive..., Dorlo [/bib_ref] , miltefosine has a long terminal-elimination half-life and still can be detected, at low levels of uncertain relevance, in human plasma specimens collected 5-6 months after a 28-day treatment course [bib_ref] Pharmacokinetics of miltefosine in Old World cutaneous leishmaniasis patients, Dorlo [/bib_ref]. Persons of both sexes also should be informed that the potential for adverse effects on human fertility has not been adequately evaluated but that reproductive effects have been noted in animal studies (impaired fertility in rats of both sexes and testicular atrophy in male rats) [bib_ref] Highlights of prescribing information, Fda [/bib_ref] [bib_ref] Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment..., Dorlo [/bib_ref] [bib_ref] Miltefosine treatment of Leishmania major infection: an observational study involving Dutch military..., Van Thiel [/bib_ref]. CL during pregnancy: General principles regarding whether and how to treat CL are applicable in the context of pregnancy. Not all persons who have CL (vs VL) need to be treated or need to receive (or to start with) drug therapy (e.g., a combination of wound care plus a physical modality, such as heat or cryotherapy [bib_ref] LeishMan recommendations for treatment of cutaneous and mucosal leishmaniasis in travelers, Blum [/bib_ref] [bib_ref] Cutaneous leishmaniasis: clinical report of two cases and review of the recent..., Valesky [/bib_ref] , might suffice or constitute a temporizing measure in some persons). Not all persons who may benefit from drug treatment need to receive systemic therapy or need to receive it promptly (e.g., in some persons, the therapy may be postponed until later in pregnancy or after delivery). Although pregnancy has been associated with development of atypically large or exuberant CL lesions in some persons [bib_ref] Cutaneous leishmaniasis during pregnancy: exuberant lesions and potential fetal complications, Morgan [/bib_ref] [bib_ref] Atypical manifestations of tegumentary leishmaniasis in a transmission area of Leishmania braziliensis..., Guimaraes [/bib_ref] [bib_ref] Two Women Presenting Worsening Cutaneous Ulcers during Pregnancy: Diagnosis, Immune Response, and..., Conceicao-Silva [/bib_ref] , even those with exophytic lesions do not necessarily need to be treated during pregnancy [bib_ref] Cutaneous leishmaniasis during pregnancy: exuberant lesions and potential fetal complications, Morgan [/bib_ref]. Various cautionary notes also apply. The effects, if any, of immunologic, hormonal, or other pregnancy-associated changes on the risks for mucosal dissemination of Viannia parasites or on the risks for development or progression of ML are not known; the possibility of an association between untreated CL and adverse fetal outcomes [bib_ref] Cutaneous leishmaniasis during pregnancy: exuberant lesions and potential fetal complications, Morgan [/bib_ref] has not been excluded; the potential for maternal local drug therapy (e.g., with intralesional Sb V or topical paromomycin) to cause fetal toxicity has not been evaluated; miltefosine is contraindicated during pregnancy (as discussed above); and oral "azole" compounds should not be viewed as safe alternatives for pregnant women. ## Lactating women In general, the potential for drug-associated risks to breastfeeding infants cannot be excluded [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref]. Amphotericin B probably is compatible with breastfeeding [bib_ref] Drug use and breastfeeding, Ilett [/bib_ref] : the concentration of drug (if present at all) in breast milk likely would be low; and its oral bioavailability is known to be low. Sb V therapy may be compatible with breastfeeding: on the basis of data in a case report, breastfeeding infants are unlikely to be exposed to detectable or toxic antimony levels [bib_ref] Concentration of Pentostam in human breast milk, Berman [/bib_ref]. Lactating women should be advised not to breastfeed during treatment with miltefosine or for 5 months thereafter [bib_ref] Highlights of prescribing information, Fda [/bib_ref] : miltefosine is presumed to be transferred into breast milk [bib_ref] Development of miltefosine as an oral treatment for leishmaniasis, Sindermann [/bib_ref] [bib_ref] Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment..., Dorlo [/bib_ref] ; and the possibility that a breastfeeding infant might experience toxic effects cannot be excluded on the basis of available data. ## Children The morbidity that can be associated with CL, coupled with the lack of optimal treatment modalities for cases of CL that warrant therapy, can be especially problematic for children. Facial lesions/scars, in particular, can have longlasting social and psychological consequences; however, not all persons with CL who would or could benefit from treatment are candidates for local therapy (see XIV); and even local (not just parenteral) therapies may be challenging to administer [bib_ref] Social impact of leishmaniasis, Reithinger [/bib_ref] [bib_ref] Leishmania tropica in children: a retrospective study, Solomon [/bib_ref] [bib_ref] Can a simple outpatient-based treatment be used to treat cutaneous leishmaniasis in..., Burden-Teh [/bib_ref]. For example, some children may need to be sedated before intralesional injections of Sb V [bib_ref] Leishmania tropica in children: a retrospective study, Solomon [/bib_ref] ; the need to retreat on multiple days compounds such issues [bib_ref] Adverse effects of intralesional meglumine antimoniate and its influence on clinical laboratory..., Esfandiarpour [/bib_ref]. As a broad generalization, otherwise healthy young children typically tolerate systemic antileishmanial therapies as well as, if not better than, adultswhich, as discussed below regarding Sb V and miltefosine, might in part reflect lower drug exposures in some children. Pediatric cases of VL (and systemic fungal infections) have been treated with amphotericin B compounds, including L-AmB, without reports of unusual side effects [bib_ref] Liposomal amphotericin B for complicated visceral leishmaniasis (kala-azar) in eastern Sudan: How..., Salih [/bib_ref] [bib_ref] First-line liposomal amphotericin B for pediatric visceral leishmaniasis in southern France, Minodier [/bib_ref] or of the need for pediatric-specific dosage regimens. ## Dosing issues for systemic pentavalent antimonial (sb v ) and miltefosine therapy Perspective is provided below regarding particular dosing issues of clinical relevance-e.g., some children may have suboptimal or subtherapeutic drug exposures when treated with parenteral Sb V or oral miltefosine according to conventional weight-based regimens. Sb V : In some studies/settings, young children (variably defined) have had lower initial response rates or less durable responses to parenteral Sb V therapy compared with older children or adults treated with the same weight-adjusted dosage regimen [bib_ref] Treatment failure in children in a randomized clinical trial with 10 and..., Palacios [/bib_ref] [bib_ref] Noninferiority of miltefosine versus meglumine antimoniate for cutaneous leishmaniasis in children, Rubiano [/bib_ref] [bib_ref] Pharmacokinetics of antimony in children treated for leishmaniasis with meglumine antimoniate, Cruz [/bib_ref]. In a pharmacokinetic (PK) study in Colombians with CL treated with meglumine antimoniate (20 mg Sb V /kg IM daily), children aged 3-6 years had a statistically significant (42%) lower plasma exposure to antimony (Sb) than adults aged 20-36 years, in the context of a significantly (75%) higher weight-adjusted renal clearance of Sb in young children [bib_ref] Pharmacokinetics of antimony in children treated for leishmaniasis with meglumine antimoniate, Cruz [/bib_ref]. To achieve Sb plasma exposures comparable to those in adults treated with a daily dose of 20 mg Sb V per kg of body weight, young children may need higher weight-(or otherwise-) adjusted doses. However, this PK study was not designed to assess exposure-response relationships or to assess the relationship between drug concentrations in plasma and at the intracellular target site; nor was it designed to evaluate the clinical need for (or the benefits/risks of) alternative dosing regimens/algorithms, either for this setting in Colombia or for pediatric leishmaniasis elsewhere [bib_ref] Pharmacokinetics of antimony in children treated for leishmaniasis with meglumine antimoniate, Cruz [/bib_ref]. As a broader point also applicable to adults, the optimal descriptor(s) of body size/physiologic function for Sb V dosing purposes has not been established. Adjustments in the Sb V dosage regimen (e.g., use of a lower daily dose in mg/kg) or selection of an alternative antileishmanial agent may be prudent for some persons who are elderly or obese or who have pertinent comorbid conditions (e.g., renal insufficiency); see below. Miltefosine: As of 2014, the FDA-approved indications for miltefosine are limited to non-pregnant, non-breastfeeding persons infected with particular Leishmania species who are ≥12 years of age and weigh ≥30 kg [bib_ref] Highlights of prescribing information, Fda [/bib_ref] ; and the FDAapproved capsule size is 50 mg, although 10-mg capsules also are manufactured. The conventional target dose is ∼2.5 mg of miltefosine per kg of body weight per day, some data suggest that doses <2 mg/kg are associated with lower response rates [bib_ref] Impavido®) for the treatment of visceral, mucosal and cutaneous leishmaniasis, Fda [/bib_ref] , an upper limit of 150 mg per day was established in the past because of poor tolerability at higher doses, and divided dosing (in increments of 50 mg) is recommended to minimize gastrointestinal symptoms. In this context, the FDA-approved dosage regimen for persons who weigh 30 to 44 kg is one 50-mg capsule twice a day (total, 100 mg/day) for 28 consecutive days; and the maximum daily dose of 150 mg (in 3 divided doses) applies to all persons who weigh ≥45 kg (≥99 pounds) [bib_ref] Highlights of prescribing information, Fda [/bib_ref]. Using conventional weight-based dosing, persons who weigh >60 kg (>132 pounds)-as most North American adults do, in contrast to the majority of the persons in the clinical trials to date-receive <2.5 mg/kg per day (e.g., persons >75 kg receive <2 mg/kg per day). In the United States, use of miltefosine in persons who are <12 years of age or who weigh <30 kg constitutes offlabel use. However, younger children ≥2 years of age were included in some clinical trials of miltefosine for CL in South America [bib_ref] Noninferiority of miltefosine versus meglumine antimoniate for cutaneous leishmaniasis in children, Rubiano [/bib_ref] [bib_ref] Miltefosine in the treatment of cutaneous leishmaniasis caused by Leishmania braziliensis in..., Machado [/bib_ref] and for VL in South Asia [bib_ref] Phase 4 trial of miltefosine for the treatment of Indian visceral leishmaniasis, Bhattacharya [/bib_ref] [bib_ref] Oral miltefosine treatment in children with mild to moderate Indian visceral leishmaniasis, Sundar [/bib_ref] [bib_ref] Increasing failure of miltefosine in the treatment of kala-azar in nepal and..., Rijal [/bib_ref] [bib_ref] Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment..., Dorlo [/bib_ref] [bib_ref] Clinical infectious diseases : an official publication of the Infectious Diseases Society..., Bhattacharya [/bib_ref] [bib_ref] Failure of miltefosine treatment for visceral leishmaniasis in children and men in..., Ostyn [/bib_ref] [bib_ref] Optimal dosing of miltefosine in children and adults with visceral leishmaniasis, Dorlo [/bib_ref] [bib_ref] Failure of miltefosine in visceral leishmaniasis is associated with low drug exposure, Dorlo [/bib_ref]. Of particular note, in clinical trials of VL in South Asia and in associated PK analyses, young children (from 2 to 11 or 14 years of age), in comparison with adults, had lower cure rates (lower initial response rates or higher relapse rates) and lower plasma drug exposures; the maximum weight of the adults with VL (vs CL) whose data were included in the PK analyses was 58 kg [bib_ref] Optimal dosing of miltefosine in children and adults with visceral leishmaniasis, Dorlo [/bib_ref]. To address the apparent difference in drug exposure between young children and adults, with the goal of improving response rates in children with VL, a dosing algorithm with nonlinear, allometric scaling based on fat-free mass has been proposed [bib_ref] Optimal dosing of miltefosine in children and adults with visceral leishmaniasis, Dorlo [/bib_ref] ; in the algorithm, the maximum daily dose remains unchanged at 150 mg. Clinical evaluations of the allometric regimen are pending [bib_ref] Failure of miltefosine in visceral leishmaniasis is associated with low drug exposure, Dorlo [/bib_ref] , and the applicability of the proposed regimen to adults with comparatively high body weights remains to be established. ## Older adults and persons with pertinent comorbid conditions In general, as with other special populations, cases of VL should be treated even in older adults and persons with comorbid conditions, whereas not all cases of CL need to be treated or require systemic therapy (e.g., intralesional [vs parenteral] Sb V therapy may be an option for some persons [bib_ref] Intralesional meglumine antimoniate for treatment of cutaneous leishmaniasis patients with contraindication to..., Vasconcellos [/bib_ref]. Patient-and drug-specific characteristics (e.g., the likelihood and severity of various drug-associated toxicities; [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref] should be considered when assessing the potential risks and benefits of various treatment and monitoring approaches. Some comorbid conditions (e.g., cardiac or renal dysfunction) or older age, as a proxy or surrogate marker, may increase the risk for certain drug-associated toxicities [bib_ref] LeishMan recommendations for treatment of cutaneous and mucosal leishmaniasis in travelers, Blum [/bib_ref] [bib_ref] Treatment of American tegumentary leishmaniasis in special populations: A summary of evidence, Silva [/bib_ref] [bib_ref] Recommendations for treating leishmaniasis with sodium stibogluconate (Pentostam) and review of pertinent..., Herwaldt [/bib_ref] [bib_ref] High mortality among older patients treated with pentavalent antimonials for visceral leishmaniasis..., Chappuis [/bib_ref] [bib_ref] The effect of age on the frequency of adverse reactions caused by..., Diniz [/bib_ref]. Therefore, certain antileishmanial medications should not be used or should be used only with additional precautionary measures (e.g., expert consultation, dosage adjustments, and more frequent monitoring for toxicity) in persons with pertinent comorbid conditions or laboratory abnormalities. Examples of issues and principles pertinent to Sb V therapy [bib_ref] Recommendations for treating leishmaniasis with sodium stibogluconate (Pentostam) and review of pertinent..., Herwaldt [/bib_ref] are provided here for illustrative purposes. Baseline laboratory testing and periodic monitoring (at least weekly) of the electrocardiogram (ECG), serum chemistry values, and complete blood count are recommended [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref]. Because laboratory manifestations of toxicity typically develop gradually, such testing/monitoring should help minimize the risk for life-threatening or irreversible adverse events [bib_ref] Recommendations for treating leishmaniasis with sodium stibogluconate (Pentostam) and review of pertinent..., Herwaldt [/bib_ref] [bib_ref] Systematic review of the adverse effects of cutaneous leishmaniasis treatment in the..., Oliveira [/bib_ref] [bib_ref] Electrocardiographic and biochemical adverse effects of sodium stibogluconate during treatment of cutaneous..., Lawn [/bib_ref] [bib_ref] Monitoring toxicity associated with parenteral sodium stibogluconate in the day-case management of..., Wise [/bib_ref]. Because antimony is renally excreted, baseline renal insufficiency, depending in part on its severity and etiology, may warrant modifying the dosage regimen (decreasing the daily dose or increasing the dosing interval) or selecting an alternative therapy. Modifying the dosage regimen, monitoring more frequently (e.g., twice weekly or even more frequently), or selecting an alternative drug also may be prudent for some persons with baseline hepatic, pancreatic, or cardiac disease-e.g., for persons with arrhythmia-associated conditions, including persons who have baseline prolongation of the corrected QT interval (QTc) or who are receiving medications (besides Sb V ) that may prolong the QTc. Sb V therapy should be interrupted if concave ST segments or QTc prolongation develop, especially if the absolute value of the QTc is >0.50 sec [bib_ref] Recommendations for treating leishmaniasis with sodium stibogluconate (Pentostam) and review of pertinent..., Herwaldt [/bib_ref] [fig_ref] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy [/fig_ref]. Acknowledgments: The Panel expresses its gratitude for thoughtful reviews of an earlier version by Anthony Bryceson, Pierre Buffet, James Maguire, Henry Murray, Abhay Satoskar, as well as Edward Ryan (Chair) and members of the ASTMH Standards and Treatment Guidelines Committee. The panel also thanks Dean Winslow, the liaison of the IDSA Standards and Practice Guidelines Committee, and Genet Demisashi for their efforts guiding us through the process. Financial Support. Support for these guidelines was provided by the Infectious Diseases Society of America and the American Society of Tropical Medicine and Hygiene. ## Potential conflict of interest: The following list is a reflection of what has been reported to IDSA. To provide thorough transparency, IDSA requires full disclosure of all relationships, regardless of relevancy to the guideline topic. Evaluation of such relationships as potential conflicts of interest (COI) is determined by a review process that includes assessment by the SPGC Chair, the SPGC liaison to the development Panel, the Board of Directors liaison to the SPGC, and, if necessary, the Conflict of Interest (COI) Task Force of the Board. This assessment of disclosed relationships for possible COI will be based on the relative weight of the financial relationship (i.e., monetary amount) and the relevance of the relationship (i.e., the degree to which an association might reasonably be interpreted by an independent observer as related to the topic or recommendation of consideration). The reader of these guidelines should be mindful of this when the list of disclosures is reviewed. For activities outside of the submitted work, N.A. has received payment from Up to Date. [fig] Figure 1: Approach and implications to rating the quality of evidence and strength of recommendations using the GRADE methodology (unrestricted use of the figure granted by the U.S. GRADE Network) [/fig] [fig] Figure 2: Maps of the Geographic Distribution of Cutaneous Leishmaniasis (CL). Notes: Adapted and modified from Chapter 277, Leishmania species. Principles and Practice of Infectious Diseases [/fig] [fig] Figure 3: Maps of the Geographic Distribution of Visceral Leishmaniasis (VL) [/fig] [fig] Figure 4: Clinical photographs of cutaneous Leishmaniasis (CL). A. Typical New World cutaneous leishmaniasis (NWCL) ulcerative lesion caused by Leishmania (Viannia) braziliensis infection acquired in Peru (the patient also had mucosal involvement). Photograph from Chris Ohl, Wake Forest Univ, NC. B. L. tropica CL, with thick crusted eschar that should be debrided before diagnostic testing or topical treatment. Photograph from Moshe Ephros. C and D: Before and after treatment of a L. major lesion, demonstrating the scarring nature of this infection.Photographs from Naomi Aronson. E. Nodular lesion caused by L. infantum infection, acquired in Sicily. Photograph from Christina Coyle, Albert Einstein University, NY. F. L. tropica leishmaniasis recidivans, with typical recurrence around the edge of a scar on the face. Photograph from Moshe Ephros. G and H. Secondary infection of CL lesions: G shows suppurative staphylococcal superinfection, and H shows impetiginous streptococcal superinfection. Purulence is not typical of CL unless secondarily infected. Photograph from Naomi Aronson. I. L. mexicana ulcerative lesion of the ear (Chiclero's ulcer), with a superficial necrotic appearance and edema. Photograph from Naomi Aronson. J. L. (V.) panamensis infection of the eyelid. Photograph from Naomi Aronson. K. Sporotrichoid NWCL; note the subcutaneous nodules along the lymphatic drainage and two large ulcerative lesions. Photograph from Peter Weina. L. Phlebitic change and large ragged ulcer caused by L. major infection acquired in northern Afghanistan. Photograph from Naomi Aronson. M. CL lesion over colored tattoo. Photograph from Naomi Aronson. N. Multiple small circumferential papules that formed soon after initiation of therapy for a plaque-like lesion caused by L. major. Photograph from Naomi Aronson. O. Verrucous CL on the tip of the nose of a patient in Afghanistan. Photograph from Peter Weina. [/fig] [fig] Recommendation 18: We suggest that identification of the infecting parasite to the species level be attempted in cases of suspected CL. Species identification may help inform clinical management decisions for individual persons (e.g., whether and how to treat) [Weak, moderate]. [/fig] [fig] Recommendations 42: Additional therapy is recommended (but not necessarily always with a different agent or approach) when there is development of new skin lesions or worsening of existing lesions. Additional therapy is also recommended if there is incomplete healing by 3 months after completion of the treatment course [Strong, low]. 43. We recommend that therapeutic failure be assessed by physical appearance. Relatively little improvement or worsening while on therapy suggests an inadequate response and an alternate treatment approach should be planned [Strong, low]. Remark: A paradoxical increase in the local inflammatory response may be seen in the first 2-3 weeks of treatment and can be difficult to differentiate from therapeutic failure. 44. Consultation with a leishmaniasis expert about other treatment options is recommended for management of persons' lesions associated with therapeutic failure [Strong, very low]. [/fig] [fig] Recommendations 70: Liposomal amphotericin B (L-AmB) is recommended as the drug of choice for immunosuppressed persons with VL ( [/fig] [table] Table 1: Clinical Characteristics of Cutaneous Leishmaniasis (CL) that may Modify Management in North America Simple CL Complex CL Caused by a Leishmania species that can be associated with increased risk for ML, particularly Viannia spp. in the "mucosal belt" of Bolivia, Peru, and Brazil ♦ [/table] [table] Table 2: Leishmaniasis Reference Diagnostic Laboratories in North America Please visit http://apps.who.int/whocc/List.aspx?cc_subject=Leishmaniasis& to access additional laboratories that are World Health Organization (WHO) Collaborating Centers, http://www.who.int/leishmaniasis/collaborating_centres/en/ 1 Additional WHO leishmaniasis laboratories are listed in WHO Technical Report Series 949 "Control of the leishmaniasis" pages 162-3 [42]. 2 Recommend contact with reference laboratories in advance for instructions to optimize specimen collection and shipping. Tests performed in the above laboratories are provided free of charge. ML. In immunocompromised persons, cutaneous, mucosal, and visceral dissemination may occur [FACT, no grade]. 30. Persons with CL should be actively monitored by clinical Initial systemic therapy (see XIII) may be used in persons with CL in whom it is not practical to use local therapy or (possibly) if more rapid healing of large, cosmetically or functionally concerning lesions is preferred [Weak, very low]. 34. Less common cutaneous syndromes, such as leishmaniasis recidivans (caused by L. tropica and occasionally other species), diffuse cutaneous leishmaniasis (caused by L. mexicana, L. amazonensis, and L. aethiopica), and disseminated cutaneous leishmaniasis (caused by L. [V.] braziliensis),usuallyrequiresystemictherapy[Strong,low]. Eschar(s) overlying ulcers should be debrided before administration of local therapy and any secondary infection managed to maximize treatment effect [Strong, very low].XV. What are the recommended timeframes and findings to assess response to treatment in a person with CL?Recommendations 40. Response to treatment is assessed by clinical criteria; repeat parasitologic testing is not recommended if the skin lesion appears to be healing[Strong, low]. Remark:The healing process may continue after the treatment course is completed especially for large ulcerative lesions. 41. Persons with CL should have their skin lesions monitored for 6-12 months after treatment for clinical evidence of therapeutic failure, which is initially seen at the border of a healed lesion[Strong, low]. Remark: The first sign of healing is usually flattening of the skin lesion. [/table] [table] Table 3: Approach to Syndromic Treatment of Leishmaniasis in North America 1,2 [/table] [table] Table 4: Drugs Used in North America for Systemic a Antileishmanial Therapy: Adverse Events, Monitoring for Toxicity, and Mitigation Approaches b [/table] [table] Recommendations 5: All persons at risk for ML-on the basis of the etiologic agent of the Leishmania infection, if known, and the region in the New World in which infection was acquired -should be questioned about and examined for mucosal symptoms and signs, respectively, even during the initial evaluation [Strong, low]. 6. During all evaluations (i.e., initial and subsequent), persons at risk for ML should be questioned explicitly about the development, evolution, and other characteristics of mucosal symptoms; and they should have a thorough examination of the naso-oropharyngeal mucosa even if they do not have any mucosal symptoms [Strong, low]. 7. Persons at risk for ML should be educated and provided personalized documentation about the importance of seeking medical attention for possible ML if they ever develop persistent, atypical (unusual for the person) naso-oropharyngeal/laryngeal manifestations that do not have a clear etiology [Strong, low]. 8. Persons at risk for ML who have persistent mucosal symptom(s) or compatible abnormalities of the nasooropharyngeal mucosa should be referred to a specialist for an otorhinolaryngologic examination, which typically should include fiberoptic endoscopy [Strong, low]. 9. Clinicians might refer some at-risk persons without documented mucosal symptoms or signs to an otolaryngologist, especially if it was not possible to conduct a thorough review of systems and mucosal examination or if the assessments may not have been adequate or reliable [Weak, very low]. [/table] [table] 24: We recommend that immunocompetent persons with skin lesions that are caused by infection with We recommend that any decision to observe a patient with CL without treatment should be reevaluated periodically, and the decision not to treat should be reconsidered if healing does not progress as anticipated [Strong, very low].28. In all cases of CL, wound care, individualized documentation of lesion evolution, and patient education regard- [/table]	None	http://www.ajtmh.org/deliver/fulltext/14761645/96/1/24.pdf?itemId=%2Fcontent%2Fjournals%2F10.4269%2Fajtmh.16-84256&mimeType=pdf&containerItemId=content/journals/14761645	Naomi Aronson, Barbara L. Herwaldt, Michael Libman, Richard Pearson, Rogelio Lopez-Velez, Peter Weina, Edgar Carvalho, Moshe Ephros, Selma Jeronimo, and Alan Magill Uniformed Services University of the Health Sciences, Bethesda, MD; Center for Disease Control and Prevention, Atlanta, GA; McGill University Health Centre, Montreal, Que, Canada; University of Virginia School of Medicine, Charlottesville, VA; University of Alcalá, Madrid, Spain; Walter Reed Army Institute of Research, Silver Spring, MD; Universidade Federal da Bahia, Salvador, BA, Brazil; Carmel Medical Center, Haifa, Israel; Federal University of Rio Grande do Norte, Natal, RN, Brazil; Bill and Melinda Gates Foundation, Seattle, WA
ec2f8d0f00343397310af0c93f9e33a16149dbe7	pubmed	The Japanese Society of Pathology Practical Guidelines on the handling of pathological tissue samples for cancer genomic medicine	The Japanese Society of Pathology Practical Guidelines on the handling of pathological tissue samples for cancer genomic medicine Clinical cancer genomic testing based on next-generation sequencing can help select genotype-matched therapy and provide diagnostic and prognostic information. Pathological tissue from malignant tumors obtained during routine practice are frequently used for genomic testing. This article is aimed to standardize the proper handling of pathological specimens in practice for genomic medicine based on the findings established in Pathology International. 2021;71:725-740.wileyonlinelibrary.com/journal/pin \| 725This 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. # Introduction In Japan, cancer genomic testing (also termed cancer gene panel testing or genomic profile testing) using solid tumor tissue samples has increased rapidly since the national health insurance system coverage started in 2019. [bib_ref] Cancer genomic medicine in Japan, Mano [/bib_ref] [bib_ref] Precision oncology and the universal health coverage system in Japan, Ebi [/bib_ref] In routine pathological practice, most tissue samples obtained by biopsy or surgery are processed as formalin-fixed paraffin-embedded (FFPE) materials. The FFPE process enables long-term storage of tissues and cells at room temperature, facilitating multiple molecular tests for diagnostic, prognostic, and predictive markers in addition to morphological diagnosis. Moreover, the development of various breakthrough technologies, such as multiplex or comprehensive genomic analyses, have accelerated the use of FFPE samples in clinical practice and research settings. As with fresh samples used in research, FFPE samples must be prepared to minimize the degeneration of biomolecules such as nucleic acids and proteins; however, this has long been considered difficult in most hospitals due to the heavy workload of routine practice. Meanwhile, given the introduction of advanced technologies such as next-generation sequencing (NGS) in clinical settings, the quality of FFPE samples processed by pathological laboratories should be kept high for use in cancer genomic testing. Several variable preanalytic factors affect the FFPE sample quality. [bib_ref] A review of preanalytical factors affecting molecular, protein, and morphological analysis of..., Bass [/bib_ref] Therefore, it is essential for the clinicians who collect and submit specimens, pathology technologists who prepare them, and their supervisors to be aware of these factors in their medical institutions . As a result, several guidelines established for the diagnostics utilized for predicting drug efficacy (companion diagnostics in cancer F I G U R E 1 Inter-institutional differences in the results of genomic testing using formalin-fixed paraffin-embedded (FFPE) samples prepared in routine practice. In total, 2573 gastrointestinal cancer FFPE samples (biopsy and surgical specimens) prepared during routine practice were submitted by 19 institutions participating in the SCRUM-Japan/GI-SCREEN nationwide, large-scale genome screening research project. Among them, data were analyzed for 16 institutions that submitted ≥40 samples for genomic testing. The FFPE samples were sent to a Thermo Fisher Scientific Clinical Laboratory Improvement Amendments-certified laboratory, where they were subjected to quality control (QC) assay and next-generation sequencing according to the laboratory's standard operating procedures. Manual microdissection was performed when required, and the ΔC t values were determined after DNA and RNA extraction. Targeted sequencing (Oncomine Cancer Research Panel; OCP, 143 genes and Oncomine Solid Tumour DNA/Fusion Transcript Kit; CE-IVD, 26 genes) using the Ion PGM™ System (Thermo Fisher Scientific) was performed on the samples that passed the QC. (a) The samples were classified into three categories based on the ΔC t values (high [HQ], intermediate , and low quality [LQ]); those for which ΔC t values could not be obtained owing to very LQ were classified as PCR-failures (AmpFail). Overall (indicated as "All"), 48.7%, 35.4%, and 15.9% of the samples from the 19 institutes were classified as high, intermediate, and LQ/PCR-failure samples for DNA integrity, respectively. There were marked differences in quality among the samples from the 16 institutions that submitted ≥40 samples. (b) Samples (HQ, IQ, and LQ) for which ΔC t values were obtained were analyzed using a comprehensive gene panel (143-gene panel) and a small panel . The success rates of these analyses highly correlated with the result from the QC assay shown in (a). The institutions with high proportions of LQ samples and PCR-failures also exhibited high failure rates for both panels, and marked differences in quality were observed among the samples from these 16 institutions. Overall ("All" in b), the success rate was 68.1% for the comprehensive gene panel andpatients provide recommendations for the fixation process. Over 2000 FFPE samples from gastrointestinal cancer patients were analyzed in the nationwide cancer genome screening project, SCRUM-Japan/GI-SCREEN, which revealed inter-laboratory differences in sample quality . [bib_ref] on behalf of SCRUM-Japan GI-SCREEN Pathology Group, Impact of DNA integrity on..., Kuwata [/bib_ref] In another clinical research project, TOP-GEAR, FFPE samples from over 200 patients with various types of cancers were analyzed, and the results of genomic testing based on FFPE samples were clinically validated in hospitals that comply with Clinical Laboratory Improvement Amendment (CLIA) requirements. [bib_ref] Feasibility and utility of a panel testing for 114 cancer-associated genes in..., Sunami [/bib_ref] In 2017, the Ministry of Health, Labour, and Welfare (MHLW) initiated a consortium to promote genomic cancer medicine that outlined the framework for the national cancer genomic medicine platform in Japan and presented the blueprint for genomic medicine using NGS . Medical institutions and hospitals have been requested to meet the FFPE sample quality standards for NGS testing when performing cancer genome profiling tests approved for Japan's national insurance system. [bib_ref] Precision oncology and the universal health coverage system in Japan, Ebi [/bib_ref] Stricter sample quality controls are required for genomic testing in analyzing multiple genes than the current requirements for singleplex gene testing. Hence, the Japanese Society of Pathology (JSP) released Japanese-language guidelines on the handling of pathological tissue samples for genomic medicine in March 2018, following the release of the tentative edition in September 2017. This article (practical guidelines) is based on the content of the Japanese-language guidelines and intends to cover the FFPE sample handling requirements used in cancer genomic testing systems approved as in vitro diagnostics (IVD) and medical devices by the MHLW and covered by the national health insurance system. Therefore, the guidelines deal with requirements for highly comprehensive genomic analyses such as whole-exome and whole-transcriptome sequencing secondarily. Due to technological innovation, advances in knowledge, and improvements in the genomic medicine system, the scope of these practical guidelines is expected to change continuously. ## Effective handling of ffpe tissue samples The practical guidelines described here aim at enabling the introduction of cancer genomic medicine in the future. Parts 1 and 2 outline the proper handling of FFPE samples for cancer genomic testing in the entire preanalytical phase and the initial process of the analytical phase, which are both performed in the pathology laboratories of medical institutions. Effective FFPE sample processing is necessary for accurate diagnosis; simultaneously, it is essential to follow the recommended molecular testing methods such as immunohistochemistry, particularly for CDx. Therefore, extreme shortening of the fixation process is difficult, as this can lead to insufficient fixation of protein molecules, although some degeneration and modification of nucleic acids and proteins is unavoidable even with adequate fixation. As the FFPE sample preparation requires extensive processing and is significantly more time-consuming than other samples such as blood, even a slight modification of operating procedures can significantly burden pathology laboratories in medical institutions that have limited technical resources and infrastructure. Therefore, it is recommended that the practical guidelines are followed to the greatest extent possible. The recommendations in the practical guidelines for genomic medicine are based on extensive empirical data, information from the scientific literature, and the previously released JSP guidelines for genome research. [bib_ref] The Japanese Society of Pathology Guidelines on the handling of pathological tissue..., Kanai [/bib_ref] The recommendation categories are classified into three groups as described in the explanatory notes below. However, recommendations for general clinical practice according to evidence-based medicine are not presented. (C) Items recommended as the best practice in a routine clinical setting (C indicates "Clinical recommendation"). (R) Items recommended when FFPE samples are used for the comprehensive genomic analysis (including whole-exome and whole-transcriptome sequencing) in the interventional study or as genomic testing not covered by the national health insurance system in Japan (R means "Research recommendation"). (N) Items that should be avoided (N indicates "Not recommended") T A B L E 2 Use of NGS in the national platform of CGM in Japan 1.2. Small endoscopically resected specimens (e.g., digestive tract specimens obtained from endoscopic mucosal resection) should be placed in formalin fixative immediately after sample collection (C). 1.3. Tissue specimens obtained by biopsy should be immediately placed in formalin fixative (C). 1.4. Specimens for preparing cell blocks should be immersed in formalin fixative as soon as possible after the necessary pretreatment (C). ## 1.5. Keeping surgical specimens at room temperature for 30 min or longer after resection should be avoided as much as possible (N). F I G U R E 2 Yield and quality of DNA obtained from formalin-fixed paraffin-embedded (FFPE) samples prepared in routine practice. The yield and quality of DNA obtained from FFPE tissue samples of 233 patients with solid tumors analyzed in the first term of the TOP-GEAR project were examined. DNA was extracted from five 10-µm sections using the QIAamp DNA FFPE Tissue Kit (Qiagen). (a) The cross-sectional tissue area was measured and multiplied by 50 µm to calculate the tissue volume. The surgical and biopsy specimens were assessed and compared (including samples not because they were from other institutions). The DNA yield per volume varied widely among the samples, with the biopsy specimens exhibiting a higher yield than the surgical specimens. (b) After DNA quality assessment using Q-values (quantity of DNA measured using qPCR/quantity of double-stranded DNA measured using the fluorescence method), the quality was compared between the surgical and biopsy specimens. The Q-values varied widely among the samples, with the biopsy specimens exhibited better quality than the surgical specimens Note for 1.1: It has been reported that the time from tissue resection to fixation affects the results, if it exceeds 2 h for the in situ hybridization (ISH) (HER2) and 1 h for the immunohistochemistry (IHC; hormone receptors). [bib_ref] Delay to formalin fixation effect on breast biomarkers, Khoury [/bib_ref] The ASCO/CAP guidelines for breast cancer recommend tissue fixation within 1 h. [bib_ref] American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical..., Hammond [/bib_ref] Note for 1.1: As the penetration rate of formalin fixative is approximately 1 mm/h, it is recommended that appropriate cuts should be made in the specimen before fixation, particularly for surgical specimens, so that they are thin enough to enable complete tissue fixation by the time of gross cutting. [bib_ref] Effect of fixatives and tissue processing on the content and integrity of..., Srinivasan [/bib_ref] Note for 1.1-1.3: If the specimens are intended for clinical research, it is necessary to immerse them in fixing solution immediately after resection or collection. [bib_ref] The Japanese Society of Pathology Guidelines on the handling of pathological tissue..., Kanai [/bib_ref] Note for 1.1 and 1.5: Due to the complex pre-fixation process, surgical specimens tend to be of lower quality and yield less nucleic acid than biopsy specimens .Note for 1.4: Among cytological specimens, some fluid specimens obtained from the body cavity are processed as cell blocks. Commonly used preparing method of cell block include cell collection method via centrifugation and GUIDELINES FOR SAMPLE HANDLING FOR CGM \| 729 cell solidification method via gelation, in each of which there are several different procedures, and none of which is currently standardized. Although the applicability of these processing methods to genomic medicine is unknown, they have been used in many institutions in Japan, and can be used in molecular testing for CDx.(b) Fixation process Composition of formalin fixative 1.6. For buffering formalin fixative, a neutral buffered solution should preferably be used; avoid acidic or unbuffered solutions (C). 1.7. A 10% solution (3.7% formaldehyde) should preferably be used as a formalin fixative (C). Optimal fixation time 1.8. Following the recommendations in several CDx guidelines , tissue specimens (surgically or endoscopically resected specimens and biopsy specimens) should be fixed for 6−48 h (C) . 1.9. Sample quality deteriorates due to inadequate fixation; therefore, insufficient fixation and over fixation should be avoided (N). Optimal volume of fixative for formalin fixation 1.10.Ten times the sample volume per tissue should be used for formalin fixation (C). 1.11.Formalin fixation can be performed at room temperature (C). Note for 1.6 and 1.7: In several CDx assays using IHC, a 10% neutral buffered formalin solution is recommended 7,12-19 . Detection of protein expression by IHC is affected by the composition and concentration of the formalin fixative. [bib_ref] Optimal fixation for total preanalytic phase evaluation in pathology laboratories: a comprehensive..., Sato [/bib_ref] Moreover, results of a comparative analysis of DNA data quality using ΔC t and DNA integrity number (DIN) values supported the use of a 10% neutral buffered solution. [bib_ref] The Japanese Society of Pathology Guidelines on the handling of pathological tissue..., Kanai [/bib_ref] Note for 1.8: The known effects of formalin fixation on the quality of nucleic acids include chemical modifications of nucleic acid bases in addition to nucleic acid fragmentation. Notably, the deamination of cytosine that changes cytosine into uracil produces thymine (a C > T substitution) during the PCR amplification process. [bib_ref] A high frequency of sequence alterations is due to formalin fixation of..., Williams [/bib_ref] [bib_ref] Sequence artifacts in DNA from formalinfixed tissues: causes and strategies for minimization, Do [/bib_ref] Extent of deamination significantly increases with increasing fixation time over 72 h; therefore, samples should preferably not be fixed for more than 48 h (C) . Note for 1.8: The fixation of minute tissue specimens obtained by biopsy using techniques such as endobronchial ultrasonography (EBUS) or cytological specimens for cell block preparation can be completed in a shorter duration (e.g., 6−24 h). [bib_ref] Molecular testing guideline for selection of lung cancer patients for EGFR and..., Lindeman [/bib_ref] Note for 1.8: It is difficult to prepare an NGS library (particularly when using comprehensive gene panels) from FFPE samples that were fixed for prolonged duration, particularly when using samples that were fixed for 7 days or longer (N) . In the GI-SCREEN study described above, the samples were classified into the three quality categories based on the results of assays performed using primer sets for specific housekeeping genes that differed in amplicon size . As the FFPE blocks used in this analysis were prepared 3 years earlier, the ΔC t value of 2-day-fixed samples was classified as "intermediate." For amplicon sequencing using the AIT12 and TST15 panels, libraries were prepared using 40 and 20 ng dsDNA, respectively. After performing a library QC, the samples were analyzed using the GeneReader (Qiagen) and MiSeq systems (Illumina). All the samples were successfully analyzed with both small gene panels. Therefore, it can be inferred that the small gene panels are useful for the analysis of formalin-fixed paraffin-embedded (FFPE) samples containing low-quality nucleic acids. However, the total number of reads decreased as formalin fixation time increased [A, B]; this effect varied depending on the gene panel used for analysis Note for 1.8: If there are remaining specimens that can be used for future genomic testing after performing routine pathological diagnosis, or when a re-biopsy is planned immediately for cancer genomic testing, the use of superior, non-formalin fixatives can be considered for preserving nucleic acids (R). 6 (c) Post-fixation processes Decalcification 1.12. When using specimens containing hard tissues, an EDTA decalcification should be performed (C); acid decalcification should be avoided (N). [bib_ref] The Japanese Society of Pathology Guidelines on the handling of pathological tissue..., Kanai [/bib_ref] Paraffin-embedding 1.13. Conventional tissue processors (closed automated instruments) can be used while referring to general procedures (C). However, the influence of the reagents, processing protocol, and processor maintenance (e.g., the frequency of replacement) remains unknown. There are insufficient data on rapid-type processors (continuous rapid automated instruments). ## (continues) Storage of FFPE blocks 1.14. FFPE blocks can be stored at room temperature (C). However, the blocks should be stored in a cool, dark place (C) and not exposed to high humidity (N) (C F I G U R E 6 Effects of prolonged formalin fixation on microarray testing. The effects of fixation time (1, 2, 3, 7, and 14 days) on microarray analysis (GeneChip Human Genome U133 + 2.0 arrays; Affymetrix) performed for breast cancer-recurrence risk prediction testing were examined using breast cancer samples from 11 cases. The cDNA was synthesized using 100 ng RNA extracted from each sample. After the yield was determined, the microarray testing was performed, and the fluorescence intensity was measured. (a) Examining the cDNA yield after the reverse transcription reaction and two quality control (QC) parameters for microarray testing (SF and % p values) revealed a significant change after 3-day fixation (p < 0.05; *p < 0.01) [A-C]. The SF value reflects the mean fluorescence intensity corresponding to the expression level obtained from all probes. It is expressed as a coefficient and used to normalize the mean fluorescence intensity to a specific level. A high value indicates the array is dark due to inappropriate measurement resulting from sample quality or procedural complications. The % p values indicate the proportion of expressed probes compared to all probes. A value below a certain proportion indicates that the measurement is likely to be inappropriate, and that the microarray data are less reliable. (b) Using 1-day fixation as the control, a correlation analysis was performed to examine the effects of formalin fixation time on the overall expression level of the microarray probes. The results indicated that the correlation coefficients decreased with increased fixation time. In particular, the correlation coefficients for gene probes with a low expression level decreased significantly 2.3. Thin sectioning of FFPE blocks should be performed with extreme caution to avoid cross-contamination. As a precaution, the microtome blade should be changed for each sample. Additionally, care (such as wearing gloves) should be taken to prevent nucleic acid degradation (C). Reconfirmation with H&E-stained slides and marking 2.4. For genomic testing, H&E-stained and unstained slides are freshly prepared from the FFPE block selected by the pathologist. Next, in principle, the pathologist should mark the test area for nucleic acid extraction on the H&E-stained slides and assess the tissue volume (total number of nucleated cells), the tumor volume (total number of tumor cells), and tumor content (percentage of tumor cells with respect to total nucleated cells) (C). [bib_ref] Guidance for laboratories performing molecular pathology for cancer patients, Cree [/bib_ref] Note for 2.2: The quality of nucleic acids within the FFPE block deteriorates over time . Although the impact of the storage period varies depending on the type of genomic testing used, it is preferable to use FFPE blocks prepared within three years (C, R) and 26 ). Note for 2.2: The GI-SCREEN study results demonstrated that the quality of an FFPE sample (ΔC t value) and the NGS analysis success rate decreased as the storage period increased. Therefore, as much as possible, the use of recently prepared FFPE blocks is recommended (C) . Note for 2.4: In general, genomic testing requires 10-500 ng DNA. However, the quantity required varies depending on the gene panel size. Pathologists, who assess the tumor volume and tumor content (C, R), should note that the tumor content should be assessed based on the number of nucleated cells, not on the proportion of the area occupied by tumor cells. Note for 2.4: The DNA yield obtained from one nucleated cell is~6 ng. Thus, approximately 2000 cells (~60-100 mm 2 tumor cell-rich areas on an unstained slide) should be used to extract 10 ng DNA. [bib_ref] Analysis of pre-analytic factors affecting the success of clinical next-generation sequencing of..., Chen [/bib_ref] Note for 2.4: The tumor content should be ≥30% (minimum 20%) to detect mutations such as single nucleotide variants and small insertion and deletions, and ≥50% if the analysis includes the detection of copy number alterations. Furthermore, non-tumor cells should be eliminated as much as possible when analyzing gene expression levels. If the tumor content is not sufficiently high, it is necessary to remove the non-tumor areas manually (e.g., by microdissection) (C, R). In targeted sequencing, it is recommended that sequence coverage of the targeted regions be at least 250-500, and the detection threshold of the variant allele frequency be 5%-10%. [bib_ref] Guidelines for validation of next-generation sequencing-based oncology panels: a joint consensus recommendation..., Jennings [/bib_ref] [bib_ref] Analysis of pre-analytic factors affecting the success of clinical next-generation sequencing of..., Chen [/bib_ref] Note for 2.4: The tumor content should preferably be recorded in the pathological diagnosis report when observing the H&E-stained slides. If non-tumor tissue is removed by manual microdissection, it should be recorded in the genomic testing report along with tumor content (C). ## (b) nucleic acid extraction from ffpe samples Nucleic acid extraction 2.5. When extracting nucleic acids for genomic testing, commercially available standardized kits suitable for use in clinical settings are preferred (C). If a kit is recommended for a specific genomic test, it should be used for the extraction (C, R). ## Measurement of the purity and yield of nucleic acids 2.6. The purity and yield of the extracted nucleic acids should be determined with a spectrophotometer using the A260/A280 ratio, and using the fluorescence method or similar quantitation methods (C, R). Assessment of nucleic acid quality 2.7. If the nucleic acids extracted from the FFPE samples have been stored for a long period, or if deterioration of nucleic acid quality is suspected due to over fixation, it is recommended that the quality of the nucleic acids should be assessed (C, R). Note for 2.5: Commercial kits for nucleic acid extraction from FFPE samples should be carefully selected, as the purity and yield differ among kits. [bib_ref] Comparison of eight commercially available kits for DNA extraction from formalin-fixed paraffin-embedded..., Janecka [/bib_ref] Note for 2.5: Additional treatment with uracil DNA N-glycosylase (UNG) during nucleic acid extraction enables the removal of chemical modifications generated by formalin (mainly by deamination of cytosine bases). UNG can suppress the production of reads containing artifacts by restoring part of the base substitution in the original base sequences caused by formalin fixation . Note for 2.6: The A260/A280 ratios for the purity of DNA and RNA extracted from FFPE samples typically range between 1.7-1.9 and 1.9-2.1, respectively. Caution should be exercised if the ratio is low, as this suggests contamination with proteins. However, if DNA is contaminated with RNA, the A260/A280 ratio will be slightly higher. [bib_ref] DNA qualification workflow for next generation sequencing of histopathological samples, Simbolo [/bib_ref] Additionally, checking the A260/A230 ratio or the scan results between A220 and A320 to screen for other contaminants is desirable. Note for 2.7: The known quality control (QC) indicators for nucleic acid integrity assessment are listed in . ## Perspectives Cancer genomic testing under the national health insurance system was started in 2019, and so far, FFPE samples have been handled following the Japanese version of the practical guidelines released in 2018 by the JSP (https://pathology.or.jp/genome_med/). The NCC Oncopanel, one of the IVD-approved NGSbased testing systems, has been performed in more than 2000 patients in Japan as of April 2020, with a success rate of ≥90% (unpublished data), similar to that observed in the MSK-IMPACT study. [bib_ref] Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000..., Zehir [/bib_ref] However, some samples did not work; therefore, further improvements in the sample preparation methods are needed. Genomic testing in Japan is mainly based on DNA, whereas the larger-scale gene panel test system for over 400 genes, currently under development, uses both DNA and RNA extracted from FFPE samples. The use of FFPE samples in NGS-based wholeexome and whole-transcriptome analyses has increased in recent years, as evident from the exploratory studies performed during or after the completion of intervention-based clinical trials conducted at the same level as clinical practice. Therefore, samples should be handled in a manner that enables the extraction of higher-quality RNA as well as DNA. In addition to NGS-based testing, the development of non-NGS-based profile testing is in progress; therefore, it is necessary to apply these procedures in various genomic testing systems. As genomic technologies are changing rapidly, revising these guidelines to match the actual situation in Japan will be considered. # Acknowledgments We thank the pathologists, clinicians, medical technologists, and research technicians at the collaborative institutions for help with obtaining empirical data on the handling of samples. We also thank Drs Katsuya Tsuchihara (National Cancer Center) and Takashi Kohno (National Cancer Center) for critical advice and constructive suggestions. This work was supported by the Japanese Society of Pathology (JSP), and the guideline was developed F I G U R E 8 Effects of formalin-fixed paraffin-embedded (FFPE) block storage duration on DNA quality (TOP-GEAR project). The effects of the FFPE block storage duration were examined using samples from 131 patients subjected to the NCC Oncopanel in the first half of the first term of the TOP-GEAR project. The storage durations were compared to the Q-values of DNA and the yields of the primary PCR products in NGS library preparation. In the comparison of primary PCR product yields, the sample data from NGS libraries prepared using SureSelect XT Reagents (Agilent) were used. The Q-values of DNA extracted from FFPE samples and the yields of the primary PCR products correlated to some extent with the FFPE block storage duration. The low quality of DNA may have been partially due to the long-term storage of the FFPE blocks in collaboration with two major research projects; the SCRUM-Japan GI-SCREEN and TOP-GEAR. The total number of reads and the mean read depth were ≥eightfold higher in the UNG+ samples. As previously reported, DNA quality improved with UNG treatment; however, the effect was not uniform. Thus, the effects in preliminary experiments should be checked to decide whether UNG treatment is required [formula] n o i t a x i f y a d - 3 n o i t a x i f y a d - 3 n o i t a x i f y a d - 3 n o i t a x i f y a d - 3 [/formula] # Author contributions ## Qc measure target explanation C t value (ΔC t , ΔΔC t ) DNA/RNA It is a simple method requiring no special instrument to assess the quality of nucleic acids using C t (also called Cq) values obtained by real-time PCR (DNA) or real-time RT-PCR (RNA). In the quality assessment method for DNA, the difference between C t values (ΔC t value) obtained from two amplicons of different lengths (e.g., a short-chain amplicon of 50-100 bp and a long-chain amplicon of 100-300 bp) is usually used. In the SCRUM-Japan/GI-SCREEN study, [bib_ref] DNA qualification workflow for next generation sequencing of histopathological samples, Simbolo [/bib_ref] ΔC t value calculation was performed for over 2000 FFPE samples, demonstrating its usefulness DIN DNA DIN is a value on a 1-10 scale that is assigned based on the degradation of gDNA as measured by the Genomic DNA ScreenTape assay using the Agilent 2200/4200 TapeStation system to assess the quality of DNA from FFPE samples Q-value DNA The Q-value is a measure of the quality of DNA developed by the National Cancer Center, [bib_ref] Comprehensive screening of target molecules by nextgeneration sequencing in patients with malignant..., Tanabe [/bib_ref] which is calculated by dividing the value measured using the real-time PCR method (PCR-active DNA quantity) by the value measured using the fluorescence method (dsDNA quantity). The success rate of sequencing (when an NCC Oncopanel v2 is used) is~85% when the Q-value is 0.2 or higher DV200 RNA DV200 is a measure of RNA quality that was developed by Illumina, and it calculates the proportion of RNA fragments equal to and longer than 200 nucleotides using Fragment Analyzer using AATI or an Agilent 2100 Bioanalyzer. The quality classification by DV200 is assigned as follows: >70% as high, 50%-70% as medium, 30%-50% as low, and <30% as too degraded. [bib_ref] Evaluation of DNA and RNA quality from archival formalin-fixed paraffin-embedded tissue for..., Fujii [/bib_ref] FFPE samples that are too degraded at <30% are not recommended for use in library preparation for RNA sequencing [fig] •: Main variable factors affecting the preanalytical phase of FFPE sample processing Processes Persons in charge of the process Preanalytical variable factors Pre-fixation process Clinicians (persons who collect specimens) Time from the cessation of blood flow to the removal of tissues (warm ischemic time) Time from the removal of tissues to their fixation (cold ischemic time) Composition of the fixative (i.e., concentration, buffered action, and pH of solution) Time and temperature of formalin fixation Ratio of the volume of fixatives to tissue volume during formalin fixation Treatment methods to penetrate tissues (i.e., immersion, injection, or acceleration by microwaves) Post-fixation process Pathologists Pathology technologists Conditions for decalcification (i.e., avoidance of acid decalcification) Tissue processor type and the frequency of replacement of the reagents used in the machine Conditions for dehydration and clearing (i.e., the types of reagents, temperature, and time used) Conditions for paraffin immersion (i.e., the type of paraffin, temperature, and time used) (Post-FFPE process) Pathology technologists Storage of FFPE blocks (the duration and condition) Storage of unstained FFPE slides (the duration) Abbreviation: FFPE, formalin-fixed paraffin-embedded. [/fig] [fig] FF: I G U R E 9 Effects of formalin-fixed paraffin-embedded (PE) block storage duration on RNA quality. The effects of storage duration on quality of RNA extracted from PE blocks were examined using PE tissue samples from 169 patients with nonsmall cell lung cancer. One hundred PE block samples were prepared in 2007, and 49 and 20 were prepared in 2012 and 2013, respectively. Using the semiconductor-based Ion PGM System, amplicon sequencing analyses were performed in 2014 using the Ion AmpliSeq™ RNA Fusion Lung Cancer Research Panel (Thermo Fisher Scientific). In this fusion gene panel, the median total number of reads was 288 838 (range: 157 085−431 332) for the blocks prepared in 2013; 257 516 (range: 149 998−435 890) for blocks prepared in 2012; and 282 887 (range: 4987−562 580) for blocks prepared in 2007. Among the 169 samples, four samples were judged difficult to assess because the total number of reads from blocks prepared in 2007 was ≤20 000. The blocks prepared in 2007 showed fewer reads than those prepared in 2012 or 2013, indicating the effects of sample deterioration over time I G U R E 10 Effects of formalin-fixed paraffin-embedded (PE) block storage duration on DNA and RNA quality. DNA and RNA were extracted from PE tissue samples from 110 patients with non-small cell lung cancer and quantitated using PicoGreen dsDNA and PicoGreen RNA quantitation reagents (Thermo Fisher Scientific). Up to 10 ng DNA or RNA was used for gene mutation and fusion gene analyses. Using the Ion PGM System, amplicon sequences were analyzed on DNA samples obtained in 2014−2015 using the Ion AmpliSeq™ Colon and Lung Cancer Panel and RNA with the Ion AmpliSeq™ RNA Fusion Lung Cancer Research Panel (Thermo Fisher Scientific). (a) In the DNA gene-mutation panel analysis, the median total number of reads was 412 715. Among the 110 samples, five samples were judged difficult to analyze because their total number of reads was ≤50 000, and one sample was judged difficult to analyze as it showed 35C > T substitutions, which is considered high. However, the total number of reads was sufficient [A, B]. In the RNA fusion gene panel analysis, the median total number of reads was 256 836. Among the 110 samples, four samples were judged difficult to analyze because their total reads were 20 000 or fewer [C]. (b) The success rate of the DNA mutation analysis was 81.8% (n = 11) for PE samples prepared ≥4 years before the analysis (2004-2010), 94.8% (n = 58) for those prepared ≤3 years (2011-2013), and 97.6% (n = 41) for those prepared the same year as the analysis (2014-2015) [D]. The success rate of the RNA fusion gene analysis was 81.8% (n = 11) for PE samples prepared ≥4 years before the analysis (2004-2010), 96.6% (n = 58) for those prepared ≤3 years (2011-2013), and 100% (n = 41) for those prepared the same year as the analysis (2014-2015) [E] [/fig] [fig] F: I G U R E 11 Chemically induced base substitution due to prolonged duration of formalin-fixed paraffin-embedded (PE) block storage and the effect of uracil DNA N-glycosylase (UNG)-treatment on base repair. Amplicon sequencing using the TruSeq Amplicon Cancer Panel (Illumina) was performed on surgical specimens obtained from two colorectal cancer patients, fixed for 1 and 3 days, respectively. The analysis was performed twice in 2014 (immediately after PE block preparation) and again in 2017 (3 years post-preparation). A comparative analysis was performed in 2017 to examine the effects of UNG treatment on samples fixed for up to 3 days using two nucleic acid extraction kits, the QIAamp DNA PE Tissue Kit (without treatment), and the GeneRead DNA PE Tissue Kit (with treatment) (Qiagen). (a) In both samples (1 and 3 days fixation), the base substitution increased due to long-term storage [A-D]. In particular, the C > T substitution increased significantly (lower insets in A and B are magnifications of upper diagrams). The number of base changes resulting from long-term storage was proportional to the number at the beginning of storage. (b) A lower number of C > T base substitutions were observed in the UNG-treated samples (UNG+) compared to the untreated (UNG-) samples, while the number of some types of base substitutions, such as T > C substitutions, increased. [/fig]	None	None	Clinical cancer genomic testing based on next‐generation sequencing can help select genotype‐matched therapy and provide diagnostic and prognostic information. Pathological tissue from malignant tumors obtained during routine practice are frequently used for genomic testing. This article is aimed to standardize the proper handling of pathological specimens in practice for genomic medicine based on the findings established in “Guidelines on the handling of pathological tissue samples for genomic medicine (in Japanese)” published by The Japanese Society of Pathology (JSP) in 2018. The two‐part practical guidelines are based on empirical data analyses; Part 1 describes the standard preanalytic operating procedures for tissue collection, processing, and storage of formalin‐fixed paraffin‐embedded (FFPE) samples, while Part 2 describes the assessment and selection of FFPE samples appropriate for genomic testing, typically conducted by a pathologist. The guidelines recommend that FFPE sample blocks be used within 3 years from preparation, and the tumor content should be ≥30% (minimum 20%). The empirical data were obtained from clinical studies performed by the JSP in collaboration with leading Japanese cancer genome research projects. The Japanese Ministry of Health, Labour, and Welfare (MHLW) recommended to comply with the JSP practical guidelines in implementing cancer genomic testing under the national health insurance system in over 200 MHLW‐designated core and cooperative cancer genome medicine hospitals in Japan.
ba190fa206cb44d8069c60dc1c7e38f4a6f84c12	pubmed	Japanese consensus guidelines for pediatric nuclear medicine	Japanese consensus guidelines for pediatric nuclear medicine The Japanese Society of Nuclear Medicine has recently published the consensus guidelines for pediatric nuclear medicine. This article is the English version of the guidelines. Part 1 proposes the dose optimization in pediatric nuclear medicine studies. Part 2 comprehensively discusses imaging techniques for the appropriate conduct of pediatric nuclear medicine procedures, considering the characteristics of imaging in children.Overview of the guidelinesObjectives and background of the guidelines Nuclear medicine studies are important examinations that produce images of organ function and the pathophysiology of diseases, information that cannot be obtained by other diagnostic imaging methods. Nuclear medicine studies, like other radiological examinations, cause medical radiation exposure. Therefore, ''justification of practice'' and ''optimization of protection'' should always be kept in mind, particularly in children because they are considered to be more sensitive to radiation than adults. In Japan, pediatric doses were recommended by a subcommittee, the Medical and Pharmaceutical Committee, Japan Radioisotope Association in 1988. The European Association of Nuclear Medicine proposed the standardization of pediatric radiopharmaceutical administered doses in 1990 [bib_ref] A radiopharmaceuticals schedule for imaging in paediatrics, Piepsz [/bib_ref] , and published new, more detailed guidelines for calculating doses entitled ''Pediatric Dosage Card'' in 2007 [bib_ref] Optimised tracer-dependent dosage cards to obtain weight-independent effective doses, Jacobs [/bib_ref] [bib_ref] The new EANM paediatric dosage card, Lassmann [/bib_ref]. The Society of Nuclear Medicine and Molecular Imaging also proposed appropriate radiopharmaceutical administered doses for pediatric nuclear medicine studies in 2010 as part of the project to reduce medical radiation exposure of children called ''Image Gently'' [bib_ref] Pediatric radiopharmaceutical administered doses: 2010 North American consensus guidelines, Gelfand [/bib_ref] [bib_ref] Minimizing and communicating radiation risk in pediatric nuclear medicine, Fahey [/bib_ref] [bib_ref] Virtual reality for dose optimization in pediatric nuclear medicine, Zanzonico [/bib_ref]. In 2011, an incident of intentional administration of excessive radioactivity to children in nuclear medicine studies at a hospital in Japan was disclosed. With this case as the springboard, the Japanese Society of Nuclear Medicine set up a committee to review the appropriate conduct of pediatric nuclear medicine studies, including the radiopharmaceutical administered doses, in 2012. After review for approximately 1 year, the committee has prepared consensus guidelines for the appropriate conduct of pediatric nuclear medicine studies. Outline and structure of the guidelines Generally, guidelines should be objective and neutral, based on high-level evidence. In pediatric nuclear medicine studies, however, it is difficult to accumulate a sufficient number of cases and thus prepare guidelines based on evidence-based medicine (EBM). Therefore, the present guidelines have been prepared based on consensus reached by experts who are thoroughly familiar with pediatric nuclear medicine studies. The original guidelines are written in Japanese and consist of three parts. Part 1 proposes the dose optimization in pediatric nuclear medicine studies. The method for calculating the doses is based on the above-mentioned European Association of Nuclear Medicine's guidelines. The computed doses are almost equivalent to those proposed by the Society of Nuclear Medicine and Molecular Imaging, and are generally lower than those conventionally used in Japan. There is a global trend to reduce radiation exposure in clinical practice, and awareness of dose reduction should be raised among health care workers involved in nuclear medicine studies. Maintenance and renewal of equipment as well as improvement of imaging techniques and image reading skills may be required when lower doses were administered. Part 2 comprehensively discusses imaging techniques for the appropriate conduct of pediatric nuclear medicine procedures, considering the characteristics of imaging in children. Part 3 provides pediatric illnesses for which nuclear medicine studies are highly useful and that may partly justify the use of radiopharmaceuticals causing radiation exposure in children. In this English version, Parts 1 and 2 have been translated. Although the guidelines may have some shortcomings in content, they are based on the current consensus of the Committee. The guidelines are subject to revision in accordance with the global trend toward standardization of pediatric nuclear medicine studies. ## Part 1: pediatric radiopharmaceutical administered doses ## Concepts and methods for calculation In the report concerning the recommendation for pediatric doses published in 1988 in Japan, the characteristics of various methods for calculating doses are discussed and compared with each other. Most of the methods presented in the report are based on the adult doses, which were multiplied by certain coefficients related to age, weight, body surface area, etc., to derive the pediatric administered dose. The proposed formula recommended by the subcommittee is ''Pediatric dose (MBq) = adult dose 9 (age ? 1)/(age ? 7)''. This formula has been widely used in the clinical practice of pediatric nuclear medicine studies in Japan since then. The adult dose included in the formula generally refers to the adult reference dose proposed by the Japanese Society of Nuclear Medicine; however, it has not been uniform across the nation, since some medical institutions use other reference doses. In addition, weightbased calculation methods are considered more reasonable than age-based calculation methods, because the prevalence of overweight children has recently been increasing and sick children are likely to have a lower body weight than children of the same age with a normal body weight. Both formulas proposed by the European Association of Nuclear Medicine and the Society of Nuclear Medicine and Molecular Imaging, respectively, directly compute the administered dose from the body weight of the patient, not based on the adult administered dose. Especially the method proposed by the European Association of Nuclear Medicine is designed to yield weight-independent effective doses. After considering all the points mentioned above, we determined the calculation method, ''JSNM pediatric dosage card'', which is a modified version of the method proposed by the European Association of Nuclear Medicine (EANM pediatric dosage card), selecting radiopharmaceuticals that are routinely used for pediatric nuclear medicine studies in Japan, and considering the current dosage of the radiopharmaceuticals. The pediatric administered dose is computed as follows using the class, baseline activity, and weight-dependent multiple as presented in [fig_ref] Table 1: Class and baseline activity/minimum activity of radiopharmaceuticals An excessive dose may be... [/fig_ref]. ## Formula for calculation Administered activity (MBq) = baseline activity in [fig_ref] Table 1: Class and baseline activity/minimum activity of radiopharmaceuticals An excessive dose may be... [/fig_ref] 9 weight-dependent multiple in [fig_ref] Table 2: Weight-dependent multiples for each class [/fig_ref]. If the calculated activity is smaller than the minimum recommended activity, the minimum activity should be administered. If the calculated activity exceeds the adult dose specified at each institution, the adult dose should be administered. Baseline activity: Mostly equals the activity adopted by the Pediatric Task Group, the European Association of Nuclear Medicine, which was set based on the European adult administered activity. For some radiopharmaceuticals, the activity was originally determined based on the adult administered activity in Japan. These values are for calculation purposes and equal the activity to be administered to a child weighing 3 kg. ## Examples of calculation Minimum activity: Mostly equals the minimum activity that was empirically determined by the European Association of Nuclear Medicine. For some radiopharmaceuticals, the activity was originally determined based on the pediatric administered activity in Japan. Weight-dependent multiple: Factors dependent on body weight that were determined to obtain weight-independent effective doses Remarks The radiopharmaceuticals listed in [fig_ref] Table 1: Class and baseline activity/minimum activity of radiopharmaceuticals An excessive dose may be... [/fig_ref] are administered intravenously, except for sodium iodine (I-123) which is administered orally. The activities to be administered in particular studies for which the radiopharmaceuticals are administered by other routes are individually presented in Part 3. The guidelines generally cover children aged 15 years and younger. Not all of those aged 16 years and older, however, can be given the adult administered activities. The guidelines may have to be applied even to a child aged 16 years or older if he/she is considered a growing youth, and careful determination of the appropriate dosage is required. ## Part 2: technical considerations for pediatric nuclear medicine imaging procedures ## General concepts The pediatric radiopharmaceutical administered doses proposed in Part 1 are mostly lower than those that have been widely used in Japan. Attempts should be made to achieve good imaging performance with these lower doses. Although it is theoretically possible to obtain some information, even with low doses of radiopharmaceuticals, by spending a longer time, too lengthy restraining of the body may cause unexpected body motions, resulting in completely unusable data. It is therefore important to keep children at rest during the examination and to prioritize the information to be collected within the limited time of the examination. If the quality of the images is judged to be insufficient due to body motions, imaging has to be repeated, but continuation of the examination may be impossible due to the mental status of the patient. To prevent such a situation, it is important to communicate with the patients before the examination and to monitor them carefully and talk to them frequently during the examination. Prior to an examination, close communications with the concerned departments should be secured and the patient's background factors such as age, height, body weight, disease and symptoms should be fully grasped. It is preferable to prioritize the images to be taken and select the imaging method in advance, based on these background factors, and to use an individual protocol that is appropriate for the circumstances. ## Special considerations ## Procedures during imaging During imaging, efforts should be made to keep the children at rest and to acquire appropriate images within a Modifications of the routine imaging protocol or the preparation of imaging protocol variations may also be required. Once a radiopharmaceutical is administered, imaging should not easily be discontinued in the course of the procedure, for example, because the patient is crying or has woken up. Utmost efforts should be made to complete the examination by trying to calm the patient down by appropriate means or allowing differences in the imaging time. To be prepared for a sudden change in the medical condition of patients during the examination, rescue medications indicated for children, resuscitation equipment, oxygen, etc., as well as the proper medical environment and staff to deal with an unexpected accident, must be available. ## Infusion of radiopharmaceuticals Vascular access should be secured well in advance to make the best use of the limited examination time. If it is planned to administer a sedative, vascular access should be secured before the administration. After administration of the radiopharmaceutical through the intravenous line, a small amount may remain in the three-way stopcock or the syringe that was used, and the residual amount should be washed or flushed with an adequate volume of saline. Careful attention should be paid to the infusion of smallvolume radiopharmaceuticals and Tc-99m-MAA, which adheres to the walls of the tubes or syringe. For the measurement of the administered activity, a properly calibrated dose calibrator should be used. ## Restraining body motions Keeping children at rest during the examination is critical and ways must therefore be devised to restrain body motions. Some children fall asleep in a quiet examination room with dim lights. For immobilization, soft (for infants) or hard (for schoolchildren) Velcro fasteners, or elastic bandages of different widths may be used to maintain the positioning of the patients during lengthy examinations, without applying excessive pressure. The clearances between adjoining sites of the body should be secured by placing towels between the arm or leg and the trunk, to facilitate the correct interpretation of the images. Sometimes, immobilization is counterproductive. In children who can understand to some extent, allowing them to watch their favorite video program or to hold a favorite toy or stuffed animal may help to distract and relax them. ## Sedation and anesthesia If immobilization using the above-mentioned tips is not sufficient to restrain body motions, sedation or anesthesia may be necessary. Since sedation and anesthesia are somewhat invasive, their justification and optimization should be considered, as with the use of radiopharmaceuticals. The staff involved in imaging examinations must monitor the child for respiratory depression or misswallowing from the time of sedation or anesthesia until the end of the examination, and ask the concerned staff to continue careful observation of the child after the examination is over. Participation of an anesthesiologist in the imaging team may be considered [bib_ref] Nuclear medicine in the first year of life, Treves [/bib_ref]. # Equipment and analysis Optimal imaging of children requires special considerations for the appropriate choices of equipment, image acquisition and analytical methodologies. The dose of the radiopharmaceutical conventionally used at the institution should be compared with the dose proposed by the guidelines and the acquisition conditions may be re-determined. Especially for examinations with limitations of the acquisition time and timing, such as dynamic imaging and SPECT, prior evaluation of the acquisition protocols is important. In addition to changes in the acquisition time and pixel size, the choice of an appropriate collimator is critical. To detect detailed abnormalities, a high-resolution collimator may be the most appropriate, even if a slightly longer imaging time is required. To acquire a less noisy image during a limited time, on the other hand, a high-sensitivity collimator may be a good choice. An appropriate collimator is not only selected based on the visual quality of the image, but also on the ability to detect abnormal findings or the feasibility of diagnosis. For SPECT imaging of a small child, the detectors cannot get close to the patient on an imaging bed designed for adults. The use of a narrow bed that is specially designed for children may be preferable. To examine small organs, the acquisition of magnified images can help with image interpretation. The magnification of an image, however, reduces the information density, resulting in deterioration of the image quality and thereby requiring a longer acquisition time. If body motions of patients cannot be properly restrained, the use of motion correction programs or the need for reacquisition may be considered after the linogram/sinogram has been reviewed. However, motion correction programs should not be overestimated and if large or frequent body motions are observed, reacquisition should be made. Processing of inappropriate data including body motions, which may lead to a misdiagnosis, should be avoided. To handle lower radiation exposure to children and shorter imaging time, the use of an advanced reconstruction method should also be considered. Filtering of images, 3D-OSEM (ordered-subset expectation maximization), which is known to reduce statistical noise, and corrections of scatter, attenuation and resolution are helpful to improve image quality. The equipment to be used has to be checked periodically and they should be adequately maintained and managed. If natural aging degradation of the imaging system such as its sensitivity and uniformity is noted and appropriate imaging is considered to be impossible, prompt renewal of the equipment should be considered. The administered doses of radiopharmaceuticals should not be increased to compensate for the deterioration of equipment. ## Handling of urination Imaging examinations of children should start after a diaper change or urination. Incomplete urination may cause body motions due to the urge to urinate and cause obscuration of the targeted site due to a full bladder. If spontaneous urination is incomplete or urinary incontinence during imaging is expected, a balloon catheter may be introduced beforehand. The catheter should be covered with a lead plate during imaging to avoid including unnecessary signals in the image due to the urinary catheter. Even if a balloon catheter is placed, not all urine may be discharged through the catheter, and some urine may leak between the urethra and the catheter, causing contamination of diapers and the body surface with urine. Although many schoolchildren are able to spontaneously discharge urine, and urine in the bladder is less likely to affect the image quality, some children may feel the need to urinate sooner due to excessive nervousness, resulting in discontinuation of the examination. Most radiopharmaceuticals are excreted into the urine. Therefore, the bladder wall is the most exposed to radiation in general. Voiding prompted by adequate hydration and continuous urinary drainage with a balloon catheter are preferable to reduce radiation exposure. Frequent diaper changing may be helpful to reduce radiation exposure to the gonads [bib_ref] Visual pediatric nuclear Medicine, Yano [/bib_ref]. ## Spect/ct and pet/ct Although additional CT images may improve the diagnostic performance of SPECT or PET alone, the use of SPECT/CT or PET/CT should be determined after considering the increase in radiation exposure from CT scans. The unnecessary creation of high-resolution CT images should then be avoided, and radiation exposure from CT scans should be minimized by effectively using exposure reduction techniques. [table] Table 1: Class and baseline activity/minimum activity of radiopharmaceuticals An excessive dose may be calculated of a heavy patient compared to the conventionally administered dose; therefore, a smaller dose should be considered since this dose is the maximum b Both the rest first and the stress first protocols are applicable. The second dose is two to three times the first dose [/table] [table] Table 2: Weight-dependent multiples for each class [/table]	None	https://link.springer.com/content/pdf/10.1007%2Fs12149-014-0826-9.pdf	None
668a2e0fd636feaccdf48679bd5f27a4e177fa7e	pubmed	A new decision tree for diagnosis of osteoarthritis in primary care: international consensus of experts	A new decision tree for diagnosis of osteoarthritis in primary care: international consensus of experts Background and aims Although osteoarthritis (OA) is managed mainly in primary care, general practitioners (GPs) are not always trained in its diagnosis, which leads to diagnostic delays, unnecessary resource utilization, and suboptimal patient outcomes. Methods To address this situation, an International Rheumatologic Board (IRB) of 8 experts from 3 continents developed guidelines for the diagnosis of OA in primary care. The focus was three major topologies: hip, knee, and hand/finger OA. The IRB used American College of Rheumatology diagnostic criteria. Results Care pathways based on clinical and radiological findings were developed to identify intervention thresholds for GPs/specialists. To optimize usefulness in the primary care setting, the guidelines were formatted as an uncomplicated, but comprehensive one-page decision tree for each topology, highlighting key aspects of the evaluation process and incorporating red flags. In a two-phase validation stage, the draft guidelines were evaluated by rheumatologists and GPs for project execution, content and perceived benefit. The strength of the guidelines lies in their user-friendly diagram and potential for broad application. Such guidelines will allow GPs to make an easy but definite diagnosis of OA and offer clear guidance about situations requiring an expert opinion. The guidelines have potential to improve patient outcomes and reduce the number of unnecessary procedures.Discussion and conclusionsThis project demonstrated the feasibility of developing easy-to-use and effective visual decision trees to facilitate the diagnosis and management of OA of the hip, knee and hand/finger in primary care. The next step should be to conduct a large impact study of implementation of these recommendations in the diagnostic management of OA in general practice in different areas. # Introduction Osteoarthritis (OA) is the most common form of arthritis and a leading cause of pain and disability worldwide [bib_ref] Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and..., Vos [/bib_ref] [bib_ref] The global burden of hip and knee OA: estimates from the global..., Cross [/bib_ref] [bib_ref] OA: Models for appropriate care across the disease continuum, Allen [/bib_ref]. The most frequently affected peripheral joints are the hip, knee and hand/finger [bib_ref] Epidemiology and burden of OA, Litwic [/bib_ref]. Risk factors for OA include sex, previous joint injury, obesity and metabolic syndrome, genetic predisposition, mechanical factors such as malalignment or abnormal joint shape, and advancing age [bib_ref] OA: a disease of the joint as an organ, Loeser [/bib_ref] [bib_ref] Ageing and the pathogenesis of OA, Loeser [/bib_ref]. Long regarded as a "degenerative wear and tear" condition, OA is increasingly being recognised as a dynamic joint pathological process caused by destruction and repair for which treatment interventions can be applied. In 2012, the World Health Organization (WHO) reported that OA is the single most common cause of disability in older adults [bib_ref] (eds) Priority medicines for Europe and the world-2013 update, Wittenauer [/bib_ref]. Worldwide, an estimated 10% of men and 18% of women over 60 years of age have symptomatic OA; approximately 80% of these have movement limitations and 25% are unable to perform major activities of daily living. With the global increase in the older population, the prevalence of diseases such as OA will also increase. Indeed, by the year 2050, the WHO estimates that 130 million people will have OA and 40 million will be severely disabled by OA [bib_ref] (eds) Priority medicines for Europe and the world-2013 update, Wittenauer [/bib_ref]. OA is a frequent cause of healthcare consultations. In France, for example, on an annual basis, OA is responsible for approximately 9 million consultations, 14 million prescriptions and 300,000 radiological examinations [http:// www.stop-arthr ose.org]. In 2010, the total direct costs for treating all patients with OA in France was estimated at about €3 billion per year [bib_ref] Annual cost of patients with OA of the hip and knee in..., Bertin [/bib_ref] , which emphasizes the burden of the disease to healthcare systems and to society in general. The burden of OA includes not only physical impairment [bib_ref] Determinants of physical functioning in women with knee OA, Nur [/bib_ref] and its associated costs but also psychological impairment (e.g., distress, devalued self-worth) [bib_ref] Epidemiology and burden of OA, Litwic [/bib_ref]. OA plays a prominent role in multimorbidity, which has been shown to reduce quality of life [bib_ref] Quality of Life assessment in musculo-skeletal health, Beaudart [/bib_ref] and to increase work disability, treatment burden and healthcare costs [bib_ref] The contribution of musculoskeletal disorders in multimorbidity: implications for practice and policy, Duffield [/bib_ref]. The disease is also associated with a higher risk of mortality, estimated to be increased by 1.5 in hip and knee OA [bib_ref] All cause and disease specific mortality in patients with knee or hip..., Nüesch [/bib_ref] [bib_ref] The impact of musculoskeletal diseases on mortality-comparison with internal diseases: a 15-year..., Kasai [/bib_ref]. Despite the availability of evidence-based treatment guidelines for OA [bib_ref] An algorithm recommendation for the management of knee OA in Europe and..., Bruyere [/bib_ref] , large gaps remain in the overall quality of care. According to patients, pain is generally insufficiently considered and managed [bib_ref] Analgesic use for knee and hip OA in community-dwelling elders, Marcum [/bib_ref] [bib_ref] Pain relief in OA: patients' willingness to risk medication-induced gastrointestinal, cardiovascular, and..., Richardson [/bib_ref]. Diagnostic procedures are often inconsistent, and behavioural and rehabilitative strategies to prevent and treat OA are generally underutilized [bib_ref] OA: Models for appropriate care across the disease continuum, Allen [/bib_ref]. Uptake of core non-pharmacological measures such as weight loss and exercise programmes tends to be low, especially in older patients (> 65 years of age) even if these treatment modalities have no severe side effects [bib_ref] Uptake of the NICE OA core treatments in community dwelling older adults..., Healey [/bib_ref]. Besides experiencing pain and loss of function, patients may be frustrated because their disease is not being taken seriously [bib_ref] OA: Models for appropriate care across the disease continuum, Allen [/bib_ref] [bib_ref] Comparison of patient experiences of the OA consultation with GP attitudes and..., Paskins [/bib_ref] [bib_ref] A systematic review and evidence synthesis of qualitative studies to identify primary..., Egerton [/bib_ref]. A Cochrane systematic review suggested that interventions such as improving general practitioner (GP) training regarding OA pain and use of influential physicians may increase guideline-consistent behaviour and improve patient outcomes [bib_ref] Professional interventions for general practitioners on the management of musculoskeletal conditions, Brown [/bib_ref]. Therefore, we need to establish guidelines for the diagnosis of OA in the primary care setting, taking into account barriers to implementing the guidelines as well as possible solutions to overcome these barriers [bib_ref] Mexican Clinical Practice Guideline recommendations for the management of hip and knee..., Loyola-Sanchez [/bib_ref] [bib_ref] OA guidelines: barriers to implementation and solutions, Ferreira De Meneses [/bib_ref] [bib_ref] Australian general practitioner attitudes to clinical practice guidelines and some implications for..., Basedow [/bib_ref]. Surprisingly, the OA scientific community had developed several guidelines for OA treatment before establishing clear recommendations for OA diagnosis. This paradox must be changed. # Methods ## Expert panel ## Guideline development process The guidelines development initiative was a multistage process. In the first stage, the IRB identified and agreed on OA phenotypes and diagnostic criteria and developed preliminary care pathways for managing OA within the context of a primary care consultation. The draft guidelines subsequently underwent a two-stage validation process. The first stage involved evaluation of the project by 41 rheumatologists. Rheumatologists from across France who worked in hospitals and/or private practice and with known expertise in managing OA were invited to participate in a reading committee. Questionnaires were used to capture rheumatologists' opinions on all aspects of the project, including the project execution process, guideline content, and perceived benefit and value of the guidelines. After incorporating rheumatologists' feedback, a second validation phase was undertaken with 20 GPs in tandem with one of the author. Two meetings were held, one in Toulouse and one in Versailles (both in France). Study Coordinator Dr Pierre Monod and IRB member Professor François Rannou were present at both meetings. A 54-item questionnaire has been developed during two physical meetings of the IRB in Paris with the help of CLI-NACT, a French society independent from Pierre Fabre, and expert in clinical research. A 54-item questionnaire was used to capture the GPs' level of agreement on the overall usefulness of the project and the content, ease of use and benefits of the guidelines and their practicality for use in daily practice. GPs were invited to propose amendments to the guidelines and provide any additional comments. # Results ## Establishing the need for guidelines The need to establish guidelines for the diagnosis of OA in primary care arose from recognising that diagnostic uncertainties exist in this setting and that GPs have limited time to devote to a chronic disease with few effective management solutions. In everyday practice, GPs may be unsure about when to refer patients, often for fear of "bothering" specialists with a "simple" case of OA. Some patients are referred for unnecessary examinations, others at a late stage, and others who could receive primary care. Management delays represent a missed opportunity for the patient and can result in suboptimal outcomes. Moreover, many patients with OA are dissatisfied with their disease burden and with the attitude of "inevitability and fatalism" often held by care providers. The IRB deemed that such guidelines would allow GPs to make an easy but definite diagnosis of OA and offer clear guidance about situations requiring expert opinion. This objective would have potential to improve patient outcomes and reduce the number of unnecessary referrals or procedures. The guideline development process was validated by the rheumatologist reading committee based on unanimous agreement that early diagnosis of patients with suspected OA needs to be improved (100%) and that improved management would reduce the prescription of unnecessary supplementary examinations such as knee MRI and vascular Doppler (100%). Despite general good agreement by participating rheumatologists that not all patients with suspected OA need to be seen by a specialist, there was some reluctance by rheumatologists to be excluded from the care of these patients, particularly during treatment initiation/optimisation (14.8%). The GPs agreed unanimously that OA assessment must be improved in primary care (100%) and that the board's procedure was beneficial (100%) and useful (100%). ## Establishing phenotypes The main reasons for performing disease phenotyping are to identify specific treatment solutions and monitor the progression of the phenotype over time to adapt management. To this end, the IRB identified four main OA phenotypes: - Inflammatory OA - Mechanical OA: trauma, dysplasia, misalignment, overweight and obesity, hypermobility - Early-onset OA - Systemic OA: metabolic, microcrystals, hormonal, micro-inflammation These phenotypes were applied to the three most common peripheral OA localizations: hip, knee, and hand/finger. There was agreement within the IRB to exclude OA of the spine from the project. ## Diagnostic criteria, care pathways and red flags by oa topography: main amendments recommended by rheumatologists and gps ## Diagnostic criteria The IRB used American College of Rheumatology (ACR) diagnostic criteria [bib_ref] Development of criteria for the classification and reporting of OA. Classification of..., Altman [/bib_ref] to develop simple definitions to characterize patients who present in primary care with pain in the hip, knee or hand/finger. For each affected joint, a diagnosis of OA can be made on the basis of joint pain, age over 50 years, and the presence of joint space narrowing and/ or osteophyte(s) on plain radiographs, which is the current standard imaging modality in clinical practice for diagnosing and monitoring OA. Other diagnostic criteria suggested by the rheumatologist reading committee were mainly a physical examination (12.2%) and radiographic assessment (12.2%). The committee also highlighted the need to further elaborate the characteristics of pain. Although most rheumatologists (78.1%) were of the opinion that specialist assessment was not necessary once a diagnosis was made, notable exceptions were for differential diagnosis (22.0%) and cases of ineffective treatment or need for local treatment (14.9%). After reviewing rheumatologists' feedback, the IRB took a considered decision not to amend the diagnostic criteria so as to avoid delaying diagnosis and complicating initial management. The definition "abnormal pain of an intensity and duration that would be considered unusual for this disease" was refined by describing intensity (visual analogue scale [VAS] score > 7] and duration (longer than 10 days). The qualifier "magnetic resonance imaging (MRI) is not indicated" was added to the diagnostic criteria for knee pain. ## 3 The GPs unanimously agreed that the diagnostic criteria for hip, knee and hand/finger pain were satisfactory (100%) and relevant to primary practice (100%). The GPs also requested greater clarification of the terms "rapidly destructive coxarthrosis (RDC)" and labral anomalies, possibly in an Appendix to the guidelines. ## Diagnostic algorithm of hip oa in primary care Guidelines for OA of the hip are presented in . The preliminary diagnostic criteria for OA of the hip are hip pain and radiographic joint space narrowing and/ or osteophytes. Additional investigations ## - age In patients ≤ 50 years of age, investigate an architectural defect (dysplasia, labrum). If present, seek expert opinion. In patients > 70 years of age, primary care management. In patients 50 to 70 years of age, investigate the remaining diagnostic criteria in a stepwise fashion. ## - pain For joint pain of abnormal intensity and/or duration, consider the presence of RDC or a subchondral bone microfracture →red flag. If present, seek expert opinion urgently. If joint pain is not of abnormal intensity and/or duration, proceed to the next criterion. ## - morphological anomalies In the absence of morphological anomalies on plain radiographs, manage the OA in primary care. If morphological anomalies are present on plain radiographs, refer the patient for expert opinion. Guidelines for the diagnostic management of hip pain in primary care. Explanatory terminology and acronyms: Abnormal pain: pain of an intensity or duration that is unusual for OA of the hip ; VAS score > 7 or duration longer than 10 days. RDC: rapidly destructive coxarthrosis or microfracture of the subchondral bone responsible for nocturnal pain and limping for which the only effective treat-ment is unloading body weight from the limb. Labral abnormalities: joint pain sometimes occurring with no radiographic or ultrasound abnormality, most common in young and/or athletic patients, requiring a specialist opinion. Situations requiring urgent expert opinion are denoted by red typeface ## Diagnostic algorithm of knee oa in primary care Guidelines for OA of the knee are presented in [fig_ref] Figure 2: Guidelines for the diagnostic management of knee pain in primary care [/fig_ref]. Preliminary diagnostic criteria for OA of the knee are a patient presenting knee pain, > 50 years of age, and radiographic joint space narrowing and/or osteophyte(s) shown on a radiograph performed within the previous 6 months [bib_ref] Concordance between clinical and radiographic evaluations of knee OA, Parsons [/bib_ref] and MRI is not indicated for the first-line diagnosis of knee OA. Associated metabolic/inflammatory syndrome must always be screened. Additional investigations ## - effusion The presence of effusion is a red flag. Puncture and drainage of the knee is required, with fluid analysis. The patient is to be referred for expert opinion. In the absence of effusion, proceed to the next criterion. ## - pain If "abnormal", unusual, or intense pain is present on examination, refer the patient for expert opinion. If pain is absent, manage the condition in primary care. In the event of recurrent pain or loss of efficacy of NSAIDs (i.e., disease progression), refer the patient for expert opinion. ## Diagnostic algorithm of hand/finger oa in primary care Guidelines for OA of the hand/finger are presented in [fig_ref] Figure 3: Guidelines for the diagnostic management of hand/finger pain in primary care [/fig_ref]. Preliminary diagnostic criteria for hand/finger OA are hand/finger pain, radiographic osteophyte with or without joint space narrowing, and a family history of hand/finger OA. ## Additional investigations If the patient is female, < 50 years of age, and non-menopausal, refer for an expert opinion. For all other clinical situations, proceed to the next criterion. The presence of swelling, isolated metacarpophalangeal joint pain, psoriasis, or several joints affected or persistent pain are red flags. If present, refer the patient for expert opinion. If absent, examine the patient clinically for the site of pain and presence of deformity. Interphalangeal OA must be distinguished from base-ofthe-thumb OA because of their different physiopathogenesis. Although the severity of hand/finger OA is defined by the number of affected joints, no consensus was reached on cut-off points (i.e., number of joints required) to establish grades of severity. ## Key aspects of the validation process informing the development of the guidelines Globally, the rheumatologist reading committee considered the proposed recommendations for diagnostic management of hip, knee and hand OA in primary care to be logical, easy to understand, and with well positioned GP/specialist thresholds guided by useful red flags. The main amendments proposed for managing hip pain were to include additional red flags (functional impact, inflammatory pain, inflammatory syndrome) to be more exhaustive. The rheumatologists confirmed that MRI is not indicated for the diagnosis of knee OA and should not be prescribed. Many rheumatologists (78.1%) agreed with the concept of a more rapid referral of patients presenting hand/finger joint pain. Nearly three-quarters (73.2%) of the group agreed with the IRB's recommendation that a polyarticular condition warrants an immediate signal alert and proposed to set a severity threshold at 2 or 3 or more affected joints. However, no consensus was reached on this issue. There was consensus or strong agreement among GPs on key aspects of the care pathways for OA of the hip, knee and hand/finger. The GPs declared that selected entry points met expectations, that specialist intervention thresholds were well positioned with clinically relevant red flags, and that the guidelines would improve the management of OA of the hip, knee and hand/finger in primary practice. Main comments put forward by GPs about the guidelines for diagnostic management of hip pain centred on identifying strategies to improve their knowledge of RDC and recognising that not all GPs can identify an architectural defect. In terms of the guidelines for diagnostic management of knee OA, the GPs commented that the proposed care pathway is compromised by prolonged waiting times for specialist appointments, that systematic effusion puncture is not always possible in primary care, and that insufficient emphasis is placed on OA of the knee in patients < 50 years of age, which is commonly encountered in primary care. The GPs emphasized the usefulness of guidelines in terms of educating patients that MRI is unnecessary for first-line diagnosis and management of OA of the knee and expressed considerable interest about their role in screening for associated metabolic syndrome. Although the diagnostic guidelines for hand/finger pain were considered simpler and more useful than those for hip and knee pain because of entry into care pathways via red flags, the GPs were uncertain as to the justification for some of the red flags. A proposal advanced was to include screening for haematochromatosis for isolated metacarpophalangeal joint disease. # Discussion Many clinical practice guidelines are available for managing OA in primary care. Some examples include guidelines from the European Society for Clinical and Economic Aspects of Osteoporosis and OA [bib_ref] An algorithm recommendation for the management of knee OA in Europe and..., Bruyere [/bib_ref] , the American Academy of Orthopedic Surgeons [bib_ref] AAOS clinical practice guideline: treatment of OA of the knee: evidence-based guideline,..., Brown [/bib_ref] , ACR [bib_ref] American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and..., Hochberg [/bib_ref] , Chinese Orthopedic Association, European League Against Rheumatism [bib_ref] EULAR evidence based recommendations for the management of hand OA-report of a..., Zhang [/bib_ref] [bib_ref] Standing Committee for International Clinical Studies Including Therapeutic Trials ESCISIT. EULAR Recommendations..., Jordan [/bib_ref] , National Institute for Health and Clinical Excellenceand OA Research Society International [bib_ref] OARSI guidelines for the non-surgical management of knee OA, Mcalindon [/bib_ref]. Despite the uniformly high quality of these guidelines, their implementation in clinical practice has been low [bib_ref] OA guidelines: barriers to implementation and solutions, Ferreira De Meneses [/bib_ref]. Barriers to guideline implementation are complex and multifactorial, ranging from evidence limitations and human behaviour to presentation in an inappropriate format to the end user [bib_ref] Mexican Clinical Practice Guideline recommendations for the management of hip and knee..., Loyola-Sanchez [/bib_ref] [bib_ref] OA guidelines: barriers to implementation and solutions, Ferreira De Meneses [/bib_ref]. As a rule, primary care physicians prefer shorter formats, such as flowcharts or algorithms and single-page checklists, over longer formats [bib_ref] Australian general practitioner attitudes to clinical practice guidelines and some implications for..., Basedow [/bib_ref]. The strengths of the IRB's guidelines for diagnosis of OA in primary care lie in their user-friendly diagrams. A diagnosis of OA can be confirmed by the presence of three simple ACR criteria without the need to seek specialist opinion or perform further investigations. The care pathways map a logical approach to managing the diagnosed patient, incorporating only strictly necessary physical examinations, clinical criteria, and specialist intervention thresholds into the management algorithm. The convenient and informative one-page graphical format is designed to facilitate normal work flow in primary care and lends itself to future integration into prescribing software. Moreover, the guidelines have been developed by an international panel of experts for application across a wide range of countries and healthcare systems. The purpose of developing guidelines for the diagnosis of OA in primary care was to provide GPs with an easy and effective tool to facilitate the diagnosis of OA and to improve care of the diagnosed patient. To ensure the exhaustiveness of the clinical situations addressed in our guidelines, validate their content and confirm their utility in the primary care setting, the project execution process was iterative, informed in two separate stages with feedback after evaluation by rheumatologists and primary care physicians. Although the reading committee approved the justification for developing guidelines to improve the diagnosis of OA in primary care (i.e., to improve patient care) and acknowledged the importance of GP involvement, some concerns were raised about GPs' level of knowledge in certain areas (e.g., their ability to differentiate joint pain from tendinitis and to interpret radiographs) and about removing the rheumatologist from the centre of patient care, especially for situations such as the differential diagnosis and progressive disease. There were some reservations about excluding OA of the spine and some support for developing guidelines for OA of the ankle, foot and shoulder. The simple bases for diagnosing OA also drew some criticism. In particular, a frequent comment was that pain should be investigated in more detail in terms of type, site and nature (referred, mechanical or inflammatory). The guidelines were well received by GPs who were in strong agreement about their ease of use, potential benefit and practicality for diagnosing and managing OA of the hip, knee, or hand/finger in primary care. The three selected OA sites were considered relevant, although the shoulder was mentioned as another site to consider. A consistent finding during the GP validation stage was that for each of the OA sites, less than half of the group believed that the guidelines reflected current clinical practice, whereas most of the group believed that these guidelines would improve the diagnostic management of OA. The inference is that current practice may be suboptimal and that our guidelines have the potential to improve current practice, which is a core objective of any guideline development initiative. During the course of evaluation, the GPs identified certain areas in which they may be lacking expertise (e.g., diagnosis of RDC, identification of an architectural defect). Such insight is valuable in terms of informing continuing education programmes and other activities aimed at upskilling primary care physicians. The feedback received after consultation with rheumatologists and GPs validated most aspects of these guidelines and 1 3 informed several important amendments. The relatively minor changes to the diagnostic criteria from the first draft to the final version confirmed the decision to use the validated ACR criteria. Specifying the intensity and duration of hip and knee pain that would be considered unusual for the setting was a small but important change that eliminated ambiguity and has the potential to limit referrals to the neediest cases. Transferring the responsibility for caring for patients > 70 years of age without abnormal pain and morphological anomalies from specialist care to primary care reflects not only the global trend in population ageing (and associated increase in the prevalence of OA) but also the general better health and well-being of older individuals as compared with previous generations. Significant cost-savings might be expected to accrue from caring for otherwise healthy older adults with OA of the hip in primary care. An important element of the care pathway for OA of the knee is the indication to systematically screen patients for the presence of metabolic/inflammatory syndrome (fasting glucose, lipid profile, overweight, hypertension). Such screening is common and appropriate in primary care and can identify modifiable risk factors for a wide range of diseases. The addition of "MRI is not indicated" in the diagnostic criteria for suspected OA of the knee was highly valued by GPs as a means of educating patients that MRI is not necessary for a first-line diagnosis. This subtle yet strong message has potential to generate significant time and cost-savings and is consistent with objectives to expedite diagnoses and eliminate unnecessary examinations [bib_ref] EULAR recommendations for the use of imaging in the clinical management of..., Sakellariou [/bib_ref]. The guideline development project has several limitations. Among 665 rheumatologists invited to participate in the reading review, only 41 (6.2%) returned the questionnaire. The main reasons for not participating were lack of time, the voluntary aspect of survey, and a general lack of interest in studies or surveys. Thus, although the reading committee was in reasonably strong agreement about the benefit of the proposed recommendations, this low response incorporates a degree of bias because it reflects the opinion of only those rheumatologists with an interest in the subject and who agreed to participate. It might be assumed that their participation was linked to this particular interest in the subject and to the issues covered by the recommendations. Another limitation was the modest number of GPs who participated in the validation phase (n = 13), so the representativeness of the sample cannot be guaranteed. A larger validation study would help ensure the validity of our guidelines and might be useful to promote their wide use. Although OA can occur in any joint, the guidelines cover only the three major peripheral topographies. This was recognised as a limitation by the rheumatologists and GPs who suggested other sites (e.g., spine, shoulder) that could benefit from expert guidance. Finally, we acknowledge that the guidelines provide limited recommendations for treatment approaches, pharmacological, non-pharmacological and other (e.g., lifestyle advice); however, (1) this was not the primary aim of our work and (2) this compromise was deemed necessary to keep within the one-page format and is compensated to some degree by the user-friendly interface showing essential GP/specialist intervention thresholds. # Conclusions This guidelines project has demonstrated the feasibility of developing easy-to-use and effective visual decision trees to facilitate the diagnosis of OA of the hip, knee and hand/finger in primary care. The next step should be to conduct a large impact study of implementation of these recommendations in the diagnostic management of OA in general practice in different areas. ## 3 ## Appendix : evaluation of the process [fig] Figure 2: Guidelines for the diagnostic management of knee pain in primary care. Knee radiographs proposed in accordance with the French classification of procedures: anteroposterior weight-bearing, 0° and 30° flexion, profile and 30° flexion skyview (femoro-patellar view). Abnormal pain: pain of an intensity or duration that is unusual for OA of the knee; VAS score > 7 or duration longer than 10 days. Metabolic/inflammatory syndrome assessment: fasting glucose, investigation of an abnormal lipid profile, BMI/overweight, arterial hypertension. NSAIDs: non-steroidal anti-inflammatory drugs. Situations requiring urgent expert opinion are denoted by red typeface [/fig] [fig] Figure 3: Guidelines for the diagnostic management of hand/finger pain in primary care. IP: interphalangeal; MCP: metacarpophalangeal. Situations requiring urgent expert opinion are denoted by red typeface [/fig]	None	https://link.springer.com/content/pdf/10.1007/s40520-018-1077-8.pdf	None
4b83e9b7c38673a62bd8d9b3951b18bf98a1363e	pubmed	Vitamin D supplementation in the prevention and management of major chronic diseases not related to mineral homeostasis in adults: research for evidence and a scientific statement from the European society for clinical and economic aspects of osteoporosis and osteoarthritis (ESCEO)	Vitamin D supplementation in the prevention and management of major chronic diseases not related to mineral homeostasis in adults: research for evidence and a scientific statement from the European society for clinical and economic aspects of osteoporosis and osteoarthritis (ESCEO) mechanistic studies, large cohort studies, and small clinical trials obtained for autoimmune diseases (including type 1 diabetes, multiple sclerosis, and systemic lupus erythematosus), cardiovascular disorders, and overall reduction in mortality require further confirmation. # Abstract Introduction Optimal vitamin D status promotes skeletal health and is recommended with specific treatment in individuals at high risk for fragility fractures. A growing body of literature has provided indirect and some direct evidence for possible extraskeletal vitamin D-related effects. ## Purpose and methods members of the european society for clinical and economic aspects of osteoporosis and Osteoarthritis have reviewed the main evidence for possible proven benefits of vitamin D supplementation in adults at risk of or with overt chronic extra-skeletal diseases, providing recommendations and guidelines for future studies in this field. Results and conclusions Robust mechanistic evidence is available from in vitro studies and in vivo animal studies, usually employing cholecalciferol, calcidiol or calcitriol in pharmacologic rather than physiologic doses. Although many cross-sectional and prospective association studies in humans have shown that low 25-hydroxyvitamin D levels (i.e., <50 nmol/L) are consistently associated with chronic diseases, further strengthened by a dose-response relationship, several meta-analyses of clinical trials have shown contradictory results. Overall, large randomized controlled trials with sufficient doses of vitamin D are missing, and available small to moderate-size trials often included people with baseline levels of serum 25-hydroxyvitamin D levels >50 nmol/L, did not simultaneously assess multiple outcomes, and did not report overall safety (e.g., falls). Thus, no recommendations can be made to date for the use of vitamin D supplementation in general, parental compounds, or non-hypercalcemic vitamin D analogs in the prevention and treatment of extra-skeletal chronic diseases. Moreover, attainment of serum 25-hydroxyvitamin D levels well above the threshold desired for bone health cannot be recommended based on current evidence, since safety has yet to be confirmed. Finally, the promising findings from Introduction Adequate vitamin D status is undoubtedly necessary for the maintenance of optimal mineral and skeletal homeostasis, as well as for the prevention and cure of secondary hyperparathyroidism, rickets and osteomalacia [bib_ref] Serum 25-hydroxyvitamin D Levels: variability, knowledge gaps, and the concept of a..., Fuleihan [/bib_ref]. The measurement of serum levels of 25-hydroxyvitamin D [25(OH)D] is used both to determine vitamin D status and to estimate the benefit of vitamin D supplementation [bib_ref] Benefit-risk assessment of vitamin D supplementation, Bischoff-Ferrari [/bib_ref]. According to different guidelines, the thresholds for serum 25(OH)D have been set at 50 or 75 nmol/l (i.e., 20 or 30 ng/ml) for bone health [bib_ref] Guidelines for preventing and treating vitamin D deficiency and insufficiency revisited, Holick [/bib_ref] [bib_ref] IOM committee members respond to Endocrine Society vitamin D guideline, Rosen [/bib_ref] [bib_ref] Vitamin D supplementation in elderly or postmenopausal women: a 2013 update of..., Rizzoli [/bib_ref] [bib_ref] A pooled analysis of vitamin D dose requirements for fracture prevention, Bischoff-Ferrari [/bib_ref]. Levels of 25(OH)D beyond these thresholds do not appear to confer additional benefits for mineral homeostasis [bib_ref] Serum 25-hydroxyvitamin D Levels: variability, knowledge gaps, and the concept of a..., Fuleihan [/bib_ref] [bib_ref] Monthly high-dose Vitamin D Treatment for the prevention of functional decline: a..., Bischoff-Ferrari [/bib_ref]. According to international recommendations, vitamin D status has to be determined in subjects at risk for disorders of bone and mineral metabolism [bib_ref] Guidelines for preventing and treating vitamin D deficiency and insufficiency revisited, Holick [/bib_ref] [bib_ref] Vitamin D supplementation in elderly or postmenopausal women: a 2013 update of..., Rizzoli [/bib_ref]. Nonetheless, the wide availability of 25 (OH)D commercial assays has caused the requests for the assessment of vitamin D status to increase markedly in recent years and, according to the above-described thresholds, many subjects have been defined as vitamin D deficient [bib_ref] Worldwide vitamin D status, Van Schoor [/bib_ref]. Alternatively, current recommendations of the International Osteoporosis Foundation with 600 IU per day in younger and middle aged adults and 800 IU per day in older adults ensure that over 97% of individual reach a replete vitamin D status with 20(OH)D levels of 20 ng/ml [bib_ref] Benefit-risk assessment of vitamin D supplementation, Bischoff-Ferrari [/bib_ref] [bib_ref] Dose response to vitamin D supplementation in postmenopausal women: a randomized trial, Gallagher [/bib_ref]. Nonetheless, while this mainly applies to the North American individuals, it might not apply to populations that do not usually fortify their foods with vitamin D thus displaying lower vitamin D levels [bib_ref] Benefit-risk assessment of vitamin D supplementation, Bischoff-Ferrari [/bib_ref]. Several reports have shown that vitamin D deficiency is associated with an array of chronic diseases [bib_ref] Non-musculoskeletal benefits of Vitamin D, Wimalawansa [/bib_ref] [bib_ref] Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects, Christakos [/bib_ref]. Yet, the causal effect of low serum levels of 25(OH)D on the onset and progression of diseases that are unrelated to mineral homeostasis, has yet to be demonstrated in large clinical trials. Most evidence is still based on observational studies [association with ultraviolet B radiation (UVB) exposure, 25(OH)D levels] [bib_ref] Non-musculoskeletal benefits of Vitamin D, Wimalawansa [/bib_ref] [bib_ref] Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects, Christakos [/bib_ref]. Large, randomized controlled clinical trials assessing the benefits of sufficient dose of vitamin D supplementation on different chronic diseases outside the skeleton as primary endpoints are still lacking, and no specific thresholds have been defined in this field for each different effect. Notably, meta-analyses have limitations because of the selection of studies, quality of endpoint assessment, analytical aspects and interpretation of the results [bib_ref] Vitamin D and multiple health outcomes: umbrella review of systematic reviews and..., Theodoratou [/bib_ref] [bib_ref] The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes, Bischoff-Ferrari [/bib_ref]. Moreover, there is still much uncertainty whether achieving values of serum 25 (OH)D greater than the recommended thresholds may lead to any benefit in overall health [bib_ref] Monthly high-dose Vitamin D Treatment for the prevention of functional decline: a..., Bischoff-Ferrari [/bib_ref] [bib_ref] The nonskeletal effects of vitamin D: an endocrine society scientific statement, Rosen [/bib_ref]. Nonetheless, assessment of vitamin D status and vitamin D supplementation are nowadays widely prescribed by different specialists and general practitioners for a variety of chronic conditions not classically linked to mineral and bone metabolism abnormalities [bib_ref] Changing patterns of prescription in vitamin D supplementation in adults: analysis of..., Cianferotti [/bib_ref]. Members of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, along with experts in the field of vitamin D, convened a meeting in February 2016 to broadly review the main evidence for possible proven benefits of vitamin D supplementation in adults at risk of or with overt chronic extra-skeletal diseases, providing recommendations and guidelines for future studies in this field. Therefore, the aims of this paper were: to summarize and highlight the main available evidence of vitamin D-related extraskeletal benefits, reviewed in detail elsewhere, mainly ensuing from systematic reviews of large cohort data, small randomized controlled trials (RCTs), and meta-analyses of clinical trials; to give recommendations for clinical practice; to issue the research agenda on the possible advantages of vitamin D treatment on extra skeletal chronic diseases, focusing on cardiovascular diseases and overall mortality, diabetes mellitus, main autoimmune diseases, and cancer. ## Molecular rationale (mechanistic data) for possible extraskeletal vitamin d-mediated effects The biologically active form of vitamin D, calcitriol [1,25 (OH) 2 D], is a multifunctional steroid hormone produced by the kidney [fig_ref] Figure 1: Vitamin D metabolism [/fig_ref]. It exerts its actions through the activation of the vitamin D receptor (VDR), a nuclear receptor almost ubiquitously expressed in most vertebrate cells, but mostly present in the intestine, where it stimulates active calcium absorption [bib_ref] Vitamin D supplementation in elderly or postmenopausal women: a 2013 update of..., Rizzoli [/bib_ref]. As demonstrated by in vitro and in vivo evidence, calcitriol can also be synthesized in a series of tissues in normal or pathologic conditions. Extrarenal calcitriol mainly acts in an autocrine or paracrine manner, in order to modulate functions not classically related to mineral homeostasis. Whilst renal calcitriol production is regulated by parathyroid hormone (PTH) and fibroblast growth factor 23, two hormones that respectively enhance or inhibit its production, the synthesis of extrarenal calcitriol is driven by the bioavailable substrate, i.e., serum 25(OH)D. Concentrations of free or bioavailable 25 (OH)D in the local circulation at the target tissues are also regulated by the levels of vitamin D binding protein (VDBP) [bib_ref] Effects of vitamin D binding protein phenotypes and vitamin D supplementation on..., Sollid [/bib_ref]. The ubiquitous presence of the VDR and the possible production of extra-renal calcitriol driven by the concentration of the non-active pre-hormone, 25(OH)D, constitute the physiological conditions for the potential extra-skeletal effects of calcitriol and suggest a possible role for parental vitamin D or 25(OH)D in maintaining or enhancing these processes [bib_ref] Subclinical vitamin D deficiency, Cianferotti [/bib_ref]. A recent RCT conducted in a small group of healthy adults has demonstrated that any increase in vitamin D levels would significantly affect the expression of genes belonging to several pathways involved in the pathogenesis of major chronic diseases [bib_ref] Influence of vitamin D status and vitamin D3 supplementation on genome wide..., Hossein-Nezhad [/bib_ref]. Many in vitro studies have shown the effects of the active hormone calcitriol on cells belonging to extramusculoskeletal tissues expressing both the VDR and 1alpha hydroxylase (1αOHase), the enzyme which ultimately activates the pro-hormone 25(OH)D [bib_ref] Extraskeletal actions of vitamin D, Bikle [/bib_ref]. The model of the VDR knockout mouse, which develops hyperparathyroidism and rickets soon after weaning, has reproduced in vivo the ligand dependent and independent VDR-mediated effects also on organs not related to mineral homeostasis, such as skin, cardiovascular/renin-angiotensin system, and metabolic system [bib_ref] Vitamin D and health: perspectives from mice and man, Bouillon [/bib_ref] [bib_ref] Physiological functions of vitamin D: what we have learned from global and..., Suda [/bib_ref]. The global VDR knockout mice also develop alopecia, hypertension, impaired insulin secretion, skeletal muscle fiber atrophy with motor deficits, left ventricular hypertrophy and failure, and cardiac fibrosis [bib_ref] Vitamin D and health: perspectives from mice and man, Bouillon [/bib_ref] [bib_ref] Physiological functions of vitamin D: what we have learned from global and..., Suda [/bib_ref] [bib_ref] Vitamin D receptor is essential for normal keratinocyte stem cell function, Cianferotti [/bib_ref] [bib_ref] Cardiomyocyte-specific deletion of the vitamin D receptor gene results in cardiac hypertrophy, Chen [/bib_ref] [bib_ref] In vitro and in vivo analysis of the immune system of vitamin..., Mathieu [/bib_ref] [bib_ref] Vitamin D and its role in skeletal muscle, Ceglia [/bib_ref] [bib_ref] The vitamin D receptor regulates tissue resident macrophage response to injury, Song [/bib_ref]. These mice are more prone to skin cancer formation and impaired response to injury [bib_ref] Novel mechanisms for the vitamin D receptor (VDR) in the skin and..., Bikle [/bib_ref]. Many in vitro studies have shown the direct effects of calcitriol in modulating the functions of cells belonging to different human and animal tissues. Vitamin D, cardiovascular diseases, and mortality: evidence The observations that both systolic and diastolic blood pressure (SBP and DBP, respectively) increase with the distance from the equator [bib_ref] Sodium, potassium, body mass, alcohol and blood pressure: the intersalt study. the..., Elliott [/bib_ref] , and that seasonality for major events such as hospitalizations and in-hospital death and mortality in a large dataset [bib_ref] Seasonal variation in chronic heart failure hospitalizations and mortality in France, Boulay [/bib_ref] , suggested that vitamin D could play a role in modulating cardiovascular health and mortality. At a mechanistic level, several lines of evidence link vitamin D to cardiovascular health. First, the VDR has been found to be present in key tissues linked to cardiovascular health, such as myocardial, endothelial, smooth muscle, and pancreatic beta cells, as well as macrophages [bib_ref] Vitamin D and cardiovascular disease, Norman [/bib_ref] [bib_ref] Vitamin D and cardiovascular disease prevention, Pilz [/bib_ref]. Second, in situ production of the active hormone by the 1αOHase has been confirmed in all of the same tissues, suggesting a requirement for calcitriol [bib_ref] Vitamin D and cardiovascular disease, Norman [/bib_ref] [bib_ref] Vitamin D and cardiovascular disease prevention, Pilz [/bib_ref]. Third, the VDR knock-out mouse has been shown to suffer from hypertension and congestive heart failure [bib_ref] Vitamin D and health: perspectives from mice and man, Bouillon [/bib_ref] , further supported by the VDR mediated downregulation of the expression of renin, which is one of the major determinants in cardiovascular risk [bib_ref] The relationship between vitamin D and the renin-angiotensin system in the pathophysiology..., Vaidya [/bib_ref]. Forth, deletion of the VDR in cardiomyocytes resulted in ventricular hypertrophy among mice [bib_ref] Cardiomyocyte-specific deletion of the vitamin D receptor gene results in cardiac hypertrophy, Chen [/bib_ref]. Finally, in humans, several large cohort studies have demonstrated that low serum 25(OH)D levels are predictive of an increased risk of incident hypertension [bib_ref] Plasma 25-hydroxyvitamin D levels and risk of incident hypertension, Forman [/bib_ref] [bib_ref] Vitamin D intake and risk of incident hypertension: results from three large..., Forman [/bib_ref] , myocardial infraction [bib_ref] 25-Hydroxyvitamin D and risk of myocardial infarction in men: a prospective study, Giovannucci [/bib_ref] , and sudden cardiovascular death [bib_ref] Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with..., Dobnig [/bib_ref] [bib_ref] Vitamin D and mortality in older men and women, Pilz [/bib_ref]. Notably, regarding a desirable 25(OH)D range for optimal cardiovascular health, these large cohort studies suggested that for incident hypertension in both men and women, cardiovascular mortality and all-cause mortality, individual who had 25(OH)D levels between 50 and 130 nmol/l may have the lowest prospective risk [bib_ref] Benefit-risk assessment of vitamin D supplementation, Bischoff-Ferrari [/bib_ref]. In a prospective cohort study of 3258 consecutive patients of both genders and a mean age of 62 years scheduled for coronary angiography, both all-cause and cardiovascular mortality increased in a dose-dependent manner with decreasing quartiles of baseline serum 25(OH)D levels [bib_ref] Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with..., Dobnig [/bib_ref]. In a prospective study of elderly men, low serum 25(OH)D was associated with a substantial excess risk of death compared to 25(OH)D values greater than 50-70 nmol/l [bib_ref] Low serum vitamin D is associated with increased mortality in elderly men:..., Johansson [/bib_ref]. Consistent findings come from the Longitudinal Study Amsterdam where among 1317 senior men and women (age: 65-85 years) those with deficient serum 25(OH)D levels had a significantly higher risk of overall mortality (HR 1.46; 95% CI 1.12-1.91 for 25(OH)D <25 nmol/l and HR 1.24; 95% CI 1.01-1.53 for 25(OH)D 25-49.9 nmol/l) [bib_ref] Vitamin D, PTH and the risk of overall and disease-specific mortality: results..., Hilali [/bib_ref]. Extending to peripheral artery disease, an inverse doseresponse relationship was observed cross-sectionally between 25(OH)D status and peripheral arterial diseases among individuals age 40 years and older in the large US population-based NHANES III (2001-2004) study [bib_ref] Serum 25-hydroxyvitamin D levels and the prevalence of peripheral arterial disease: results..., Melamed [/bib_ref]. While a Mendelian randomization study has pointed to a possible causal relationship between 25(OH)D levels and hypertension by meta-analyzing data for up to 108,173 individuals from 35 studies [bib_ref] LifeLines Cohort Study investigators; International Consortium for Blood Pressure (ICBP); Cohorts for..., Vimaleswaran [/bib_ref] , a similar study has failed to confirm a causal relationship between serum 25(OH)D levels and mortality rates [bib_ref] Vitamin D and mortality: a Mendelian randomization study, Trummer [/bib_ref]. Several RCTs, albeit small and short-term, have assessed the effects of vitamin D supplementation on cardiovascular parameters among vitamin D deficient individuals. In a group including 18 subjects with hypertension, randomized to be exposed to UVB or ultraviolet A radiation thrice weekly over a period 6 weeks at suberythematous doses, both systolic blood pressure (SBP) and diastolic blood pressure (DBP) decreased by 6 mmHg in the UVB-treated group [bib_ref] Ultraviolet B and blood pressure, Krause [/bib_ref]. Furthermore, a subsequent study, carried out on a group of 148 community-dwelling elderly women, demonstrated that the administration of 800 IU of cholecalciferol (plus calcium) led, in the short term (8 weeks), to a mean significant decrease of 13 and 6 mmHg in SBP and DBP, respectively, being more effective than calcium alone [bib_ref] Effects of a short-term vitamin D(3) and calcium supplementation on blood pressure..., Pfeifer [/bib_ref]. In a pharmacokinetic study comparing calcidiol and cholecalciferol, 20 healthy postmenopausal women with low vitamin D status (mean age 61.5 years) were randomized to receive 20 mcg of calcidiol or 20 mcg (i.e. 800 IU) of cholecalciferol, leading to a period of 4 months to mean serum 25(OH)D targets of 174 and 76 nmol/l, respectively. In the group of women receiving calcidiol, blood pressure was significantly lower at each measured time-point after the 1st week of treatment, with sustained mean 5.7 mmHg decrease in SBP over 4 months of treatment demonstrated in the group of women receiving calcidiol vs. no change in the ones receiving cholecalciferol (P = 0.002), independently of age, body mass index (BMI), and baseline SBP [bib_ref] Oral supplementation with 25(OH)D3 versus vitamin D3: effects on 25(OH)D levels, lower..., Bischoff-Ferrari [/bib_ref]. In a short-term 8-week trial among 200 individuals with hypertension and serum 25(OH)D levels less than 75 nmol/l (mean 52.9 nmol/l) were randomized to receive 2800 IU of cholecalciferol or placebo for 8 weeks [bib_ref] Effects of vitamin D on blood pressure and cardiovascular risk factors: a..., Pilz [/bib_ref] and vitamin D treatment did not decrease blood pressure [bib_ref] Effects of vitamin D on blood pressure and cardiovascular risk factors: a..., Pilz [/bib_ref]. The authors hypothesized that their null finding may have been due to the fact that too many participants were not vitamin D deficient at baseline. This is consistent with their post-hoc subgroup analysis among participants who were vitamin D deficient at baseline, who did have a significant benefit on the renin-angiotensin system with vitamin D treatment group based on a reduction in their plasma aldosterone concentration [bib_ref] Effects of vitamin D supplementation on plasma aldosterone and renin-a randomized placebo-controlled..., Grübler [/bib_ref]. At the level of published meta-analyses of clinical trials on the effect of vitamin D supplementation and blood pressure, where blood pressure was measured as primary or secondary end-point, or simply measured, a benefit of vitamin D supplementation on blood pressure could not be demonstrated [bib_ref] Effect of vitamin D on blood pressure: a systematic review and meta-analysis, Witham [/bib_ref] [bib_ref] Effects of vitamin D supplementation on blood pressure, Wu [/bib_ref] [bib_ref] Systematic review: vitamin D and cardiometabolic outcomes, Pittas [/bib_ref] [bib_ref] Vitamin D and cardiovascular outcomes: a systematic review and meta-analysis, Elamin [/bib_ref] [bib_ref] D-PRESSURE Collaboration. Effect of Vitamin D Supplementation on Blood Pressure, A systematic..., Beveridge [/bib_ref]. The most recent meta-analysis included 46 trials (total of 4541 participants) and suggested a null effect of vitamin D on blood pressure, irrespective of subgroup [bib_ref] D-PRESSURE Collaboration. Effect of Vitamin D Supplementation on Blood Pressure, A systematic..., Beveridge [/bib_ref]. At the level of published meta-analyses of clinical trials on the effect of vitamin D supplementation and mortality, the most recent Cochrane meta-analysis focused on allcause mortality and cancer mortality among 75,927 individuals from 38 studies on all-causes mortality and 44,492 individuals from 4 studies on cancer-mortality. This analysis showed a significant 6% reduction in all cause mortality and a 12% reduction in cancer mortality in supplemented subjects if compared with placebo or calcium [bib_ref] Gluud: Vitamin D supplementation for prevention of mortality in adults, Bjelakovic [/bib_ref]. In a sequential meta-analysis taking into account RCTs with vitamin D supplementation of any duration and quality, the authors found a significant 4% reduction in allcause mortality [bib_ref] The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes:..., Bolland [/bib_ref]. In order to assess the effect on single causes of mortality, another meta analysis including the randomized evaluation of calcium or vitamin D (RECORD) trial, and additional 21 RCTs among seniors, concluded that vitamin D supplementation might protect against cardiac failure in older individuals, but does not appear to protect from stroke or myocardial infarction [bib_ref] Cardiovascular disease and vitamin D supplementation: trial analysis, systematic review, and meta-analysis, Ford [/bib_ref]. Desirable 25(OH)D levels for optimal risk reduction in mortality have been explored in several epidemiologic studies [bib_ref] Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with..., Dobnig [/bib_ref] [bib_ref] Low serum concentrations of 25-hydroxyvitamin D in older persons and the risk..., Visser [/bib_ref] [bib_ref] Prospective study of serum 25-hydroxyvitamin D level, cardiovascular disease mortality, and all-cause..., Ginde [/bib_ref] [bib_ref] 25-Hydroxyvitamin D levels and the risk of mortality in the general population, Melamed [/bib_ref] [bib_ref] Circulating calcitriol concentrations and total mortality, Zittermann [/bib_ref] [bib_ref] Vitamin D and risk of cause specific death: systematic review and meta-analysis..., Chowdhury [/bib_ref] [bib_ref] Vitamin D status and incident cardiovascular disease and all-cause mortality: a general..., Skaaby [/bib_ref] , most of which suggested a continuous inverse relationship between increasing values of 25(OH)D and a lower risk of mortality. In some studies and reviews, however, a U-shape or reverse J-shaped relationship has been described with an increased risk of mortality both at low and higher levels of 25(OH)D [bib_ref] 25-Hydroxyvitamin D levels and the risk of mortality in the general population, Melamed [/bib_ref] [bib_ref] Plasma vitamin D and mortality in older men: a community-based prospective cohort..., Michaëlsson [/bib_ref] [bib_ref] Vitamin D and mortality, Pilz [/bib_ref] [bib_ref] U-shaped relationship between vitamin D levels and long-term outcome in large cohort..., Aleksova [/bib_ref] [bib_ref] Do studies reporting 'U'-shaped serum 25-hydroxyvitamin D-health outcome relationships reflect adverse effects?, Grant [/bib_ref]. In summary, evidence that link vitamin D to cardiovascular health is limited to mechanistic studies, large cohort studies and small clinical trials among vitamin D deficient adults. Large clinical trials with a sufficient dose of vitamin D, ideally tested among individuals at risk of vitamin D deficiency, are missing for blood pressure, any major cardiovascular events and mortality. Two ongoing trials are addressing this gap with available results in 2018 [VITAL Study [bib_ref] The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a..., Manson [/bib_ref] , DO-HEALTH trial. Both trials test 2000 IU vitamin D against placebo with VITAL addressing major cardiovascular events and DO-HEALTH blood pressure as primary endpoints. Based on available data, effects are most likely expected in deficient individuals and both trials have undertaken recruitment strategies to target adults (VITAL: age 50+; DO-HEALTH: age 70+) at risk of vitamin D deficiency, although they did not select for vitamin D deficient subjects (i.e., serum 25(OH)D less than 20 ng/ml). All ongoing large-scale multicenter clinical trials with predefined cardiovascular endpoints are listed in [fig_ref] Table 1: Ongoing large-scale randomized controlled trials in subjects aged 50 years or more,... [/fig_ref]. ## Vitamin d, type ii diabetes and obesity: evidence Many studies have shown an association of type II diabetes (T2D), metabolic syndrome and obesity with a poor vitamin D status [bib_ref] Vitamin D and diabetes, Mitri [/bib_ref]. After the first observation that vitamin D status itself affects pancreatic secretion of insulin after proper stimulus in rats [bib_ref] Vitamin D deficiency inhibits pancreatic secretion of insulin, Norman [/bib_ref] , further experimental studies have demonstrated that pancreatic beta-cells express the VDR and 1αOHase [bib_ref] Vitamin D and diabetes, Mitri [/bib_ref] and that calcitriol directly stimulates insulin production by pancreatic islets [bib_ref] The in vitro effect of 1 alpha,25-dihydroxyvitamin D3 on insulin production by..., Emden [/bib_ref] , modulates peripheral insulin sensitivity and systemic inflammation in vitro and in vivo in animal models [bib_ref] Vitamin D and diabetes, Mitri [/bib_ref]. In humans, a polymorphism of the VDR possibly impairing the response to calcitriol has been shown to be a significant and positive predictor of T2D and myocardial infarction. In the NHANES III, serum 25(OH)D levels were inversely correlated with the prevalence of T2D and measures of insulin resistance in a dose-dependent pattern in some, but not in all, ethnic groups (i.e., non-Hispanic whites and Mexican-Americans), without correlating with betacell function [bib_ref] Third National Health and Nutrition Examination Survey., Serum 25-hydroxyvitamin D, diabetes, and..., Scragg [/bib_ref]. In the large longitudinal study of the Nurses Health Study, after adjustment for all the possible co-variates, the risk of developing T2D was reduced by 33% in women with higher intake of vitamin D and calcium (>1200 mg and >800 IU daily, respectively) [bib_ref] Vitamin D and calcium intake in relation to type 2 diabetes in..., Pittas [/bib_ref]. As far as the complications of diabetes are concerned, serum 25(OH) D levels were shown to be an independent predictor of macrovascular and microvascular problems in patients with overt T2D [bib_ref] Serum 25-hydroxyvitamin D: a predictor of macrovascular and microvascular complications in patients..., Herrmann [/bib_ref]. A meta-analysis of longitudinal observation studies by Song et al. included 21 studies with 76,000 participants and calculated the risk of developing T2D according to baseline vitamin D status [bib_ref] Blood 25-hydroxy vitamin D levels and incident type 2 diabetes: a meta-analysis..., Song [/bib_ref]. The risk of developing T2D was reduced by 38% in the subjects in the highest tertile for serum 25(OH)D levels as compared with those in the lowest tertile, with little heterogeneity among studies. The association was consistent regardless of various baseline variables, such as diagnostic criteria for diabetes, duration of follow-up, or study size, and remained significant after adjustment for BMI and intermediate biomarkers. A linear trend analysis showed that a 4 ng/ml increment in 25(OH)D levels corresponded to a 4% lower risk of developing T2D [bib_ref] Blood 25-hydroxy vitamin D levels and incident type 2 diabetes: a meta-analysis..., Song [/bib_ref]. Nonetheless, two Mendelian randomization studies have failed to demonstrate a causal relationship between a low vitamin D status and T2D or obesity, respectively [bib_ref] Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: a mendelian..., Ye [/bib_ref]. Moreover, a systematic review and meta-analysis has demonstrated that vitamin D and calcium supplements had no effects on adiposity in adults [bib_ref] Effect of vitamin D supplementation alone or with calcium on adiposity measures:..., Chandler [/bib_ref]. The authors concluded that the effort to increase 25(OH)D levels by means of supplementation might not be beneficial to reduce the risk of T2D or obesity [bib_ref] Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: a mendelian..., Ye [/bib_ref] [bib_ref] Effect of vitamin D supplementation alone or with calcium on adiposity measures:..., Chandler [/bib_ref]. The evidence from intervention trials assessing the influence of vitamin D supplementation in T2D is still scarce and mostly comprises post-hoc analyses. These RCTs were mainly designed for non-glycemic outcomes, they were often too short and the dose of administered vitamin D was heterogeneous, as reported in a recent systematic review [bib_ref] Clinical review: effect of vitamin D3 supplementation on improving glucose homeostasis and..., Seida [/bib_ref]. Whilst it appears that vitamin D supplementation has a neutral effect on glycemic outcomes in individuals with normal glucose tolerance and in people with established T2D at baseline, its potential effect seems to be more prominent in those people who are at increased risk for diabetes [bib_ref] Vitamin D and diabetes, Mitri [/bib_ref]. RCTs specifically designed to assess the effect of vitamin D supplementation on T2D risk and insulin sensitivity (homeostatic model assessment of insulin resistance, i.e., HOMA) are still a few. In one of these studies performed in healthy adults at increased risk for T2D with low vitamin D status (≤55 nmol/l), only the subgroup of subjects with prediabetes had an advantage from daily cholecalciferol, administered at a dosage sufficient to target serum levels of 25(OH)D of >75 nmol/L in terms of increase in insulin sensitivity [bib_ref] Effects of combined calcium and vitamin D supplementation on insulin secretion, insulin..., Gagnon [/bib_ref]. In healthy adult individuals with low 25(OH)D levels, supplementation with high dose vitamin D2 (50,000 IU/ week) had no effect increasing insulin secretion and insulin sensitivity in the short-term (12 weeks) [bib_ref] Insulin secretion and sensitivity in healthy adults with low vitamin D are..., Mitchell [/bib_ref]. With respect to at-risk subjects, in a recently published long-term RCT involving 511 subjects (mean age 62 years) with prediabetes within the Tromso cohort carried out in the years 2008-2015, 20,000 IU/week of cholecalciferol did not prevent the progression to overt T2D [bib_ref] Vitamin D 20,000 IU per week for five years does not prevent..., Jorde [/bib_ref]. Because of the potential adverse effects of high dose vitamin D, one ongoing placebo-controlled study (ie. D2d study) will test both the long-term safety and efficacy of daily high-dose vitamin D supplementation (4000 IU/day) on lowering the risk of progression to overt diabetes in people with increased risk for this chronic disease [bib_ref] Rationale and design of the vitamin D and type 2 diabetes (D2d)..., Pittas [/bib_ref]. In conclusion, no evidence exists, so far, that administering vitamin D could reduce T2D or obesity in the general population. The results obtained in subjects with prediabetes require further confirmation by larger and longer RCTs. Since higher doses are employed, studies on safety are also needed. ## Vitamin d and autoimmune diseases: evidence Calcitriol is a regulator of the immune system [bib_ref] Control of autoimmune diseases by the vitamin D endocrine system, Adorini [/bib_ref] [bib_ref] Further emergent evidence for the vitamin D endocrine system involvement in autoimmune..., Cutolo [/bib_ref]. Whilst it exerts stimulatory effects on innate immunity, which is aspecific and implicated in the defense against infections, it also modulates the effectors of adaptive immunity, which is acquired and antigen-specific [bib_ref] Vitamin D and autoimmunity, Rosen [/bib_ref]. The observations that the geographic prevalence of autoimmune diseases such as multiple sclerosis (MS), type 1 diabetes mellitus (T1D), rheumatoid arthritis (RA) and other rheumatic diseases increases with the distance from the equator or changes with seasonality, as well as the worsening of these diseases in conditions of low ultraviolet radiation (UV) exposure, have raised the hypothesis that vitamin D could play a role in the pathogenesis of these diseases [bib_ref] UVR, vitamin D and three autoimmune diseases-multiple sclerosis, type 1 diabetes, rheumatoid..., Ponsonby [/bib_ref] [bib_ref] The association between ultraviolet B irradiance, vitamin D status and incidence rates..., Mohr [/bib_ref] [bib_ref] Rheumatoid arthritis: circadian and circannual rhythms in RA, Cutolo [/bib_ref]. Indeed, the transcriptomic profile of the immune system in man varies with season and is shifted towards a pro-inflammatory state in wintertime [bib_ref] Widespread seasonal gene expression reveals annual differences in human immunity and physiology, Dopico [/bib_ref]. Nonetheless, the observation that UV irradiation can repress the development of experimental autoimmune encephalomyelitis (EAE), a murine model of MS, independently of 25 (OH)D levels, has in part downsized the belief that UV could act through vitamin D production to determine the abovelisted effects [bib_ref] UV radiation suppresses experimental autoimmune encephalomyelitis independent of vitamin D production, Becklund [/bib_ref]. Calcitriol has been shown to modulate in vitro the activity of key players of the immune system, such as antigen presenting cells and T-lymphocytes [bib_ref] Mechanisms underlying the regulation of innate and adaptive immunity by Vitamin D, Wei [/bib_ref]. Calcitriol inhibits the type T1 helper cell function by suppressing inflammatory cytokine production (IFN-γ and IL-2), IL-17 producing T-cells, and dendritic cell differentiation, whilst it enhances the production of cytokines by the type T2 cells (Th2) such as IL-10 and the activity of regulatory T (Treg) cells [bib_ref] Mechanisms underlying the regulation of innate and adaptive immunity by Vitamin D, Wei [/bib_ref]. In addition, calcitriol downregulates aromatase expression and inflammatory cytokines in human macrophages [bib_ref] Cutolo, 1,25-Dihydroxyvitamin D3 downregulates aromatase expression and inflammatory cytokines in human macrophages, Villaggio [/bib_ref]. These effects lead to an important defensive mechanism against inflammation and improvement of tolerogenic phenotype. These findings, together with the fact that individuals with autoimmune diseases often display a poor vitamin D status as compared with controls, have led to hypothesize a potential immunomodulatory effect for vitamin D and to study the immune system in the VDR knockout mouse model. Indeed, mice devoid of VDR failed to demonstrate gross immune abnormalities, except for impaired macrophage chemotaxis and a lower response to anti-CD3 stimulation [bib_ref] In vitro and in vivo analysis of the immune system of vitamin..., Mathieu [/bib_ref]. Moreover, vitamin D receptor knockout mice were unexpectedly protected from low-dose streptozotocin-induced diabetes mellitus and EAE was less severe in VDR null mice [bib_ref] In vitro and in vivo analysis of the immune system of vitamin..., Mathieu [/bib_ref] [bib_ref] Development of experimental autoimmune encephalomyelitis (EAE) in mice requires vitamin D and..., Wang [/bib_ref]. These immune defects were rescued by means of a diet rich in calcium, lactose and phosphate, demonstrating that they were an indirect effect of VDR disruption and that, although calcitriol is a possible pharmacologic or physiologic immunomodulator, these actions are redundant in vivo [bib_ref] In vitro and in vivo analysis of the immune system of vitamin..., Mathieu [/bib_ref]. Conversely, in animal models of autoimmune disease, a benefit of the administration of vitamin D, calcitriol or calcitriol analogs on preventing the onset or blunting the disease progression via direct modulation of immune cells (i.e., induction of tolerogenic dendritic cells) has been demonstrated [bib_ref] Control of autoimmune diseases by the vitamin D endocrine system, Adorini [/bib_ref] [bib_ref] -Dihydroxyvitamin D3 promotes tolerogenic dendritic cells with functional migratory properties in NOD..., Ferreira [/bib_ref]. Epidemiological studies have shown an association between serum 25(OH)D levels and the prevalence, incidence, severity and progression of many autoimmune diseases [bib_ref] Vitamin D and autoimmunity, Rosen [/bib_ref]. Indeed, higher levels of 25(OH)D have been associated with a decrease in the likelihood of developing autoimmune diseases such as MS, RA, T1D [bib_ref] Prospective population-based study of the association between vitamin D status and incidence..., Skaaby [/bib_ref] , especially when taken early in life [bib_ref] Control of autoimmune diseases by the vitamin D endocrine system, Adorini [/bib_ref]. A systematic review and metaanalysis has demonstrated that, despite heterogeneity, poor vitamin D status was associated to an increased risk of developing MS [bib_ref] Vitamin D status and the risk of multiple sclerosis: a systematic review..., Duan [/bib_ref]. Moreover, two Mendelian randomization studies have recently pointed to a likely causal relationship between poor vitamin D status and the risk of MS [bib_ref] Vitamin D and risk of multiple sclerosis: a mendelian randomization study, Mokry [/bib_ref] [bib_ref] Mendelian randomization shows a causal effect of low vitamin D on multiple..., Rhead [/bib_ref]. In MS, low vitamin D status has been shown to be an independent early predictor of disease activity and progression [bib_ref] Vitamin D as an early predictor of multiple sclerosis activity and progression, Ascherio [/bib_ref] , in particular in patients being treated with IFN beta-1b [bib_ref] Association of Vitamin D levels with multiple sclerosis activity and progression in..., Fitzgerald [/bib_ref]. In addition, IFN beta was indeed more effective in MS in the presence of high levels of 25(OH)D [bib_ref] Interferon-β and serum 25-hydroxyvitamin D interact to modulate relapse risk in MS, Stewart [/bib_ref]. The potential role of calcitriol as immunomodulator/ immune-suppressor gave rise to the hypothesis that calcitriol or other active vitamin D analogs, such as alfa-calcidiol, might be used as a pharmacologic agent to prevent autoimmune disease in high-risk individuals, or to treat overt autoimmune diseases and to protect transplanted organs from rejections. However, calcitriol must be administered in high doses to elicit an immunomodulatory effect and suppress proinflammatory cytokines. For this reason, it cannot be used in humans. Non-hypercalcemic analogs of calcitriol are currently under investigation. The fact that calcitriol can be synthesized by immune cells because of the expression of 1αOHase, which is regulated by its substrate, i.e., 25(OH)D, has been exploited to support the concept that vitamin D supplementation with parental vitamin D compounds could be considered for the pharmacologic adjuvant treatment of autoimmune diseases [bib_ref] Extraskeletal actions of vitamin D, Bikle [/bib_ref]. A few RCTs have demonstrated that supplementation with the pro-hormone vitamin D has similar effects with respect to calcitriol on cell-mediated immunity. Indeed, monthly supplementation with high dose (140,000 IU) vitamin D3 increased significantly peripheral regulatory Tcells in adult healthy donors in the short term of 3 months, as compared to placebo [bib_ref] The effect of vitamin D supplementation on peripheral regulatory T cells and..., Bock [/bib_ref]. Similarly, daily high dose vitamin D3 (4000 IU daily) led to a significant decrease in CD4 cytotoxic T-cell activation compared to low dose vitamin D3 (400 IU/day) [bib_ref] Vitamin D supplementation modulates T cell-mediated immunity in humans: results from a..., Konijeti [/bib_ref]. In patients relapsing-remitting MS (RRMS, study group 94 subjects) high dose vitamin D intake (50,000 IU every 5 days for 3 months) along with IFN-β treatment led to a significant increase in mental quality of life vs. placebo [bib_ref] High dose Vitamin D intake and quality of life in relapsing-remitting multiple..., Ashtari [/bib_ref]. An even higher dose of cholecalciferol (10,400 IU/ day) was proven to be safe and well tolerated, at least in the short-term (6 months), and led to pleiotropic immunomodulatory effects (decreased production of IL-17 and proportion of effector memory CD4+ cells), with a concomitant increase in central memory CD4+ cells [bib_ref] Safety and immunologic effects of high-vs low-dose cholecalciferol in multiple sclerosis, Sotirchos [/bib_ref]. These latter findings confirm previous results obtained in similar randomized controlled studies in MS (as reviewed in 110). However, larger and long-term studies are necessary to confirm the efficacy and safety of vitamin D supplementation in MS [bib_ref] Hernández-Gallego, A systematic review of randomized, double-blind, placebo-controlled trials examining the clinical..., Pozuelo-Moyano [/bib_ref]. Vitamin D supplementation early in life (2000 IU daily) has been shown to reduce the risk of developing T1D in atrisk subjects in a retrospective study in northern Finland, where individuals are likely to be vitamin D deficient for most part of the year [bib_ref] Virtanen, Intake of vitamin D and risk of type 1 diabetes: a..., Hyppönen [/bib_ref]. A recent study in mice indicated that high dose parental vitamin D3 reduced the incidence of diabetes in a mouse model, which spontaneously develops diabetes (non-obese diabetic, i.e., NOD mouse), when the vitamin was administered at high doses and lifelong from 3 weeks of age [bib_ref] Dietary supplementation with high doses of regular vitamin D3 safely reduces diabetes..., Takiishi [/bib_ref]. Randomized controlled longitudinal studies are ongoing to assess this effect of vitamin D in atrisk human young populations. As far as the early stages of disease are concerned, both alfacalcidiol and parental vitamin D3 (70 IU/Kg body weight/day) have been proven to be effective on residual beta-cell function in latent autoimmune diabetes in adults and improved suppressor function of regulatory T cells in patients with T1D, respectively, in recently published RCTs [bib_ref] Protective effects of 1-alpha-hydroxyvitamin D3 on residual beta-cell function in patients with..., Li [/bib_ref] [bib_ref] Cholecalciferol supplementation improves suppressive capacity of regulatory Tcells in young patients with..., Treiber [/bib_ref]. Data on larger groups of individuals confirming these results are still missing in T1D. The demonstration of circannual rhythms in RA and systemic lupus erythematous (SLE) and the lower risk of developing RA in the case of higher UVB exposure, suggest that a possible association with vitamin D status might exist [bib_ref] Circannual vitamin d serum levels and disease activity in rheumatoid arthritis: Northern..., Cutolo [/bib_ref] [bib_ref] Vitamin D endocrine system involvement in autoimmune rheumatic diseases, Cutolo [/bib_ref] [bib_ref] Evidence that abnormally large seasonal declines in vitamin D status may trigger..., Birmingham [/bib_ref]. However, a post-hoc analysis of the Women Health Initiative study failed to show an association between RA and solar irradiation, and suggested an increased incidence of RA with higher vitamin D exposure of just 440 IU/day vs. placebo [bib_ref] Calcium and vitamin D supplementation and incident rheumatoid arthritis: the Women's Health..., Racovan [/bib_ref]. Contradictory results arose from meta-analyses assessing the association between vitamin D intake and risk of RA and SLE in women [bib_ref] Vitamin D intake and risks of systemic lupus erythematosus and rheumatoid arthritis..., Costenbader [/bib_ref] [bib_ref] Association between vitamin D intake and the risk of rheumatoid arthritis: a..., Song [/bib_ref] , whereas a recent meta-analysis, including 24 crosssectional studies and involving 3489 subjects, showed a negative association between 25(OH)D levels and disease activity in subjects with RA [bib_ref] Serum Vitamin D level and rheumatoid arthritis disease activity: review and meta-analysis, Lin [/bib_ref]. Thus far, no RCTs have been carried out to definitively demonstrate a causal relationship between RA and vitamin D status by assessing the effects of vitamin D supplementation on the course of the disease. In SLE, a RCTs comparing the effect of daily supplementation with 2000 IU cholecalciferol against placebo in patients with active disease demonstrated that daily supplementation with cholecalciferol administered over a period of 1 year led to a significant improvement in disease activity, along with a significant decrease in inflammatory markers [bib_ref] The effect of vitamin D supplementation on inflammatory and hemostatic markers and..., Abou-Raya [/bib_ref]. Unfortunately, these results have not been confirmed in a crossover trial with a 2-year duration, in which 32 women with SLE were randomized to different regimens of cholecalciferol (25,000 IU monthly or 300,000 IU initial bolus followed by 50,000 IU monthly). The higher dose was not effective in modulating disease activity, despite an increase in the number of Treg cells [bib_ref] Phenotype modifications of T-cells and their shift toward a Th2 response in..., Piantoni [/bib_ref] [bib_ref] A 24-month prospective study on the efficacy and safety of two different..., Andreoli [/bib_ref]. A recent Cochrane meta-analysis has shown that there is insufficient evidence to consider vitamin D as a possible relief for several conditions characterized by chronic pain [bib_ref] Vitamin D for the treatment of chronic painful conditions in adults, Straube [/bib_ref]. Although the effects of calcitriol on the modulation of the immune system in vitro are consistent, it remains to be clarified whether these effects have been observed because of the higher pharmacologic doses administered in culture and whether they can be reproduced in vivo. Many of these effects seem to arise directly from the VDR-mediated actions of calcitriol, as demonstrated in animal models. While the in vivo administration of active vitamin D at high doses is not possible because of the hypercalcemic effects, it is not clear to what extent a supplementation of parental vitamin D compounds (cholecalciferol and calcidiol) or non-hypercalcemic calcitriol analogs, could lead to a modulation of the immune system, taking advantage of the possible induction of 1αOHase present in the immune cells. Promising results have recently been obtained in individuals with MS and subjects at high risk for T1D with vitamin D deficiency by means of larger doses of parental compounds (D3) or active vitamin D analogs. However, larger long-term RCTs assessing safety along with efficacy are needed. The evidence for potential benefits in rheumatic autoimmune diseases is still lacking and requires RCTs possibly carried out during the early stages of the disease to control progression, and in later stages for the prevention of flare-ups. ## Vitamin d and cancer: evidence Calcitriol controls cellular proliferation and differentiation in vitro. Calcitriol induces apoptosis, autophagy and growth arrest of cancer cells or their progenitors, enhances DNA repair and antioxidant protection, and modulates the immune system to react against cancer [bib_ref] Vitamin D and cancer: a review of molecular mechanisms, Fleet [/bib_ref]. Thus, active vitamin D may inhibit cancer progression and metastasis [bib_ref] Vitamin D and cancer: a review of molecular mechanisms, Fleet [/bib_ref]. These effects are mediated by the VDR, which is expressed by tumor cells along with 1αOHase. This, in turn, is responsible for the local conversion of the pro-hormone 25(OH)D into the biologically active vitamin D. Unfortunately, the capacity to hydroxylate the direct precursor of active vitamin D is progressively lost by cancer cells, especially in prostate cancer [bib_ref] Vitamin D and cancer: a review of molecular mechanisms, Fleet [/bib_ref]. Mice devoid of the VDR were more prone to skin cancer in response to chemical carcinogens or UVB irradiation, although they did not spontaneously develop tumors [bib_ref] Disruption of vitamin D and calcium signaling in keratinocytes predisposes to skin..., Bikle [/bib_ref]. In a murine model of bone metastasis, vitamin D deficiency favoured the growth of injected prostate cancer cells in bone likely changing the bone microenvironment [bib_ref] Vitamin D deficiency promotes prostate cancer growth in bone, Zheng [/bib_ref]. In this regard, it has been also argued that calcitriol could play a role in modulation of osteoblasts, osteoclasts and quiescent cancer cells within the pre-metastatic niche in bone and possibly prevent bone metastases. In humans, epidemiological data have shown an increased prevalence of several types of cancer in the northern areas of the northern hemisphere, suggesting an inverse trend with the amount of UV exposure [bib_ref] The role of vitamin D in cancer prevention, Garland [/bib_ref]. Many studies have shown an increased prevalence of vitamin D deficiency in individuals with cancer vs. controls and an association between low vitamin D status and increased risk of developing various tumors, such as breast, prostate, and colon cancer, as well as disease severity [bib_ref] The role of vitamin D in cancer prevention, Garland [/bib_ref] [bib_ref] The epidemiology of vitamin D and cancer incidence and mortality: a review..., Giovannucci [/bib_ref] [bib_ref] High prevalence of vitamin D deficiency despite supplementation in premenopausal women with..., Crew [/bib_ref] [bib_ref] A prospective study of plasma vitamin D metabolites, vitamin D receptor polymorphisms,..., Li [/bib_ref]. Thus, it was suggested that higher serum levels of 25(OH)D and, for prostate cancer, higher serum levels of 1,25(OH) 2 D, would inhibit colorectal, breast and prostate carcinogenesis [bib_ref] The epidemiology of vitamin D and cancer incidence and mortality: a review..., Giovannucci [/bib_ref] [bib_ref] High prevalence of vitamin D deficiency despite supplementation in premenopausal women with..., Crew [/bib_ref] [bib_ref] A prospective study of plasma vitamin D metabolites, vitamin D receptor polymorphisms,..., Li [/bib_ref] [bib_ref] Kittaka Novel vitamin D analogs for prostate cancer therapy, Chen [/bib_ref]. In particular, levels of 25(OH)D far above the thresholds generally advised for the maintenance of bone and mineral homeostasis (i.e., >50 ng/ml) would prevent cancer. Based on these observational data, it was estimated that even modest increase in serum 25(OH)D levels to 40-60 ng/ml would have prevented 58,000 new cases of breast cancer and 49,000 new cases of colon cancer in the United States and Canada each year, with correspondent reduction in cancer-related mortality rates [bib_ref] Vitamin D for cancer prevention: global perspective, Garland [/bib_ref]. Surprisingly, a recent pooled analysis demonstrated an increased risk of prostate cancer along with higher vitamin D intake [bib_ref] Neale; Pancreatic Cancer Case-Control Consortium (PanC4)., Vitamin D and pancreatic cancer: a..., Waterhouse [/bib_ref] , further confirming that no definitive conclusions can be drawn by observational studies in this field. Meta-analyses have assessed the association between VDR polymorphisms and cancers, showing that variants of the VDR or higher levels of VDBP were associated with an increased risk for certain types of cancer [bib_ref] Vitamin D receptor gene polymorphisms and the risk for female reproductive cancers:..., Mun [/bib_ref] [bib_ref] Meta-analysis of vitamin D-binding protein and cancer risk, Tagliabue [/bib_ref]. These results suggest that, besides 25(OH)D levels, the VDRmediated response to active vitamin D or the VDBPregulated exposure to active vitamin D could also be associated with the risk and progression of cancer, and could be considered additional variables in determining the vitamin D-related cancer risk and progression of cancer. Early studies examined the risk of cancer by means of secondary analyses of previous RCTs, including the Women Health Initiative, and reported no significant cancer risk reduction in individuals supplemented with vitamin D [bib_ref] Vitamin D and prevention of cancer-ready for prime time?, Manson [/bib_ref]. Some RCTs have been carried out to specifically assess whether vitamin D supplementation can indeed prevent cancer. A group of 1179 community-dwelling women was randomized to receive 1400-1500 mg supplemental calcium plus 1100 IU/day vitamin D3, calcium alone or placebo, and followed-up for a 4-year period. In the intention-to-treat analysis, the supplementation of vitamin D and calcium was shown to be effective in reducing all-cancer risk, with a cancer-free survival 77% higher in the calcium-vitamin D group vs. placebo [bib_ref] Vitamin D and calcium supplementation reduces cancer risk: results of a randomized..., Lappe [/bib_ref]. A meta-analysis took into account RCTs, prospective cohort studies and nested case-control studies mainly performed in older women, with data on risk of cancer and cancer-related mortality (three studies), or fracture outcomes (16 studies) [bib_ref] Vitamin D with or without calcium supplementation for prevention of cancer and..., Chung [/bib_ref] , It was shown that, whilst combined calcium and vitamin D supplementation (1000 IU/ day) may reduce the risk for all cancers, with a dose-response relationship observed for colon cancer but not for breast and prostate cancer, surprisingly, higher concentrations of serum 25(OH)D were associated with increased cancer risk [bib_ref] Vitamin D with or without calcium supplementation for prevention of cancer and..., Chung [/bib_ref]. A Cochrane meta-analysis included a total of 50,623 participants, healthy or diagnosed with a specific disease, from 18 RCTs trials, which compared the effect of vitamin D supplementation/treatment (cholecalciferol, ergocalciferol, calcitriol, or alfacalcidiol, at any dose or regimen) vs. placebo on the risk of cancer. No conclusion could be drawn in terms of cancer prevention [bib_ref] Vitamin D supplementation for prevention of cancer in adults, Bjelakovic [/bib_ref]. In a recently published, well-designed, multicenter, US-based RCT, 2259 subjects surgically treated for colorectal adenomas were randomized to receive daily vitamin D3 (1000 IU), calcium as carbonate (1200 mg), both or neither [bib_ref] A trial of calcium and vitamin D for the prevention of colorectal..., Baron [/bib_ref]. It was demonstrated that daily supplementation with vitamin D3, calcium, or both were ineffective in modifying the rate of recurrencies of colorectal adenomas over a period of 3-5 years [bib_ref] A trial of calcium and vitamin D for the prevention of colorectal..., Baron [/bib_ref]. As far as cancer mortality is concerned, there are conflicting results whether vitamin D supplementation reduces cancer-related mortality have been found [bib_ref] Vitamin D supplements and cancer incidence and mortality: a meta-analysis, Keum [/bib_ref] [bib_ref] The effect of prediagnostic vitamin D supplementation on cancer survival in women:..., Jeffreys [/bib_ref]. Although some evidence points to a possible role of treatment with active vitamin D analogs specifically in prostate cancer, the results of clinical studies are still underpowered and inconclusive, and require additional well-designed trials to establish efficacy [bib_ref] Kittaka Novel vitamin D analogs for prostate cancer therapy, Chen [/bib_ref] [bib_ref] Calcitriol in combination therapy for prostate cancer: pharmacokinetic and pharmacodynamic interactions, Ben-Eltriki [/bib_ref]. Secondary hyperparathyroidism is independently associated with poor prognosis in prostate cancer patients, especially when undergoing antiresorptive treatment for bone metastases [bib_ref] Prognostic role of serum parathyroid hormone levels in advanced prostate cancer patients..., Berruti [/bib_ref]. For this reason, in patients with metastatic bone disease, in whom treatment with agents such as bisphosphonates (i.e., zoledronic acid) or denosumab is commenced, vitamin D supplementation is recommended in order to normalize serum PTH levels and prevent side effects such as antiresorptive-induced hypocalcemia [bib_ref] Prognostic role of serum parathyroid hormone levels in advanced prostate cancer patients..., Berruti [/bib_ref]. In conclusion, although there is a high prevalence of low levels of vitamin D in cancer patients, insufficient evidence exists on the likely reduction of cancer incidence and mortality by vitamin D. The results of ongoing RCTs will possibly clarify these issues, in particular the optimal plasma concentrations of 25(OH)D to be achieved to get an effect for cancer prevention and/or treatment. In patients with prostate cancer undergoing antiresoptive therapy for the treatment of bone metastases, vitamin D supplementation should be undertaken to normalize serum PTH levels and decrease the risk of antiresorptive-related hypocalcemia. A similar recommendation may apply to patients with breast cancer commencing an antiresorptive therapy for prevention or treatment of bone metastases [bib_ref] El Hajj Fuleihan; International Osteoporosis Foundation Committee of Scientific Advisors Working Group..., Rizzoli [/bib_ref]. The efficacy and safety of active vitamin D analogs in certain types of cancer (i.e., prostate cancer) should be further explored. ## Vitamin d and chronic diseases in adults: considerations, recommendations and research agenda In the vitamin D field, the strong mechanistic evidence for extra skeletal outcomes mainly ensues from in vitro studies, usually employing calcitriol in pharmacologic rather than physiologic doses, and from association studies, showing that low 25(OH)D levels (i.e., <50 nmol/l) are consistently associated with chronic diseases in prospective cohort studies with a dose-response relationship. Indirect evidence arises also from studies showing a direct trend between pathologic parameters or diseases, such as cardiovascular disorders, cancer, or autoimmune conditions, and the distance from the equator as well as fluctuations with seasonality (i.e., according to sub-optimal UV exposure). Many cross-sectional studies have investigated the association between serum 25(OH)D levels and various parameters in health and disease. Although these studies have linked hypovitaminosis D to numerous disorders affecting different systems such as the cardiovascular, immune, endocrine/metabolic systems, they have not yet proven a causal relationship between a suboptimal vitamin D status and the onset and progression of these diseases. The Mendelian randomization method can be used in this setting, by using gene variants (i.e., polymorphisms) to make causal inferences in epidemiology and assess the causal effect of the exposure to different levels of serum 25 (OH) on disease in non-experimental studies [bib_ref] Evaluation of genetic markers as instruments for Mendelian randomization studies on vitamin..., Berry [/bib_ref]. This method has been recently exploited in the vitamin D field to further assess the results of cross-sectional or longitudinal studies in large cohorts of subjects, where blood samples for genetic studies were available [bib_ref] Evaluation of genetic markers as instruments for Mendelian randomization studies on vitamin..., Berry [/bib_ref]. These observations are still not supported by gross evidence in chronic diseases in humans, as demonstrated by the few available RCTs and the many meta-analyses and systematic reviews, often showing contradictory results [fig_ref] Figure 2: Calcitriol-mediated extraskeletal effects, as demonstrated in vitro and in vivo in animal... [/fig_ref]. Moreover, ecological evidence of the association between the prevalence of chronic diseases and UV irradiation arises from studies performed in the northern hemisphere, while these results are not reproduced in the southern hemisphere. There is definitely a preponderance of association studies over studies to demonstrate causality. RCTs employing parental vitamin D compounds (cholecalciferol or calcidiol) in small cohorts of subjects have shown some results, yet far from leading to recommending for vitamin D use for primary or secondary prevention of extraskeletal diseases. Overall, the available RCTs analyzing the effect of vitamin D supplementation on specific extraskeletal outcomes is still scarce and clinical benefits from large RCTs of supplementation with vitamin D compounds, assessing both multiple outcomes and safety, have yet to be reported. The inclusion of participants with baseline serum 25(OH)D above the upper limit of deficiency (i.e., 50 nmol/l) could attenuate the effect of vitamin D on the main extraskeletal outcomes. Moreover, when employing large doses of vitamin D, safety has not usually been assessed. Monthly doses of vitamin D (or vitamin D supplements administered at even longer intervals) have been considered safe as far as classic side effects (i.e., hypercalciuria and hypercalcemia) are concerned and because of the long half-life of vitamin D. Nonetheless, this concept may have to be revised both because the half-life of vitamin D can be modulated by VDBP and because other active vitamin D-related metabolites can be produced during supplementation possibly modulating the main outcomes and/or mediating non-classic, adverse effects such as falls [bib_ref] Monthly high-dose Vitamin D Treatment for the prevention of functional decline: a..., Bischoff-Ferrari [/bib_ref] [bib_ref] Annual high-dose oral vitamin D and falls and fractures in older women:..., Sanders [/bib_ref] [bib_ref] Endogenously produced nonclassical vitamin D hydroxy-metabolites act as "biased" agonists on VDR..., Slominski [/bib_ref] [bib_ref] Vitamin D and falls-the dosage conundrum, Gallagher [/bib_ref]. These issues have not been taken into consideration in the trials assessing the effect of large doses of vitamin D in MS or in individuals at high risk of developing T1D. Systematic reviews including large cohorts of patients belonging to cross-sectional or longitudinal studies or to meta-analyses of randomized intervention studies have shown an association with vitamin D status as measured by baseline or attained serum 25(OH)D levels and disease onset and progression in several contexts. One of the major concerns is represented by the U-curve relationship demonstrated by some of these studies, i.e., an increased risk both for low and high levels of serum 25(OH)D and disease or mortality. The lack of standardization of serum vitamin D assays [bib_ref] Assessment of vitamin D status-a changing landscape, Herrmann [/bib_ref] , and the fact that meta analyses often combine trials including subjects with different starting baseline levels of serum 25(OH)D and employing different regimens of vitamin D to reach the same 25(OH)D target levels, are the major limitations of these studies. Indeed, the same attained level of serum 25(OH)D can be obtained after administering large doses at large intervals of time (bolus doses determining peak levels may be linked to unwanted effects, such as falls) or small doses, administered daily or weekly. Moreover, none of these studies take into account the possible production of active metabolites with short half-life, other than 25(OH)D or 1,25(OH) 2 D, which could contribute to the efficacy and safety profile of vitamin D supplementation [bib_ref] Endogenously produced nonclassical vitamin D hydroxy-metabolites act as "biased" agonists on VDR..., Slominski [/bib_ref]. For all the above reasons, it is still not possible to recommend the use or a dosage of vitamin D or related compounds as well as targets for serum 25(OH)D levels for the prevention or treatment or chronic, extra skeletal diseases, such as cardiovascular disorders, diabetes, autoimmune diseases, cancer and mortality. Nonetheless, supplementation with vitamin D along with antiresorptive therapy administered for the prevention of skeletal-related events or to treat bone metastases is needed, to control secondary hyperparathyroidism and prevent hypocalcemia. Further studies are needed in this field . It is advisable to perform large RCTs with multiple outcomes, assigning participants of similar age to different regimens of vitamin D supplementation, also comparing Vitamin D and extraskeletal effects: research agenda - To perform large randomized controlled trials simultaneously assessing multiple outcomes, assessing the efficacy of parental vitamin D compounds (cholecalciferol, ergocalciferol, calcidiol) or non-hypercalcemic active vitamin D analogs - To employ and assess the efficacy of multiple regimens of parental vitamin D compounds - To measure baseline and attained serum 25(OH)D levels by mass spectrometry, also in order to assess serum levels of other active and non-active intermediate/final vitamin D metabolites - To enroll subjects with baseline serum 25(OH)D levels lower than 20 ng/ml (50 nmol/l) - To assess safety in clinical trials evaluating non classical toxic effects (i.e. falls), besides classical toxic effects (hypercalciuria and hypercalcemia) - To perform meta-analyses pulling together RCTs employing the same regimen, the same age group, and individuals with comparable baseline 25(OH)D levels - To publish negative results of RCTs pro-hormones besides cholecalciferol, such as ergocalciferol (vitamin D2) and calcidiol [25(OH)D], which are supposed to give rise to different active intermediate metabolites with short half-life after supplementation that could be responsible for wanted or unwanted biologic effects. Levels of baseline and attained serum 25(OH)D should be measured with standard assays (i.e., mass spectrometry). Participants with low vitamin D levels (i.e., <50 nmol/l) should be enrolled. Safety (number of falls) should always be assessed as a secondary outcome. Studies employing multiple regimens of vitamin D, possibly against placebo, should be planned in order to test whether a dose-response relationship exists. Furthermore, it is necessary to perform meta-analyses pulling together RCTs employing the same regimen, the same age group, and not just the target attained serum 25(OH)D, and individuals with comparable baseline 25(OH)D levels. Negative trials should be published and included in metaanalyses. While the administration of calcitriol should be avoided for the high risk of hypercalciuria and hypercalcemia, RCTs employing active, non-hypercalcemic vitamin D analogs should be carried out in patients with specific tumors, such as prostate cancer. # Conclusion The promising results from the growing literature on the associations between vitamin D and extraskeletal chronic is not matched by the results obtained in intervention studies. To prove a causal relationship and recommend the use of vitamin D-related compounds in extra skeletal diseases, more trials are needed to demonstrate that maintaining 25 (OH)D levels within a certain range may be useful and safe in both the prevention and treatment of these diseases. [fig] Figure 1: Vitamin D metabolism. Endogenous or exogenous cholecalciferol and calcidiol are the inactive precursors of the biological active hormone calcitriol. Calcitriol, classically produced in the kidneys under the positive and negative regulation of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), respectively, can also be synthesized in extra-renal tissues, where its production is mainly driven by the substrate, 25 hydroxyvitamin D (25(OH)D). The nearly ubiquitously expressed vitamin D receptor (VDR) mediates calcitriol actions in skeletal and extra-skeletal tissues [/fig] [fig] Figure 2: Calcitriol-mediated extraskeletal effects, as demonstrated in vitro and in vivo in animal models, likely mediating the possible extraskeletal effects in chronic diseases in humans (Asterisk shown according to Evidence Based Medicine's levels 1b-2b; ND not demonstrated, i.e. level of evidence 2c and below). The extraskeletal effects have to be further confirmed given contradictory results in meta-analyses and randomized controlled trials (RCT) [/fig] [table] Table 1: Ongoing large-scale randomized controlled trials in subjects aged 50 years or more, to assess vitamin D-mediated effects on multiple health outcomes [/table]	None	https://link.springer.com/content/pdf/10.1007%2Fs12020-017-1290-9.pdf	None
a337574f44e31b56910ce4dde8ea49adb9290d60	pubmed	Clinical practice guidelines for IgG4‐related sclerosing cholangitis	Clinical practice guidelines for IgG4‐related sclerosing cholangitis IgG4-related sclerosing cholangitis (IgG4-SC) is a distinct type of cholangitis frequently associated with autoimmune pancreatitis and currently recognized as a biliary manifestation of IgG4-related disease. Although clinical diagnostic criteria of IgG4-SC were established in 2012, differential diagnosis from primary sclerosing cholangitis and cholangiocarcinoma is sometimes difficult. Furthermore, no practical guidelines for IgG4-SC are available. Because the evidence level of most articles retrieved through searching the PubMed, Cochrane Library, and Igaku Chuo Zasshi databases was below C based on the systematic review evaluation system of clinical practice guidelines MINDS 2014, we developed consensus guidelines using the modified Delphi approach. Three committees (a guideline creating committee, an expert panelist committee for rating statements according to the modified Delphi method, and an evaluating committee) were organized. Eighteen clinical questions (CQs) with clinical statements were developed regarding diagnosis (14 CQs) and treatment (4 CQs). Recommendation levels for clinical statements were set using the modified Delphi approach. The guidelines explain methods for accurate diagnosis, and safe and appropriate treatment of IgG4-SC. # Introduction IgG4-related sclerosing cholangitis (IgG4-SC) is a distinct type of cholangitis characterized by elevation of serum IgG4 levels, dense infiltration of IgG4-positive plasma cells and lymphocytes, with fibrosis and obliterative phlebitis in the bile duct wall [bib_ref] Diagnostic criteria for IgG4-related sclerosing cholangitis based on cholangiographic classification, Nakazawa [/bib_ref]. IgG4-SC, which is frequently associated with autoimmune pancreatitis (AIP), is currently recognized as a biliary manifestation of a systemic disorder termed IgG4-related disease [bib_ref] IgG4-related disease, Kamisawa [/bib_ref]. IgG4-SC is diagnosed via a combination of imaging, serological, and histopathological findings, coexistence of other IgG4-related diseases, and effectiveness of steroid therapy according to clinical diagnostic criteria of IgG4-SC 2012 [bib_ref] Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012, Ohara [/bib_ref]. Cholangiographic findings of IgG4-SC involving the hilar and/or intrahepatic bile ducts are similar to those of hilar cholangiocarcinoma or primary sclerosing cholangitis (PSC). Some IgG4-SC cases were resected on suspicion of cholangiocarcinoma. PSC is a progressive and chronic disease with poor prognosis and does not respond GUIDELINE to steroid therapy. Therefore, IgG4-SC should be differentiated from the two diseases. However, no previous guidelines for IgG4-SC have been published. The present guidelines describe methods for the accurate diagnosis, and safe and appropriate treatment of IgG4-SC based on specialized gastroenterological knowledge, skills, and experience. Although gastroenterologists are the primary target users of these clinical practice guidelines, we cover a wide range of clinical issues for general clinicians, as various IgG4-related diseases are frequently associated with IgG4-SC. To understand characteristic features of IgG4-SC, background questions for concept, etiology, epidemiology and prognosis were described. Adults are the primary patients addressed in the guidelines, and children are excluded. The guidelines describe currently accepted standard management but do not force medical action. Appropriate management of patients should be determined based on the situation of each institute and patient. # Methods Evidence level and establishing consensus guidelines using the Delphi approach A total of 234 and 2,340 publications published between 1991 and March 2017 were retrieved from a search of the PubMed database using the key words "IgG4-related sclerosing cholangitis" and "autoimmune pancreatitis", respectively. There was only one randomized controlled trial report, and the evidence level of the other publications was below grade C (low quality). Therefore, we developed consensus guidelines using the modified Delphi approach [bib_ref] Amendment of the Japanese consensus guidelines for autoimmune pancreatitis, 2013 I. Concept..., Okazaki [/bib_ref]. This method, which provides panelists with the opportunity to discuss their judgements between the ratings' rounds, is suitable for the development of consensus guideline statement. To establish the consensus guidelines, three committees were organized, as follows: a guideline-creation committee for developing clinical questions (CQs) and statements (pancreatobiliary specialist [n = 16], radiologist [n = 1], and pathologist [n = 2]), an expert panelist committee for rating statements according to the modified Delphi method (pancreatobiliary specialist [n = 9] and pathologist [n = 1]), and an evaluation committee (pancreatobiliary special physician [n = 2], pancreatobiliary special surgeon [n = 2], gastroenterologist [n = 1], and guideline-development specialist [n = 1]) (Appendix 1). As there are only a few IgG4-SC specialists, eight creation specialists doubled as expert panelists. However, these panelists did not assess items with which they were involved. ## Clinical question (cq) preparation The guideline-creation committee proposed 18 CQs for diagnosis and treatment (4 CQs) in consideration of PICO format, which described the population, intervention, control, and outcomes. Literature search and evidence assessment Key words were extracted from the CQs, and academic papers were collected. A literature search was performed using the PubMed (MEDLINE), Cochrane Library, and Igaku Chuo Zasshi databases covering the period between 1995 and March 2017. Additionally, we searched the reference lists of articles identified by this search strategy and selected those that we judged to be relevant. Review articles and book chapters are cited to provide readers with more details and references. The search formula for each CQ will be available at the homepage of the Japan Biliary Association (http://www.tando.gr.jp/). The guidelines were developed with the use of system of the clinical practice guidelines MINDS 2014 to evaluate strength of systematic reviews. The quality of evidence was graded as A (high), B (moderate), C (low), or D (very low). ## Process for developing the original draft The guideline-creation committee members developed, evaluated, and revised statements and comments for the CQs. The revised draft was also evaluated and revised through a review meeting of the guideline committee. The draft was discussed at a symposium and special session held on 29 September 2017, during the 53 rd Annual Meeting of the Japan Biliary Association. Establishing a consensus and grading the strength of recommendations using the modified Delphi method Ratings for statements and comments pertaining to each CQ were developed using the modified Delphi approach. Ratings were on a 9-point scale, with 1 being highly inappropriate and 9 being highly appropriate. A clinical statement receiving a median score greater than 7 from the panel was regarded as valid. The creating specialists revised some of the statements and comments after discussion with expert panelists. The revised statements and comments were then rated again. Based on the two-round modified Delphi approach, final statements and comments were developed. The strength of recommendations was classified as high (strong) (recommendation 1) or low (weak) (recommendation 2), as determined according to the following factors: quality of the evidence, patient's preferences, benefits and harms (risks), and cost. A recommendation was applied when more than 70% of the expert specialists (Delphi method) agreed. The use of "We recommend-" was adopted as the style for a strong recommendation. "We suggest-" was adopted as the style for a weak recommendation. ## Evaluation by the evaluating committee and public comments The revised draft after the modified Delphi approach was evaluated by the evaluation committee using AGREE II. After final modifications were made, public comments were invited on the website of the Japan Biliary Association. Based on these public comments, some comments were modified. # Background questions What is IgG4-SC? - IgG4-SC is SC induced via an autoimmune mechanism and responds dramatically to steroid therapy. Most cases are associated with systemic IgG4-related diseases such as AIP. Comment: IgG4-SC is SC that responds dramatically to steroid therapy, with good clinical prognosis. Differential diagnosis from PSC, cholangiocarcinoma, pancreatic cancer, and secondary SC is necessary because these conditions show similar cholangiograms to IgG4-SC. IgG4-SC is a biliary manifestation of IgG4-related diseases because it is associated with systemic IgG4related diseases such as AIP [bib_ref] Close relationship between autoimmune pancreatitis and multifocal fibrosclerosis, Kamisawa [/bib_ref]. The etiology is thought to involve an autoimmune mechanism because various antibodies are detected and the disease responds well to steroid therapy [bib_ref] Recent advances in autoimmune pancreatitis: concept, diagnosis, and pathogenesis, Okazaki [/bib_ref]. IgG4-SC is diagnosed according to clinical diagnostic criteria of IgG4-SC 2012 [bib_ref] Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012, Ohara [/bib_ref]. It is treated by steroid therapy in the same manner as AIP. Since the 1970s, cases of SC associated with chronic pancreatitis have been published overseas and in Japan. In most of these reports, pancreatic disease was diagnosed as chronic pancreatitis and biliary disease as PSC. Waldram et al. reported two SC cases associated with chronic pancreatitis, diabetes and Sj€ ogren syndrome in 1975 [bib_ref] Chronic pancreatitis, sclerosing pancreatitis, sclerosing cholangitis, and sicca complex in two siblings, Waldram [/bib_ref]. Sj€ ogren et al. reported two PSC cases that responded to steroid therapy [bib_ref] Primary sclerosing cholangitis associated with fibrosis of submandibular glands and the pancreas, Sj€ Ogren [/bib_ref]. In 1991, reported lymphoplasmacytic sclerosing pancreatitis with cholangitis as a variant of PSC in Japan by studying surgical specimens [bib_ref] Lymphoplasmacytic sclerosing pancreatitis with cholangitis: a variant of primary sclerosing cholangitis extensively..., Kawaguchi [/bib_ref]. Since 1996, some cases of SC meeting the diagnostic criteria of PSC but showing a better clinical course than classic PSC have been reported. These were reported as "atypical PSC" in order to discriminate them from classic PSC [bib_ref] Atypical primary sclerosing cholangitis cases associated with unusual pancreatitis, Nakazawa [/bib_ref]. The atypical PSC cases showed characteristic findings such as onset at older age, good response to steroid therapy, biliary drainage, no association with ulcerative colitis, and frequent association with characteristic chronic pancreatitis. After the concept of AIP was established, these cases have been reported as "sclerosing cholangitis with autoimmune pancreatitis" [bib_ref] Clinical differences between primary sclerosing cholangitis and sclerosing cholangitis with autoimmune pancreatitis, Nakazawa [/bib_ref]. After the concept of IgG4-related diseases was established and isolated SC without AIP was reported, these cases have been reported as IgG4-SC [bib_ref] IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitisassociated..., Zen [/bib_ref]. The term "IgG4-associated sclerosing cholangitis" has also been used [bib_ref] Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy, Ghazale [/bib_ref]. "IgG4-related sclerosing cholangitis" became the formal name at the 1 st International Symposium on IgG4-related disease, with establishment of uniform international nomenclature and pathologic characteristics of IgG4-related disease [bib_ref] Recommendations for the nomenclature of IgG4-related disease and its individual organ system..., Stone [/bib_ref]. How is IgG4-SC classified? - Classifications based on cholangiograms and the association with AIP have been used. Inclusion of type 1 IgG4-SC into the IgG4-SC category has been disputed. Comment: Cholangiographic classification, which is useful for differential diagnosis, is the prevailing method [bib_ref] Schematic classification of sclerosing cholangitis with autoimmune pancreatitis by cholangiography, Nakazawa [/bib_ref]. Type 1 IgG4-SC involves stenosis only in the lower bile duct and thus should be differentiated from pancreatic cancer and cholangiocarcinoma [bib_ref] Diagnostic criteria for IgG4-related sclerosing cholangitis based on cholangiographic classification, Nakazawa [/bib_ref]. Type 2 IgG4-SC, in which stenosis is diffusely distributed throughout the intrahepatic and extrahepatic bile ducts, should be differentiated from PSC and is further subdivided into two subtypes: type 2a, characterized by stricture of the intrahepatic bile ducts with prestenotic dilation; and type 2b, characterized by stricture of the intrahepatic bile ducts without prestenotic dilation and reduced bile duct branches, which should be discriminated from the "pruned-tree" appearance in PSC. Type 3 IgG4-SC is characterized by stenosis in the hilar hepatic lesions and lower bile duct. Type 4 IgG4-SC presents with strictures of the bile duct only in the hilar hepatic lesions. The cholangiographic findings of types 3 and 4 IgG4-SC should be discriminated from those of cholangiocarcinoma. A national survey performed in 2015 reported that the frequencies of the types of IgG4-SC are 64% (type 1), 5% (type 2a), 8% (type 2b), 10% (type 3), and 10% (type 4) [bib_ref] Clinical features, response to treatment, and outcomes of IgG4-related sclerosing cholangitis, Tanaka [/bib_ref]. Some type 2 cases can be differentiated from PSC by endoscopic retrograde cholangiography (ERC) findings but not differentiated from cholangiocarcinoma, which exhibits diffuse and invasive development. Types 3 and 4, which exhibit localized stenosis, should be carefully differentiated from cholangiocarcinoma using bile duct biopsy and intraductal ultrasonography (IDUS) [bib_ref] Endoscopic transpapillary intraductal ultrasonography and biopsy in the diagnosis of IgG4-related sclerosing..., Naitoh [/bib_ref]. IgG4-SC cases with stenosis at hilar hepatic lesions are sometimes associated with IgG4-related inflammatory hepatic pseudotumors [bib_ref] IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitisassociated..., Zen [/bib_ref]. IgG4-SC is also classified based on the presence or absence of association with AIP. IgG4-SC is frequently associated with AIP. When IgG4-SC is not associated with AIP, this is referred to as "isolated IgG4-SC" [bib_ref] Isolated IgG4-related sclerosing cholangitis: a report of 9 cases, Graham [/bib_ref]. A Japanese multicenter study conducted by nine major hospitals of the IgG4-related disease group of the [bib_ref] Establishment of a serum IgG4 cut-off value for the differential diagnosis of..., Ohara [/bib_ref]. Type 3 and 4 IgG4-SC cases showed lower frequencies of association with AIP. A national survey performed in 2013 reported that isolated IgG4-related SC included three cases of type 1, three cases of type 2, four cases of type 3, 22 cases of type 4, and 11 cases of other types [bib_ref] Nationwide survey for primary sclerosing cholangitis and IgG4-related sclerosing cholangitis in Japan, Tanaka [/bib_ref]. Type 4 is the most frequent type not associated with AIP. Isolated type 4 IgG4-SC is very difficult to discriminate from cholangiocarcinoma. A case series reported five cases of isolated type 1 IgG4-SC [bib_ref] Isolated intrapancreatic IgG4-related sclerosing cholangitis, Nakazawa [/bib_ref]. Three of the five cases involved surgical resection of cholangiocarcinoma at the lower bile duct. The other two cases were diagnosed correctly as isolated type 1 IgG4-SC, obviating the need for surgical resection based on high serum IgG4 levels and diffuse wall thickening in the bile duct. Inclusion of the type 1 disease in the IgG4-SC categories has been disputed. Some researchers claim that the type 1 disease should not be classified as IgG4-SC for the following reasons: 1) The stricture of the lower bile duct is caused by compression due to AIP [bib_ref] Endoscopic evaluation of factors contributing to intrapancreatic biliary stricture in autoimmune pancreatitis, Hirano [/bib_ref]. This claim is based on the fact that type 1 IgG4-SC was not found in some cases of focal-type AIP with only body and tail involvement. 2) The frequency of IgG4-SC increases when type 1 IgG4-SC is included in the IgG4-SC category in epidemiologic surveys. 3) In the international consensus diagnostic criteria, IgG4-SC with extrapancreatic stenosis is regarded as additional organ involvement, which is useful in the diagnosis of AIP [bib_ref] International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association..., Shimosegawa [/bib_ref]. By contrast, others claim that type 1 IgG4-SC should be included as a class of IgG4-SC for the following reasons: 1) Pathologic examination of the bile duct wall obtained from surgically resected samples showed abundant infiltration of IgG4-positive plasma cells, storiform fibrosis, and obstructive phlebitis, which are characteristics of IgG4-SC inflammation [bib_ref] IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitisassociated..., Zen [/bib_ref]. 2) Thickening of the bile duct wall is observed continuously from the intrapancreatic to extrapancreatic bile ducts [bib_ref] Endoscopic transpapillary intraductal ultrasonography and biopsy in the diagnosis of IgG4-related sclerosing..., Naitoh [/bib_ref]. 3) Isolated type 1 IgG4-SC exhibiting no AIP findings has been reported [bib_ref] Isolated intrapancreatic IgG4-related sclerosing cholangitis, Nakazawa [/bib_ref]. Indeed, it is difficult to identify the major factor contributing to the thickening of the bile duct wall - inflammation of the bile duct or compression due to AIP. Comments on diagnostic criteria of IgG4-SC based on working group debates indicate that most cases of IgG4-SC associated with AIP exhibit stricture of the lower bile duct caused by both thickening of the bile duct wall itself and pancreatic inflammation and edema [bib_ref] Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012, Ohara [/bib_ref]. What is the positioning of IgG4-SC within SC? - SC is classified as PSC, IgG4-SC, or secondary SC according to the disease concept and clinical features. PSC is an idiopathic, progressive, and chronic intrahepatic cholestasis caused by fibrous stenosis of the intrahepatic and extrahepatic bile ducts and does not respond to steroid therapy, whereas IgG4-SC does respond to steroid therapy. PSC is positioned different from secondary SC, which should be treated etiologically. Comment: SC is classified as PSC, IgG4-SC, or secondary SC according to the disease concept and clinical features. PSC is an idiopathic, progressive, chronic intrahepatic cholestasis caused by fibrous stenosis of the intrahepatic and extrahepatic bile ducts. To correctly diagnose PSC, IgG4-SC and secondary SC must be ruled out [bib_ref] Primary sclerosing cholangitis, Lindor [/bib_ref] [bib_ref] Primary sclerosing cholangitis and the microbiota: current knowledge and perspectives on etiopathogenesis..., Tabibian [/bib_ref] [bib_ref] The 2016 diagnostic criteria for primary sclerosing cholangitis, Nakazawa [/bib_ref]. IgG4-SC and PSC show similar imaging of the bile ducts, although their disease concept, pathophysiology, therapy, and prognosis are different; therefore, it is important to distinguish these two diseases. IgG4-SC has been reported in patients over age 60 years most commonly in association with an increase in serum IgG4 levels, whereas two peaks in age distribution were clearly observed in PSC patients with an approximately 10% increase in serum IgG4 levels [bib_ref] Establishment of a serum IgG4 cut-off value for the differential diagnosis of..., Ohara [/bib_ref] [bib_ref] Nationwide survey for primary sclerosing cholangitis and IgG4-related sclerosing cholangitis in Japan, Tanaka [/bib_ref] [bib_ref] Analysis of 388 cases of primary sclerosing cholangitis in Japan; Presence of..., Takikawa [/bib_ref]. PSC is complicated by inflammatory bowel diseases such as ulcerative colitis. The prevalence of inflammatory bowel diseases in PSC patients is as high as 60-80% in Western countries and 34% in Japan [bib_ref] Nationwide survey for primary sclerosing cholangitis and IgG4-related sclerosing cholangitis in Japan, Tanaka [/bib_ref] [bib_ref] ACG clinical guideline. Primary sclerosing cholangitis, Lindor [/bib_ref] [bib_ref] Diagnosis and management of primary sclerosing cholangitis, Chapman [/bib_ref]. In contrast, IgG4-SC is often complicated by AIP, sclerosing sialadenitis, and retroperitoneal fibrosis, but not inflammatory bowel diseases. Pathologic characteristics of PSC include fibrous obliterative cholangitis, so-called "onion-skin lesions," whereas IgG4-positive plasma cells infiltrate the portal area in IgG4-SC [bib_ref] Manifestations of nonsuppurative cholangitis in chronic hepatobiliary diseases: morphologic spectrum, clinical correlations..., Ludwig [/bib_ref]. IgG4-SC responds to steroid therapy. In contrast, PSC is non-responsive to steroids and immunesuppressive agents, and currently, liver transplantation is the only effective treatment [bib_ref] Bile acids for primary sclerosing cholangitis, Poropat [/bib_ref] [bib_ref] Meta-analysis: ursodeoxycholic acid for primary sclerosing cholangitis, Triantos [/bib_ref] [bib_ref] Urosdeoxycholic acid in primary sclerosing cholangitis: a meta-analysis and systematic review, Othman [/bib_ref]. It is necessary to rule out the following features of secondary SC with obvious pathogenesis, including infection, cholangiocarcinomas, previous surgery or trauma involving the biliary tract, common bile duct stones and chronic inflammation, congenital biliary anatomic defects, corrosive cholangitis, ischemic bile duct stenosis, AIDS-related cholangitis, and biliary injury caused by intra-arterial chemotherapy [bib_ref] Primary sclerosing cholangitis, Lindor [/bib_ref] [bib_ref] ACG clinical guideline. Primary sclerosing cholangitis, Lindor [/bib_ref]. Secondary SC should be principally treated etiologically [bib_ref] Etiopathogenesis of primary sclerosing cholangitis, O'mahony [/bib_ref] [bib_ref] Primary sclerosing cholangitis, Tazuma [/bib_ref]. Are there characteristic histologic findings of IgG4-SC? - In intrahepatic and extrahepatic large bile ducts, transmural marked lymphoplasmacytic infiltration and fibrosis are observed, which give rise to bile duct wall thickening. Notably, storiform fibrosis and obliterative phlebitis are important histologic findings for diagnosing IgG4-SC. - An increase in IgG4-positive cells is characteristic but not specific; thus, a diagnosis of IgG4-SC needs to be established based on histologic findings. Comment: IgG4-SC primarily involves the intrahepatic and extrahepatic large bile ducts and is characterized by transmural marked lymphoplasmacytic infiltration and fibrosis, which gives rise to duct wall thickening [fig_ref] Figure 2: Histological findings of transmural inflammatory cell infiltration and fibrosis in the bile... [/fig_ref] [bib_ref] IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitisassociated..., Zen [/bib_ref] [bib_ref] Isolated IgG4-related sclerosing cholangitis: a report of 9 cases, Graham [/bib_ref] [bib_ref] The pathology of IgG4-related disease in the bile duct and pancreas, Zen [/bib_ref] [bib_ref] Biliary tract involvement in autoimmune pancreatitis, Nishino [/bib_ref] [bib_ref] Immunoglobulin G4 associated cholangitis: description of an emerging clinical entity based on..., Bjornsson [/bib_ref]. In contrast to PSC, in which the focus of inflammation is the epithelium, no cell damage or inflammatory cell infiltration is observed in the epithelium. Similar to IgG4-related disease in other organs, eosinophilic infiltration, storiform fibrosis [fig_ref] Figure 3: Histological findings of storiform fibrosis in the bile duct of IgG4-SC [/fig_ref] , and/or obliterative phlebitis are commonly identified, and the latter two are particularly regarded as diagnostically important. Storiform fibrosis is an irregular swirling arrangement of collagen [bib_ref] The pathology of IgG4-related disease in the bile duct and pancreas, Zen [/bib_ref] , and inflammatory cells are commonly observed. Obliterative phlebitis is an inflammatory lesion with inflammatory cells and fibrosis that involves and obliterates the venous lumen [bib_ref] The pathology of IgG4-related disease in the bile duct and pancreas, Zen [/bib_ref]. IgG4-SC lesions involve not only the bile duct walls but also the peribiliary adipose tissue, peripheral nerves, and portal regions of the liver [bib_ref] IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitisassociated..., Zen [/bib_ref] [bib_ref] IgG4-related sclerosing cholangitis in the absence of autoimmune pancreatitis mimicking extrahepatic cholangiocarcinoma, Lin [/bib_ref]. There are no histologic differences between IgG4-SC with and without AIP [bib_ref] Isolated IgG4-related sclerosing cholangitis: a report of 9 cases, Graham [/bib_ref] [bib_ref] IgG4-related sclerosing cholangitis in the absence of autoimmune pancreatitis mimicking extrahepatic cholangiocarcinoma, Lin [/bib_ref]. Infiltration of numerous IgG4-positive cells [fig_ref] Figure 5: Immunohistochemical findings of infiltration of numerous IgG4-positive cells in the bile duct... [/fig_ref] is characteristic ofbut not specific to -IgG4-SC. In PSC, numerous IgG4-positive cells can also be identified, notably in the inflamed large bile ducts, with marked inflammatory cell infiltration [bib_ref] IgG4 + plasma cell infiltrates in liver explants with primary sclerosing cholangitis, Zhang [/bib_ref] [bib_ref] Immunoglobulin G4-positive plasma cell infiltration in explanted livers for primary sclerosing cholangitis, Zen [/bib_ref] [bib_ref] Frequency and significance of IgG4 immunohistochemical staining in liver explants from patients..., Fischer [/bib_ref]. In a study of 122 explanted livers with PSC, >50 IgG4-positive cells per high power field (HPF) were observed in 15.6% of the patients [bib_ref] Frequency and significance of IgG4 immunohistochemical staining in liver explants from patients..., Fischer [/bib_ref]. In contrast to IgG4-SC, however, IgG4-positive cells are rare in the peripheral portal tracts in PSC. Numerous IgG4-positive cells may also appear in cholangiocarcinomas [bib_ref] Significance of immunoglobulin G4 (IgG4)-positive cells in extrahepatic cholangiocarcinoma: molecular mechanism of..., Harada [/bib_ref] [bib_ref] Infiltration of peritumoural but tumour-free parenchyma with IgG4-positive plasma cells in hilar..., Resheq [/bib_ref] , and >50 IgG4-positive cells per HPF were found in 9% of 54 resected specimens [bib_ref] Significance of immunoglobulin G4 (IgG4)-positive cells in extrahepatic cholangiocarcinoma: molecular mechanism of..., Harada [/bib_ref]. Thus, the diagnosis of IgG4-SC is difficult to establish based on IgG4-immunostaining alone, and histologic findings must be thoroughly evaluated. According to clinical diagnostic criteria of IgG4-SC 2012 [bib_ref] Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012, Ohara [/bib_ref] , the diagnosis can be definitively made based on histologic findings if three of the following four conditions are identified: (1) marked lymphoplasmacytic infiltration and fibrosis; (2) >10 IgG4-positive plasma cells per HPF; (3) storiform fibrosis; and (4) obliterative phlebitis. A cut-off of >10 IgG4-positive cells per HPF was adopted to make a biopsy-based diagnosis of IgG4-SC possible. In contrast, a consensus statement on the pathology of IgG4-related disease [bib_ref] Consensus statement on the pathology of IgG4-related disease, Deshpande [/bib_ref] indicated that >50 IgG4positive cells per HPF in resected specimens and >10/ HPF in biopsy samples as well as an IgG4/IgG-positive cell ratio >40% need to be satisfied, and lesions are regarded as histologically highly suggestive of IgG4related disease if two of the following three conditions are additionally satisfied: (1) marked lymphoplasmacytic infiltration; (2) storiform fibrosis; and (3) obliterative phlebitis. IgG4-SC cases that do not satisfy the requirement for an IgG4/IgG-positive cell ratio >40% have been reported [bib_ref] Isolated IgG4-related sclerosing cholangitis: a report of 9 cases, Graham [/bib_ref] , however. Is there any relationship between IgG4-SC and hepatic inflammatory pseudotumors? - IgG4-SC sometimes presents with mass-forming cholangitis, particularly around the hilar bile duct. These cases are referred to as hepatic inflammatory pseudotumors. The mass lesions consist of expanded periductal connective tissue with involvement of the liver parenchyma being uncommon. Comment: Some patients with IgG4-SC present with a hilar mass, imaging features of which mimic hilar cholangiocarcinomas [bib_ref] IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitisassociated..., Zen [/bib_ref] [bib_ref] Autoimmune pancreatitis with hepatic inflammatory pseudotumor, Kanno [/bib_ref]. Such cases are called IgG4-related hepatic inflammatory pseudotumors. However, hepatic inflammatory pseudotumors are heterogeneous in nature and not always IgG4-related. They are classified into lymphoplasmacytic and fibro-inflammatory types based on histologic findings, with the former corresponding to IgG4-related disease [bib_ref] Pathological classification of hepatic inflammatory pseudotumor with respect to IgG4-related disease, Zen [/bib_ref]. Lymphoplasmacytic-type pseudotumors typically develop in hilar bile ducts, whereas fibro-inflammatory-type lesions more commonly affect the liver parenchyma. Although a study based on surgically treated patients suggested that the lymphoplasmacytic type accounts for 37% of hepatic pseudotumors, the exact relative frequency is unknown [bib_ref] Pathological classification of hepatic inflammatory pseudotumor with respect to IgG4-related disease, Zen [/bib_ref]. What is the etiology of IgG4-SC? - Although the exact etiology is unknown, autoimmunity is the most suspected cause of IgG4-SC. Comment: Of several hypotheses that have been proposed as a potential pathogenetic mechanism of IgG4-SC, an autoimmune theory is currently regarded as most likely correct. This possibility is supported by the occasional detection of autoantibodies in patients with IgG4-SC, known disease-susceptible HLA haplotypes for AIP, and good response to corticosteroids [bib_ref] Recent advances in autoimmune pancreatitis: concept, diagnosis, and pathogenesis, Okazaki [/bib_ref] [bib_ref] HLA DRB10405-DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population, Kawa [/bib_ref]. In addition, injection of IgG isolated from patients with AIP into neonatal mice was shown to induce pancreatic injury, suggesting a potential pathogenetic effect of IgG [bib_ref] Pathogenicity of IgG in patients with IgG4-related disease, Shiokawa [/bib_ref]. An Italian research group raised the possibility that Helicobacter pylori infection initiates an immune reaction leading to the production of antibodies against the plasminogen-binding protein of Helicobacter pylori, and these antibodies could behave as autoantibodies against the pancreatic acinar cells via molecular mimicry [bib_ref] Identification of a novel antibody associated with autoimmune pancreatitis, Frulloni [/bib_ref]. However, another study could not validate these findings [bib_ref] No evidence to support a role for Helicobacter pylori infection and plasminogen..., Culver [/bib_ref]. Other potential pathogenetic models include allergy, paraneoplastic syndrome, and immune complex deposition [bib_ref] Risk of cancer in patients with autoimmune pancreatitis, Shiokawa [/bib_ref] [bib_ref] Autoimmune pancreatitis: a systemic immune complex mediated disease, Deshpande [/bib_ref]. What is the epidemiology of IgG4-SC? - In Japan, the number of patients with IgG4-SC is estimated at approximately 2,500, according to an epidemiologic study of AIP. Comment: To date, no epidemiologic study of IgG4-SC has been reported. Regarding AIP, another IgG4-related disease, an epidemiologic study in 2011 estimated the prevalence and incidence as 4.6 and 1.4 per 100,000 population, respectively [bib_ref] Nationwide epidemiological survey of autoimmune pancreatitis in Japan in 2011, Kanno [/bib_ref]. As IgG4-SC was present as a comorbidity in 39% of patients with AIP, the prevalence and incidence of IgG4-SC in patients with AIP were extrapolated as 1.8 and 0.5 per 100,000 population, respectively. According to a nationwide survey for IgG4-SC in 2015 [bib_ref] Clinical features, response to treatment, and outcomes of IgG4-related sclerosing cholangitis, Tanaka [/bib_ref] , approximately 10% of patients with IgG4-SC are not diagnosed as having AIP. Collectively, the total prevalence of IgG4-SC was estimated as 2.0 per 100,000 population, and the number of patients with IgG4-SC was thus calculated as 2,500. Case series of IgG4-SC have been reported from the United States, the United Kingdom, and Japan [fig_ref] Table 1: Comparison of clinical features of IgG4-related sclerosing cholangitis [/fig_ref] [bib_ref] Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy, Ghazale [/bib_ref] [bib_ref] Clinical features, response to treatment, and outcomes of IgG4-related sclerosing cholangitis, Tanaka [/bib_ref] [bib_ref] Type 1 autoimmune pancreatitis and IgG4-related sclerosing cholangitis is associated with extrapancreatic..., Huggett [/bib_ref]. IgG4-SC is a male-dominant disease, with males accounting for 80% of all patients. All reports agree regarding the age at highest risk for developing IgG4-SC, indicating an average or median age at diagnosis of 60-70 years. In case series from Japan, age at diagnosis ranged from 23.0 to 88.5 years, and no childhood or adolescent patients were reported [bib_ref] Clinical features, response to treatment, and outcomes of IgG4-related sclerosing cholangitis, Tanaka [/bib_ref] , unlike in the case of PSC [bib_ref] Nationwide survey for primary sclerosing cholangitis and IgG4-related sclerosing cholangitis in Japan, Tanaka [/bib_ref]. Jaundice was the most prevalent symptom at diagnosis in reports from the United States and the United Kingdom, observed in more than 70% of all patients. Jaundice was the most prevalent symptom in Japan as well, but it was observed in only 35% of patients; notably, 28% of patients were diagnosed without any apparent symptoms [bib_ref] Clinical features, response to treatment, and outcomes of IgG4-related sclerosing cholangitis, Tanaka [/bib_ref]. AIP was noted as a comorbidity in 90% of patients with IgG4-SC in all case series. Is the outcome of IgG4-SC good? - The outcome is probably excellent, as treatment with corticosteroids is effective in most cases of IgG4-SC. However, as the long-term outcome remains unclear, further studies are warranted. Comment: The outcome of patients with IgG4-SC has been investigated in retrospective cohorts in the United States [bib_ref] Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy, Ghazale [/bib_ref] , the United Kingdom [bib_ref] Type 1 autoimmune pancreatitis and IgG4-related sclerosing cholangitis is associated with extrapancreatic..., Huggett [/bib_ref] , and Japan [bib_ref] Clinical features, response to treatment, and outcomes of IgG4-related sclerosing cholangitis, Tanaka [/bib_ref]. Sample size, follow-up period, corticosteroid treatment, and outcomes are summarized in [fig_ref] Table 2: Comparison of treatment and prognosis of IgG4-related sclerosing cholangitis [/fig_ref]. Progression to cirrhosis was noted in 5.2% in the United Kingdom cohort and 7.5% in the United States cohort. Mortality due to liver or bile duct problems was found in only one case in the United States cohort and two cases (liver failure and cholangiocarcinoma) and one case involving liver transplantation in the United Kingdom. In Japan, only four cases (two cholangiocarcinoma and two hepatic failure) were recorded, accounting for 0.8%, which was lower than the United States and United Kingdom rates [bib_ref] Clinical features, response to treatment, and outcomes of IgG4-related sclerosing cholangitis, Tanaka [/bib_ref] [bib_ref] Type 1 autoimmune pancreatitis and IgG4-related sclerosing cholangitis is associated with extrapancreatic..., Huggett [/bib_ref]. Therefore, poor outcomes, including liver or bile duct disease mortality and liver transplantation, can be avoided with corticosteroid treatment in most cases of IgG4-SC, and the outcome is excellent. However, the follow-up period remains insufficient to provide conclusive results, and potential biases associated with retrospective designs might be present in these case series. In this regard, the long-term outcome remains unclear, and further studies are warranted. In the United Kingdom report, the risk of all-cause death was increased compared with matched national statistics (OR = 2.07, CI = 1.07-3.55, P = 0.02). However, cancer-related mortality was not increased compared with the national studies (incidence ratio 1.95, CI = 0.6-4.51, P = 0.17); whether mortality is increased (and its cause if so) in patients with IgG4-SC remains to be elucidated. Is IgG4-SC associated with the development of cholangiocarcinoma? - IgG4-SC is not considered a risk factor for cholangiocarcinoma because cholangiocarcinoma rarely occurs during the follow-up period. Comment: It is pathologically difficult to differentiate between cholangiocarcinoma associated with IgG4 and cholangiocarcinoma arising from IgG4-SC, as 32% to 43% of patients with biliary tract cancer exhibit >10 IgG4-positive plasma cells per HPF within and around cancerous nests [bib_ref] Cholangiocarcinoma with respect to IgG4 Reaction, Harada [/bib_ref]. Three patients with cholangiocarcinoma and IgG4-SC have been reported [bib_ref] Early bile duct cancer in a background of sclerosing cholangitis and autoimmune..., Oh [/bib_ref] [bib_ref] IgG4-associated cholangitis with cholangiocarcinoma, Straub [/bib_ref] [bib_ref] Cholangiocarcinoma developed in a patient with IgG4-related disease, Douhara [/bib_ref] ; two patients were diagnosed concurrently, and one patient was diagnosed with cholangiocarcinoma during the follow-up period of IgG4-SC treatment [bib_ref] Cholangiocarcinoma developed in a patient with IgG4-related disease, Douhara [/bib_ref]. Hirano et al. reported 14 patients with malignancy among 113 cases of IgG4related disease; however, cholangiocarcinoma occurred in only one patient 1.7 years after diagnosis of IgG4-related disease (AIP) [bib_ref] Incidence of malignancies in patients with IgG4-related disease, Hirano [/bib_ref]. Shiokawa et al. [bib_ref] Risk of cancer in patients with autoimmune pancreatitis, Shiokawa [/bib_ref] also reported that among 108 patients with AIP, cholangiocarcinoma occurred in only one patient 5.6 years after the diagnosis during the follow-up period; malignant disease occurred in 15 patients during the same period. A retrospective cohort study of 527 patients with IgG4-SC in Japan [bib_ref] Clinical features, response to treatment, and outcomes of IgG4-related sclerosing cholangitis, Tanaka [/bib_ref] showed that four patients developed cholangiocarcinoma; two of the four patients were diagnosed at the same time, whereas the remaining two patients were diagnosed 4 months and 4 years after the diagnosis of IgG4-SC, respectively. Cholangiocarcinoma arising from IgG4-SC is thought to be a rare complication. However, evaluating the risk of cholangiocarcinoma will require longer cohort studies, as IgG4-SC is a relatively new concept for clinicians. ## Algorithm for diagnosis and treatment of igg4-sc (figs 6-9) IgG4-SC is suspected when diffuse or segmental stenosis of the bile duct with wall thickening is seen and/or the serum IgG4 level is high. The diagnosis of IgG4-SC is based on clinical diagnostic criteria of IgG4-SC 2012. When associated with AIP or other IgG4-related diseases, the diagnosis is straightforward. If not or association of these diseases is not definite, differential diagnosis can be difficult due to the challenge of obtaining a sufficient sample for the diagnosis of IgG4-SC by bile duct biopsy. IgG4-SC cholangiograms are similar to those for PSC and cholangiocarcinoma. Type 1 IgG4-SC produces stenosis only in the lower bile duct (intrapancreatic duct) and thus should be differentiated from pancreatic cancer and cholangiocarcinoma. Type 2 IgG4-SC, in which stenosis is diffusely distributed throughout the intrahepatic and extrahepatic bile ducts, should be differentiated from PSC. Type 3 IgG4-SC is characterized by stenosis in the hilar hepatic lesions and lower bile duct. Type 4 IgG4-SC The proportion in 115 patients with autoimmune pancreatitis, including those without IgG4-SC presents with strictures of the bile duct only in the hilar hepatic lesions. The cholangiographic findings of types 3 and 4 IgG4-SC should be discriminated from those of cholangiocarcinoma [fig_ref] Figure 6: Algorithm for diagnosis and treatment of IgG4-SC referred from Reference 18Fig [/fig_ref]. In the diagnosis of type 1 IgG4-SC, pancreatic cancer should be ruled out by endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) when the pancreatic mass of pancreas head is detected. Then, cholangiocarcinoma should be ruled out by bile duct biopsy under ERC. When IDUS and/or biopsy of the ampulla of Vater shows characteristic findings for IgG4-SC, steroid trial is suggested. If these examinations do not show characteristic findings or steroid trial is not effective, re-evaluation or surgical operation is selected. Surgical operation is indicated when malignant cells are detected or malignant diseases cannot be ruled out after careful re-evaluation [fig_ref] Figure 7: Algorithm for diagnosis and treatment of IgG4-SC referred from Reference 18 [/fig_ref]. In the diagnosis of type 2 IgG4-SC, when characteristic cholangiogram is obtained, steroid trial is suggested. If combination of IDUS, peroral cholangioscopy (POCS), bile duct biopsy and biopsy of the ampulla of Vater reveals characteristic findings for IgG4-SC in cases without characteristic cholangiogram, steroid trial is also suggested. If these examinations do not show characteristic findings or steroid trial is not effective, other sclerosing cholangitis or cholangiocarcinoma should be considered . In the diagnosis of types 3 and 4 IgG4-SC, cholangiocarcinoma should be ruled out by bile duct biopsy under ERC. If malignant cells are not detected and IDUS, POCS and/or biopsy of the ampullary of Vater shows characteristic findings for IgG4-SC, steroid trial is suggested. If these examinations do not show characteristic findings or steroid trial is not effective, re-evaluation or surgical operation is selected. Surgical operation is indicated when malignant cells are detected or malignant diseases cannot be ruled out after careful re-evaluation . Summary of imaging findings suggestive of IgG4-SC Imaging reflects the characteristic pathologic findings, such as submucosal inflammation with little change in the epithelium and wall thickening diffusely spreading to non-stenotic bile ducts in cholangiograms. In addition, these findings are dramatically improved with steroid therapy. Two aspects should be evaluated: distribution and character of stenosis, and wall thickness. ## Distribution and character of stenosis Ruling out malignant diseases using biopsy and cytology under ERC is necessary in localized stenosis. Evaluation of cholangiographic differences is necessary in diffuse stenosis. ## Wall thickness Diffuse wall thickening with preserved epithelium in stenotic and non-stenotic lesions is a characteristic finding for IgG4-SC. Treatment of IgG4-SC [fig_ref] Figure 11: Schematic illustration of treatment of IgG4-SC Fig [/fig_ref] Oral prednisolone at 0.6 mg/kg/day is recommended for initial remission induction therapy, with gradual reduction to a maintenance dose of 5 mg/day by 2-3 months. Maintenance dose should be continued for at least 3 years. Patients with comfortable radiological and serological improvement can stop steroids. After treatment is discontinued, patients should be followed up for relapse. # Results ## Clinical questions Diagnosis CQI-1) How is IgG4-SC diagnosed? - We recommend that diagnosis of IgG4-SC be based on the following four criteria: characteristic biliary imaging findings, elevation of serum IgG4 levels, coexistence of IgG4-related diseases, except those of the biliary tract, and characteristic histopathologic features (Recommendation 1, level C). - In a specialized facility in which detailed examinations such as endoscopic biliary biopsy and EUS-FNA can be performed, we suggest evaluating the Algorithm for diagnosis and treatment of IgG4-SC referred from Reference 18 effectiveness of steroid therapy as an optional extra diagnostic criterion to confirm a diagnosis of IgG4-SC after negative work-up for malignancy (Recommendation 2, level D). Comment: As IgG4-SC exhibits various cholangiographic features similar to those of PSC, pancreatic cancer, and cholangiocarcinoma, the differential diagnosis of IgG4-SC from these three progressive or malignant diseases is very important. Two sets of diagnostic criteria for IgG4-SC have been proposed. The HISORt (histology, imaging, serology, other organ involvement, and response to steroid therapy) criteria were originally developed for AIP and adapted for IgG4-SC [bib_ref] Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy, Ghazale [/bib_ref]. In 2012, a second set of diagnostic criteria for IgG4-SC was proposed by a Japanese group [bib_ref] Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012, Ohara [/bib_ref] [fig_ref] Table 3: Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012 [3] 1 [/fig_ref]. Diagnosis of IgG4-SC is based on the following four criteria: (1) characteristic biliary imaging findings; (2) elevation of serum IgG4 levels; (3) coexistence of IgG4-related diseases, except those of the biliary tract; and (4) characteristic histopathologic features. As it is sometimes difficult to obtain sufficient biopsy specimens of the bile duct from patients suffering from IgG4-SC, evaluation of the effectiveness of steroid therapy is an optional extra diagnostic criterion to confirm a diagnosis of IgG4-SC. However, efforts should be made to collect sufficient tissue samples for diagnosis, and easy steroid trials should be avoided. The effectiveness of steroid therapy should be cautiously evaluated, as some malignant lesions improve after steroid administration [bib_ref] Comparison of steroid pulse therapy and conventional oral steroid therapy as initial..., Tomiyama [/bib_ref]. If neoplastic lesions cannot be clinically ruled out after steroid therapy, a re-evaluation should be performed to rule out malignant cholangiopancreatic diseases. IgG4-SC is frequently associated with AIP [bib_ref] Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy, Ghazale [/bib_ref] , and this association is useful for diagnosis of IgG4-SC [bib_ref] Diagnostic criteria for IgG4-related sclerosing cholangitis based on cholangiographic classification, Nakazawa [/bib_ref]. However, it is particularly difficult to accurately diagnose IgG4-SC in the absence of AIP [bib_ref] Isolated IgG4-related sclerosing cholangitis: a report of 9 cases, Graham [/bib_ref] [bib_ref] Isolated intrapancreatic IgG4-related sclerosing cholangitis, Nakazawa [/bib_ref] [bib_ref] Immunoglobulin G4-related lymphoplasmacytic sclerosing cholangitis that mimics infiltrating hilar cholangiocarcinoma: part of..., Hamano [/bib_ref]. Occasionally, IgG4-SC is associated with other systemic IgG4-related diseases, including IgG4-related dacryoadenitis/sialadenitis, IgG4-related retroperitoneal fibrosis, and IgG4-related kidney disease [bib_ref] Clinical significance of extrapancreatic lesion in autoimmune pancreatitis, Naitoh [/bib_ref]. These associations can also assist diagnosis of IgG4-SC. We use diagnostic criteria for IgG4-SC for diagnosis of IgG4-SC [bib_ref] Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012, Ohara [/bib_ref] , and we use comprehensive diagnostic criteria for IgG4-related disease 2011 [bib_ref] Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), Umehara [/bib_ref] for diagnosis of other IgG4-related diseases without organ specific diagnostic criteria. In contrast to PSC, inflammatory bowel disease is rarely observed in patients with IgG4-SC [bib_ref] Clinical characteristics of inflammatory bowel disease associated with primary sclerosing cholangitis, Sano [/bib_ref]. It should be noted that an elevated serum IgG4 level is also observed in conditions such as atopic dermatitis, pemphigus, and asthma; in particular, elevated serum IgG4 levels are observed in PSC and some malignant cholangiopancreatic diseases (e.g. pancreatic cancer and cholangiocarcinoma) [bib_ref] Establishment of a serum IgG4 cut-off value for the differential diagnosis of..., Ohara [/bib_ref] [bib_ref] Utility of serum immunoglobulin G4-associated cholangitis from cholangiocarcinoma, Oseini [/bib_ref] [bib_ref] Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis, Mendes [/bib_ref]. IgG4-SC with strictures of the bile duct in the hilar hepatic lesions must be discriminated from hilar cholangiocarcinoma. In these cases, endoscopic procedures such as endoscopic ultrasonography (EUS), IDUS, cytologic examination, and/or biopsy of the bile duct are useful for correct diagnosis [bib_ref] Isolated IgG4-related sclerosing cholangitis: a report of 9 cases, Graham [/bib_ref] [bib_ref] Isolated intrapancreatic IgG4-related sclerosing cholangitis, Nakazawa [/bib_ref] [bib_ref] Immunoglobulin G4-related lymphoplasmacytic sclerosing cholangitis that mimics infiltrating hilar cholangiocarcinoma: part of..., Hamano [/bib_ref]. CQI-2) Is an examination of serum IgG4 level recommended for diagnosing IgG4-SC? - We recommend an examination of serum IgG4 levels for the diagnosis of IgG4-SC (Recommendation 1, level C). - We suggest an examination of serum IgG4 levels for differential diagnosis from cholangiocarcinoma (Recommendation 2, level D). - We suggest an examination of serum IgG4 levels for differential diagnosis from PSC (Recommendation 2, level D). Comment: An elevation of serum IgG4 levels is seen in 90% of IgG4-SC cases [bib_ref] Establishment of a serum IgG4 cut-off value for the differential diagnosis of..., Ohara [/bib_ref] [bib_ref] Serum immunoglobulin G4 and immunoglobulin G1 for distinguishing immunoglobulin G4-associated cholangitis from..., Boonstra [/bib_ref]. Conversely, no elevation of serum IgG4 level is seen in 10% of cases [bib_ref] Establishment of a serum IgG4 cut-off value for the differential diagnosis of..., Ohara [/bib_ref] [bib_ref] Serum immunoglobulin G4 and immunoglobulin G1 for distinguishing immunoglobulin G4-associated cholangitis from..., Boonstra [/bib_ref]. However, as an elevation of serum IgG4 levels is also seen in 8-14% of cholangiocarcinoma cases [bib_ref] Establishment of a serum IgG4 cut-off value for the differential diagnosis of..., Ohara [/bib_ref] [bib_ref] Utility of serum immunoglobulin G4-associated cholangitis from cholangiocarcinoma, Oseini [/bib_ref] , IgG4-SC cannot be diagnosed based solely on an elevated serum IgG4 level (sensitivity 64-90%, specificity 87-93%) [bib_ref] Establishment of a serum IgG4 cut-off value for the differential diagnosis of..., Ohara [/bib_ref] [bib_ref] Utility of serum immunoglobulin G4-associated cholangitis from cholangiocarcinoma, Oseini [/bib_ref]. A cut-off of ≥206 mg/dL could be useful for types 3 and 4 IgG4-SC to distinguish them from cholangiocarcinoma [bib_ref] Establishment of a serum IgG4 cut-off value for the differential diagnosis of..., Ohara [/bib_ref] because types 3 and 4 IgG4-SC are known to mimic cholangiocarcinoma. An elevation of serum IgG4 levels is also seen in 9-22% of PSC cases [bib_ref] Establishment of a serum IgG4 cut-off value for the differential diagnosis of..., Ohara [/bib_ref] [bib_ref] Nationwide survey for primary sclerosing cholangitis and IgG4-related sclerosing cholangitis in Japan, Tanaka [/bib_ref] [bib_ref] IgG4 + plasma cell infiltrates in liver explants with primary sclerosing cholangitis, Zhang [/bib_ref] [bib_ref] Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis, Mendes [/bib_ref] [bib_ref] Serum immunoglobulin G4 and immunoglobulin G1 for distinguishing immunoglobulin G4-associated cholangitis from..., Boonstra [/bib_ref] [bib_ref] Significant, quantifiable differences exist between IgG subclass standards WHO67/97 and ERM-DA470k and..., Wilson [/bib_ref] [bib_ref] No negative impact of serum IgG4 levels on clinical outcome in 435..., Tanaka [/bib_ref] [bib_ref] Primary sclerosing cholangitis associated with elevated immunoglobulin G4: clinical characteristics and response..., Bj€ Ornsson [/bib_ref] [bib_ref] The spectrum of sclerosing cholangitis and the relevance of IgG4 elevations in..., Alswat [/bib_ref] [bib_ref] Association between HLA haplotypes and increased serum levels of IgG4 in patients..., Berntsen [/bib_ref] [bib_ref] The impact of elevated serum IgG4 levels in patients with primary sclerosing..., Benito De Valle [/bib_ref]. It was reported that a cut-off of ≥117 mg/dl has a sensitivity of 92% and specificity of 88% [bib_ref] Establishment of a serum IgG4 cut-off value for the differential diagnosis of..., Ohara [/bib_ref] ; with a cut-off of ≥140 mg/dl, it had a sensitivity of 90% and specificity of 85%; and with a cut-off of ≥280 mg/dl, it had a sensitivity of 70% and specificity of 98% [bib_ref] Serum immunoglobulin G4 and immunoglobulin G1 for distinguishing immunoglobulin G4-associated cholangitis from..., Boonstra [/bib_ref]. The optimal cut-off value was (4) Histopathological examination shows: a. Marked lymphocytic and plasmacyte infiltration and fibrosis b. Infiltration of IgG4-positive plasma cells: >10 IgG4-positive plasma cells/HPF c. Storiform fibrosis d. Obliterative phlebitis Option: Effectiveness of steroid therapy A specialized facility, in which detailed examinations such as endoscopic biliary biopsy and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) can be administrated, may include in its diagnosis the effectiveness of steroid therapy, once pancreatic or biliary cancers have been ruled out. ## Diagnosis Definite diagnosis: [formula] (1) + (3) (1) + (2) + (4) a, b (4) a, b, c (4) a, b, d Probable diagnosis: [/formula] (1) + (2) + Option Possible diagnosis: (1) + (2) It is necessary to exclude PSC, malignant diseases such as pancreatic or biliary cancers, and secondary sclerosing cholangitis caused by the diseases with obvious pathogenesis. If IgG4-SC cannot be clinically ruled out, a patient must not be treated with facile steroid therapy but should be referred to a specialized medical facility. reported to be 250 mg/dl, with a sensitivity of 67-89% and specificity of 95% [bib_ref] Serum immunoglobulin G4 and immunoglobulin G1 for distinguishing immunoglobulin G4-associated cholangitis from..., Boonstra [/bib_ref]. Serum IgG4 has been assayed by two world-wide systems, Binding-Site system [bib_ref] Establishment of a serum IgG4 cut-off value for the differential diagnosis of..., Ohara [/bib_ref] and Siemens system [bib_ref] Serum immunoglobulin G4 and immunoglobulin G1 for distinguishing immunoglobulin G4-associated cholangitis from..., Boonstra [/bib_ref]. In Japan, only Binding-Site system is available, whereas in Europe and the United States, both Binding-Site and Siemens systems are used. Serum IgG4 levels of Siemens system was reported to be 60% higher than those of Binding-Site system due to difference of standards for both systems [bib_ref] Significant, quantifiable differences exist between IgG subclass standards WHO67/97 and ERM-DA470k and..., Wilson [/bib_ref]. Accordingly, serum IgG4 assay with Siemens system may bring about false positive, if cut-off of Binding-Site system (≥140 mg/dl), is applied [bib_ref] Serum immunoglobulin G4 and immunoglobulin G1 for distinguishing immunoglobulin G4-associated cholangitis from..., Boonstra [/bib_ref]. An elevation of serum IgG4 levels is seen in most cases of IgG4-SC, so it is useful for the diagnosis of IgG4-SC. However, an elevation of serum IgG4 levels is not specific for the diagnosis of IgG4-SC. Cholangiocarcinoma and PSC cannot be excluded solely based on an elevation of serum IgG4 levels. ## Cqi-3) is ultrasonography (including eus) recommended for diagnosing igg4-sc? - We suggest ultrasonography for diagnosis of IgG4-SC (Recommendation 2, level D). - We suggest EUS for differential diagnosis from cholangiocarcinoma (Recommendation 2, level D). Comment: Only a few reports have described ultrasonographic findings for IgG4-SC [bib_ref] Comparison of radiological and histological findings in autoimmune pancreatitis, Kamisawa [/bib_ref] [bib_ref] Ultrasonographic imaging of bile duct lesions in autoimmune pancreatitis, Koyama [/bib_ref] [bib_ref] Abdominal ultrasonography, Inui [/bib_ref] [bib_ref] Biliary duct lesions associated with autoimmune pancreatitis, Honjo [/bib_ref]. Before the disease concept of IgG4-SC was established, Kamisawa et al. reported observing bile duct and gallbladder wall thickening in 60% of patients with AIP [bib_ref] Comparison of radiological and histological findings in autoimmune pancreatitis, Kamisawa [/bib_ref]. Koyama et al. reported characteristic bile duct and gallbladder wall thickening [fig_ref] Figure 2: Histological findings of transmural inflammatory cell infiltration and fibrosis in the bile... [/fig_ref] on ultrasonography in 37.8% of patients with AIP [bib_ref] Ultrasonographic imaging of bile duct lesions in autoimmune pancreatitis, Koyama [/bib_ref]. Characteristic wall thickening was reported as laminar structures or low echoic thickening of the wall [bib_ref] Abdominal ultrasonography, Inui [/bib_ref] [bib_ref] Biliary duct lesions associated with autoimmune pancreatitis, Honjo [/bib_ref]. Koyama et al. [bib_ref] Ultrasonographic imaging of bile duct lesions in autoimmune pancreatitis, Koyama [/bib_ref] divided patients into two groups according to ultrasonographic findings of bile duct wall thickening: (1) three-layer type, involving marked wall thickening apparent on ultrasonography as high-low-high echo of the bile duct wall; and (2) parenchymal-echo type, involving a thickened wall that occupies the entire lumen of the bile duct with appearance of parenchymal echo in the bile duct. They also reported rapid improvement in bile duct stenosis after steroid therapy but delayed improvement of the bile duct and gallbladder wall thickening [bib_ref] Ultrasonographic imaging of bile duct lesions in autoimmune pancreatitis, Koyama [/bib_ref]. Ultrasonography can detect wall thickening from the intrahepatic to extrahepatic bile ducts but cannot detect wall thickening of the intrapancreatic bile duct. It is difficult to distinguish IgG4-SC from PSC or cholangiocarcinoma using only ultrasonography. Nakamura et al. reported that the characteristic ultrasonographic findings of PSC include a homogeneous, high-low-high echo of the bile duct wall thickening, and in cases of severe wall thickening, the lumen of the bile duct becomes indistinct [bib_ref] Ultrasonographic diagnosis of primary sclerosing cholangitis, Nakamura [/bib_ref]. These findings are similar to those of IgG4-SC [fig_ref] Figure 3: Histological findings of storiform fibrosis in the bile duct of IgG4-SC [/fig_ref] ; thus, the differential diagnosis of both is difficult. . There were no significant differences between IgG4-SC and cholangiocarcinoma [bib_ref] Differential diagnosis of immunoglobulin G4-associated cholangitis from cholangiocarcinoma, Du [/bib_ref]. In one case report, ultrasonography detected a low echoic tumor in the liver, and the patient was diagnosed as having IgG4-SC based on pathologic examinations of resected specimens [bib_ref] Cholangiocellular carcinoma developed in a patient with autoimmune pancreatitis and IgG4-related sclerosing..., Hasebe [/bib_ref]. It is difficult to diagnose IgG4-SC using only ultrasonography. Ultrasonography is a useful modality for detecting wall thickening of the bile duct in patients with IgG4-SC. Furthermore, ultrasonography can detect pancreatic swelling at the same time in patients with AIP. As ultrasonography is non-invasive, it is proposed for use in the diagnosis of IgG4-SC. Few reports have described EUS findings of IgG4-SC [bib_ref] Differential diagnosis of immunoglobulin G4-associated cholangitis from cholangiocarcinoma, Du [/bib_ref] [bib_ref] Ultrasonographic evaluation in patients with autoimmune-related pancreatitis, Hyodo [/bib_ref]. Du et al. [bib_ref] Differential diagnosis of immunoglobulin G4-associated cholangitis from cholangiocarcinoma, Du [/bib_ref] reported the EUS revealed wall thickening in 17 of 18 (94.4%) patients with IgG4-SC, occupying lesions in one patient (5.6%), and dilation in 10 patients (55.6%). On the other hand, EUS revealed wall thickening in only 3 of 10 (30%) patients with cholangiocarcinoma, occupying lesions in eight patients (80%), and dilation in five patients (50%). There were significant differences between IgG4-SC and cholangiocarcinoma [bib_ref] Differential diagnosis of immunoglobulin G4-associated cholangitis from cholangiocarcinoma, Du [/bib_ref]. Du et al. reported observing thickened walls significantly more frequently in IgG4-SC cases than in cholangiocarcinoma, and significantly more occupying lesions were observed in cholangiocarcinoma than IgG4-SC cases [bib_ref] Differential diagnosis of immunoglobulin G4-associated cholangitis from cholangiocarcinoma, Du [/bib_ref]. They concluded that EUS is an effective imaging tool for diagnosis of IgG4-SC and cholangiocarcinoma [bib_ref] Differential diagnosis of immunoglobulin G4-associated cholangitis from cholangiocarcinoma, Du [/bib_ref]. Naitoh et al. reported that thickened walls detected by ultrasonography, computed tomography (CT), EUS, and IDUS involve circular-symmetrical thickening, smooth outer and inner margins, and homogeneous internal echo at the stenotic area of the bile duct. Sometimes, wall thickening is observed in the bile duct without obvious stenosis and wall thickening is observed in the gallbladder, too. Because EUS can detect characteristic findings of IgG4-SC and thus facilitate a differential diagnosis from cholangiocarcinoma, EUS is proposed for use in differential diagnosis from cholangiocarcinoma. CQI-4) Are CT and magnetic resonance imaging (MRI) recommended for diagnosing IgG4-SC? - In order to detect dilation or stenosis of bile ducts and obtain a complete image of the biliary system, we suggest contrast-enhanced CT and MRI/magnetic resonance cholangiopancreatography (MRCP) (Recommendation 2, level D). - For differential diagnosis of PSC or cholangiocarcinoma, we suggest contrast-enhanced CT and MRI/ MRCP (Recommendation 2, level D). Comment: CT and MRI enable objective detection of biliary abnormalities, including dilatation or wall thickening of bile ducts, and are considered useful for identifying bile duct lesions . Additionally, T2-weighted images or MRCP enable non-invasive imaging of the complete biliary system and determination of the distribution or degree of biliary strictures. As such, CT and MRI are considered useful for providing clues that can aid in the diagnosis of IgG4-SC [fig_ref] Figure 5: Immunohistochemical findings of infiltration of numerous IgG4-positive cells in the bile duct... [/fig_ref]. In terms of differential diagnosis of other biliary diseases, such as PSC or cholangiocarcinoma in particular, CT and MRI have both advantages and limitations. In IgG4-SC, biliary inflammation occurs transmurally, preserving the epithelial layer almost intact. In contrast, PSC mainly involves the luminal side, including the epithelium, and cholangiocarcinoma arises from the epithelial layer and grows invasively [bib_ref] The pathology of IgG4-related disease in the bile duct and pancreas, Zen [/bib_ref] [bib_ref] Immunoglobulin G4-related sclerosing cholangitis: pathologic features and histologic mimics, Zen [/bib_ref]. There are several differences regarding the primary locations of these conditions; however, it is challenging to demonstrate these differences by CT or MRI. To date, characteristic reported imaging findings for IgG4-SC include: (1) concentric bile duct wall thickening extending along the long axis; (2) smooth inner/outer margins; (3) visibility of patent bile duct in the strictures and mildness of upper bile duct dilatation; and (4) continuous bile duct wall thickening covering intrahepatic and extrahepatic bile ducts. However, the prevalence of these findings varies depending on the report; more reliable findings other than the abnormalities in the pancreas (presence of AIP) have yet to be reported [bib_ref] Immunoglobulin G4-related sclerosing cholangitis: pathologic features and histologic mimics, Zen [/bib_ref] [bib_ref] Comparative MRI analysis of morphologic patterns of bile duct disease in IgG4-related..., Tokala [/bib_ref] [bib_ref] Comparison of the multidetector-row computed tomography findings of IgG4-related sclerosing cholangitis and..., Yata [/bib_ref] [bib_ref] Comparison of CT findings of biliary tract changes with autoimmune pancreatitis and..., Maeda [/bib_ref] [bib_ref] Lymphoplasmacytic sclerosing cholangitis: assessment of clinical, CT, and pathological findings, Itoh [/bib_ref]. Although reported that MRCP can detect characteristic findings for PSC, such as multiple intrahepatic bile duct stenosis or pruned-tree appearance, the spatial resolution of MRCP falls short of that of ERC [bib_ref] Differential diagnosis of sclerosing cholangitis with autoimmune pancreatitis and periductal infiltrating cancer..., Kim [/bib_ref]. Furthermore, for detailed evaluation of bile duct wall thickening, EUS or IDUS provides more information than MRCP. However, considering the ability to non-invasively obtain a complete image of the biliary and pancreatic ducts and evaluate the concentricity of bile duct wall thickening, the degree of upstream bile duct dilatation, and the invasiveness of the lesion, it is reasonable to consider that contrast-enhanced CT or MRI/MRCP could contribute to the diagnosis of IgG4-SC when compared with ERC or IDUS. Additionally, IgG4-SC is usually accompanied by extra-bile duct lesions, the presence of which can sometimes contribute to the diagnosis [bib_ref] IgG4-related disease: dataset of 235 consecutive patients, Inoue [/bib_ref]. For systemic screening of IgG4-related lesions, it is worth performing contrastenhanced CT. Furthermore, adding high-contrast-resolution MRI (fat-suppressed T1-weighted, or diffusion-weighted images) or MRCP, which can provide complete imaging of the pancreas ducts, can sometimes reveal pancreatic lesions (e.g. AIP) not apparent in contrast-enhanced CT scans. CT and MRI/MRCP are relatively well-known diagnostic modality for general population. CT and MRI scanners are distributing nationwide and available for all patients. Although imaging protocol and quality for biliary imaging have been standardized, radiation exposure should be concerned in repeated CT examinations. Consequently, when IgG4-SC is suspected in clinical settings, systemic screening using contrast-enhanced CT and detailed evaluation of the bile ducts and pancreas using MRI/MRCP could aid in the diagnosis. - AIP is the disease most frequently associated with IgG4-SC, recognized in about 90% of patients with IgG4-SC. Apart from AIP, IgG4-SC is associated with dacryoadenitis, sialadenitis, retroperitoneal fibrosis, kidney lesions, pulmonary lesions, lymph node lesions, and vascular lesions (aorta and coronary arteries). We suggest consideration of these IgG4-related lesions (Recommendation 2, level D). Comment: Although there are not many reports describing analyses of a large number of patients with IgG4-SC, the most frequent associated disease is AIP (87-92%) [bib_ref] Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy, Ghazale [/bib_ref] [bib_ref] Clinical features, response to treatment, and outcomes of IgG4-related sclerosing cholangitis, Tanaka [/bib_ref]. On the other hand, IgG4-SC is also the disease most frequently associated with AIP. Lower bile duct strictures are observed in about 80% of patients with AIP. In AIP cases with pancreatic head lesions, lower bile duct strictures often occur because of pancreatitis or pancreatic edema; therefore, the association between IgG4-SC and AIP may be very close [fig_ref] Figure 6: Algorithm for diagnosis and treatment of IgG4-SC referred from Reference 18Fig [/fig_ref] [bib_ref] Endoscopic evaluation of factors contributing to intrapancreatic biliary stricture in autoimmune pancreatitis, Hirano [/bib_ref] [bib_ref] Mechanisms of lower bile duct stricture in autoimmune pancreatitis, Watanabe [/bib_ref]. In addition to AIP, IgG4-SC is known to be associated with dacryoadenitis [fig_ref] Figure 7: Algorithm for diagnosis and treatment of IgG4-SC referred from Reference 18 [/fig_ref] , sialadenitis, retroperitoneal fibrosis , as well as kidney, pulmonary, lymph node, and vascular (aorta and coronary artery) lesions. However, an association with inflammatory bowel diseases is rare [bib_ref] Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy, Ghazale [/bib_ref] [bib_ref] Clinical features, response to treatment, and outcomes of IgG4-related sclerosing cholangitis, Tanaka [/bib_ref] [bib_ref] Nationwide survey for primary sclerosing cholangitis and IgG4-related sclerosing cholangitis in Japan, Tanaka [/bib_ref]. Considering that IgG4-SC is a systemic IgG4-related disease, all lesions regarded as IgG4-related disease may be associated diseases of IgG4-SC. That is, associated diseases of IgG4-SC can occur in various organs, including the central nervous system (hypophysitis and hypertrophic pachymeningitis), thyroid, liver, gastrointestinal tract, prostate, eyes, skin, and mammary glands [bib_ref] Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), Umehara [/bib_ref]. ## Cqi-6) is erc recommended for diagnosing igg4-sc? - ERC shows diffuse or segmental stricture of the intrahepatic and/or extrahepatic bile ducts (Recommendation 2, level D). - ERC is useful for differentiation between IgG4-SC and PSC (Recommendation 2, level D). Comment: Biliary tract imaging in IgG4-SC reveals diffuse or segmental stricture of the intrahepatic and/or extrahepatic bile ducts. Although MRCP provides useful information, stricture of the bile duct should be assessed by direct cholangiography (i.e. by ERC or percutaneous Cholangiographic classification of IgG4-SC and the differential diagnosis of IgG4-SC referred from Reference 3 transhepatic cholangiography). In clinical practice, ERC is recommended as the most useful diagnostic imaging modality for diagnosing IgG4-SC [bib_ref] Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012, Ohara [/bib_ref] [bib_ref] IgG4-related sclerosing cholangitis: all we need to know, Zen [/bib_ref]. The characteristic features of IgG4-SC can be classified into four types based on the region of strictures as revealed by cholangiography and differential diagnosis (refer to . The main cause of biliary strictures in IgG4-SC is severe lymphoplasmacytic infiltration into the bile ducts in the long region, resulting in long strictures. The main cause of the biliary stricture in PSC, by comparison, is obliterative fibrosis, which results in short strictures and bile duct loss [bib_ref] Primary sclerosing cholangitis, Lindor [/bib_ref] [bib_ref] IgG4-related sclerosing cholangitis: all we need to know, Zen [/bib_ref] [bib_ref] Cholangiography can discriminate sclerosing cholangitis with autoimmune pancreatitis from primary sclerosing cholangitis, Nakazawa [/bib_ref] [fig_ref] Figure 2: Histological findings of transmural inflammatory cell infiltration and fibrosis in the bile... [/fig_ref] [bib_ref] Cholangiography can discriminate sclerosing cholangitis with autoimmune pancreatitis from primary sclerosing cholangitis, Nakazawa [/bib_ref] [bib_ref] Clinicopathological differentiation between sclerosing cholangitis with autoimmune pancreatitis and primary sclerosing cholangitis, Nishino [/bib_ref]. Sometimes it is difficult to distinguish between type 2b IgG4-SC and PSC based on the cholangiographic findings when the only cholangiographic finding in PSC is a pruned-tree appearance. When IgG4-SC is associated with AIP, pancreatography shows narrowing of the main pancreatic duct, which is characteristic of AIP. IgG4-SC with localized bile duct stricture must be differentiated from cholangiocarcinoma. Cholangiography cannot be used to differentiate between the hilar hepatic strictures of type 3 [fig_ref] Figure 2: Histological findings of transmural inflammatory cell infiltration and fibrosis in the bile... [/fig_ref] or type 4 IgG4-SC and hilar cholangiocarcinoma. The diagnostic procedures that are useful for making the differential diagnosis between types 3 and 4 IgG4-SC and cholangiocarcinoma are endoscopic modalities such as EUS, IDUS, and bile duct cytology and/or biopsy [bib_ref] Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy, Ghazale [/bib_ref] [bib_ref] Endoscopic transpapillary intraductal ultrasonography and biopsy in the diagnosis of IgG4-related sclerosing..., Naitoh [/bib_ref] [bib_ref] Immunoglobulin G4-related lymphoplasmacytic sclerosing cholangitis that mimics infiltrating hilar cholangiocarcinoma: part of..., Hamano [/bib_ref] [bib_ref] Utility and limitations of intraductal ultrasonography in distinguishing longitudinal cancer extension along..., Tamada [/bib_ref] [bib_ref] Usefulness of transpapillary bile duct brushing cytology and forceps biopsy for improved..., Kitajima [/bib_ref]. Type 1 IgG4-SC must be differentiated from lower bile duct cancer and pancreatic cancer . Diagnosis of IgG4-SC associated with AIP is relatively easy when endoscopic retrograde pancreatography shows narrowing of the main pancreatic duct, which is characteristic of AIP, but it is very difficult to make the differential diagnosis between isolated IgG4-SC and lower bile duct cancer [bib_ref] Isolated intrapancreatic IgG4-related sclerosing cholangitis, Nakazawa [/bib_ref]. Endoscopic transpapillary bile duct biopsy is performed to rule out cholangiocarcinoma, but it is difficult to obtain sufficient biliary tract tissue to evaluate for the characteristic histologic findings of IgG4-SC (i.e. storiform fibrosis and obliterative phlebitis). A commonly used cut-off value for IgG4-positive plasma cell infiltration is 10 cells per HPF. Reports of the sensitivity of transpapillary bile duct biopsy as a basis for making a diagnosis of IgG4-SC have ranged from 18 to 88% [bib_ref] Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy, Ghazale [/bib_ref] [bib_ref] Endoscopic transpapillary intraductal ultrasonography and biopsy in the diagnosis of IgG4-related sclerosing..., Naitoh [/bib_ref] [bib_ref] IgG4-related sclerosing cholangitis and autoimmune pancreatitis: histological assessment of biopsies from Vater's..., Kawakami [/bib_ref]. ## Cqi-7) how is igg4-sc differentially diagnosed from cholangiocarcinoma? - We recommend determination of the serum IgG4 level, concomitant diseases, cholangiogram, bile duct wall findings of contrast-enhanced CT or IDUS, mucosal findings of POCS, pathologic findings of biopsy or brush cytology, and clinical course for the differential diagnosis of IgG4-SC from cholangiocarcinoma (Recommendation 1, level D). Comment: The differential diagnosis of IgG4-SC is often difficult. Cases involving types 1, 3, and 4 disease are difficult to distinguish from cholangiocarcinoma . The sensitivity and specificity in the diagnosis of IgG4-SC based on cholangiogram by endoscopic retrograde cholangiopancreatography (ERCP) are 45% and 88% [bib_ref] Endoscopic retrograde cholangiography does not reliably distinguish IgG4-associated cholangitis from PSC or..., Kalaitzaikis [/bib_ref]. Diagnosis by cholangiogram using ERCP combined with CT and MRI has a sensitivity of 70-90% and specificity of 73-87% [bib_ref] Endoscopic retrograde cholangiography does not reliably distinguish IgG4-associated cholangitis from PSC or..., Kalaitzaikis [/bib_ref] [bib_ref] Diagnostic performance of imaging criteria for distinguishing autoimmune cholangiopathy from primary sclerosing..., Gardner [/bib_ref]. However, a cholangiogram is crucial for differential diagnosis of IgG4-SC from PSC because of specific findings. Several points facilitate a differential diagnosis of IgG4-SC based on cholangiogram findings. Some cholangiocarcinomas exhibit high serum IgG4 levels, as in IgG4-SC; the sensitivity and specificity of IgG4 level determination for the diagnosis are 64-100% and 81-88%, respectively, with an IgG4 cut-off level of 140 mg/dl [bib_ref] Clinical characteristics of inflammatory bowel disease associated with primary sclerosing cholangitis, Sano [/bib_ref] [bib_ref] Diagnostic performance of imaging criteria for distinguishing autoimmune cholangiopathy from primary sclerosing..., Gardner [/bib_ref]. A higher cut-off level of 560 mg/dl (four times the upper normal limit) provides for more reliable differential diagnosis of IgG4-SC from cholangiocarcinoma, with a sensitivity of 17% and specificity of 99% [bib_ref] Utility of serum immunoglobulin G4-associated cholangitis from cholangiocarcinoma, Oseini [/bib_ref]. IgG4-SC is often accompanied by the IgG4-related disease AIP [bib_ref] Diagnostic criteria for IgG4-related sclerosing cholangitis based on cholangiographic classification, Nakazawa [/bib_ref] [bib_ref] Clinical clues to suspicion of IgG4-associated sclerosing cholangitis disguised as primary sclerosing..., Oh [/bib_ref]. Then, the presence of concomitant IgG4-related disease suggests the possibility of IgG4-SC, thus warranting screening of the whole body. Contrast-enhanced CT is useful for differential diagnosis, and homogeneous enhancement of the bile duct walls in the arterial phase is characteristic of IgG4-SC. By contrast, in cases involving cholangiocarcinoma, the bile duct wall is enhanced in two layers. Smoothness of the inner lumen and the outer layer is also characteristic of IgG4-SC [bib_ref] Comparative MRI analysis of morphologic patterns of bile duct disease in IgG4-related..., Tokala [/bib_ref] [bib_ref] Comparison of sclerosing cholangitis with autoimmune pancreatitis and infiltrative extrahepatic cholangiocarcinoma: multidetector-row..., Arikawa [/bib_ref] [bib_ref] Clinical features and CT findings in the differential diagnosis of IgG4-related sclerosing..., Matsusaki [/bib_ref] ]. An additional advantage of contrastenhanced CT is that it enables the detection of tumor invasion and metastatic lesions outside the bile ducts. IDUS is useful for differential diagnosis in conjunction with ERCP. Wall thickening in the non-stricture areas is characteristic of IgG4-SC, and a sensitivity of 95-100%, specificity of 91%, and accuracy of 94% were reported with a wall thickness cut-off of 0.8 mm in non-stricture areas [bib_ref] Diagnostic criteria for IgG4-related sclerosing cholangitis based on cholangiographic classification, Nakazawa [/bib_ref] [bib_ref] Endoscopic transpapillary intraductal ultrasonography and biopsy in the diagnosis of IgG4-related sclerosing..., Naitoh [/bib_ref]. Findings of tortuous and dilated arteries in the bile duct by POCS are features of IgG4-SC, and partially dilated arteries were detected in a case of cholangiocarcinoma [bib_ref] Peroral cholangioscopic diagnosis of biliary-tract diseases by using narrow-band imaging (with videos), Itoi [/bib_ref]. Biopsy is recommended for differential diagnosis, but the sensitivity for detecting malignancy (55-72%) was low [bib_ref] Diagnostic criteria for IgG4-related sclerosing cholangitis based on cholangiographic classification, Nakazawa [/bib_ref] [bib_ref] Endoscopic transpapillary intraductal ultrasonography and biopsy in the diagnosis of IgG4-related sclerosing..., Naitoh [/bib_ref]. In addition, IgG4 staining also showed low sensitivity (18-52%) for biopsy specimens in IgG4-SC cases [bib_ref] Endoscopic transpapillary intraductal ultrasonography and biopsy in the diagnosis of IgG4-related sclerosing..., Naitoh [/bib_ref] [bib_ref] IgG4-related sclerosing cholangitis and autoimmune pancreatitis: histological assessment of biopsies from Vater's..., Kawakami [/bib_ref]. There was a report of an increase in the rate of positive IgG4 staining to 72% with additional papillary biopsy; however, papillary biopsy is considered a supplementary method and should not be performed alone [bib_ref] IgG4-related sclerosing cholangitis and autoimmune pancreatitis: histological assessment of biopsies from Vater's..., Kawakami [/bib_ref]. Simultaneous performance of brush cytology at strictures and bile fluid cytology were shown to be favorable for improving the diagnostic utility of bile duct biopsy. Elevation in bile fluid IgG4 levels has been reported in cases of IgG4-SC but not PSC and cholangiocarcinoma, with sensitivity and specificity values of 100% at a cut-off [bib_ref] Measurement of IgG4 in bile: a new approach for the diagnosis of..., Vosskuhl [/bib_ref]. There is a possibility monitoring of bile IgG4 levels will be useful for differential diagnosis. Most reports regarding the differential diagnosis of IgG4-SC and cholangiocarcinoma discussed in this section were characterized by small sample sizes and low evidence levels. A review of these reports suggests that IgG4-SC should be distinguished from cholangiocarcinoma using a variety of methods because the diagnostic utility of each modality alone is insufficient. CQI-8) What are the useful findings for differentiation between IgG4-SC and PSC? - We recommend consideration of age of onset, serum IgG4 level, coexisting diseases, image findings of biliary trees, liver histology, responsiveness to steroid therapy, and clinical course to differentially diagnose IgG4-SC from PSC (Recommendation 1, level D). Comment: PSC is a chronic inflammatory liver disease with poor prognosis characterized by progressive fibrosis of intrahepatic and extrahepatic bile ducts terminally leading to liver failure via cholestatic cirrhosis [bib_ref] Primary sclerosing cholangitis, Lindor [/bib_ref] [bib_ref] Primary sclerosing cholangitis. Review and reports of six cases, Schwartz [/bib_ref] [bib_ref] Current concepts. Primary sclerosing cholangitis, Larusso [/bib_ref]. Although PSC and IgG4-SC exhibit similar cholangiograms, these diseases recently became distinguishable with the establishment of their etiology. As the therapeutic strategies and prognoses of these diseases differ, the differential diagnosis is of great importance. PSC and IgG4-SC exhibit clinical differences related to (1) age of onset, (2) serum IgG4 levels, (3) coexisting diseases, (4) image findings of biliary trees, (5) liver histology, (6) responsiveness to steroid therapy, and (7) clinical course [fig_ref] Table 4: Differential characteristics of IgG4-SC and PSC [/fig_ref]. Whereas IgG4-SC primarily affects elderly patients over 60 years of age, there are two peaks in the age distribution in PSC, one in younger (20-30 years old) patients and the other in more elderly patients [bib_ref] Analysis of 388 cases of primary sclerosing cholangitis in Japan; Presence of..., Takikawa [/bib_ref]. The serum IgG4 level is frequently elevated in IgG4-SC but not in PSC. A multicenter survey in Japan demonstrated a diagnostic sensitivity for IgG4-SC of 89.9% when a cut-off value of 135 mg/dl was employed [bib_ref] Establishment of a serum IgG4 cut-off value for the differential diagnosis of..., Ohara [/bib_ref]. In a subsequent nationwide survey, serum IgG4 levels were elevated in 83.9% of IgG4-SC cases [bib_ref] Epidemiology of primary sclerosing cholangitis and IgG4-related sclerosing cholangitis, Tanaka [/bib_ref]. In contrast, high serum IgG4 levels were observed in only 11.5% and 12.9% of PSC cases in these two reports, suggesting that a serum IgG4 level is a reliable biomarker for distinguishing IgG4-SC from PSC. However, the diagnosis of IgG4-SC should not be made solely on the basis of serum IgG4 levels, as false-positive results are observed in approximately 10% of PSC cases. PSC is frequently accompanied by inflammatory bowel diseases such as ulcerative colitis, with a prevalence of 60-80% in Western countries [bib_ref] ACG clinical guideline. Primary sclerosing cholangitis, Lindor [/bib_ref] [bib_ref] Diagnosis and management of primary sclerosing cholangitis, Chapman [/bib_ref]. A Japanese nationwide survey in 2013 reported a lower incidence of inflammatory bowel disease in PSC patients of 34%. However, endoscopic examination of the colorectum is recommended in PSC patients, regardless of the absence of symptoms of inflammatory bowel disease [bib_ref] Nationwide survey for primary sclerosing cholangitis and IgG4-related sclerosing cholangitis in Japan, Tanaka [/bib_ref] , as inflammatory bowel disease is occasionally diagnosed after a definitive diagnosis of PSC [bib_ref] ACG clinical guideline. Primary sclerosing cholangitis, Lindor [/bib_ref] [bib_ref] Diagnosis and management of primary sclerosing cholangitis, Chapman [/bib_ref]. In contrast, IgG4-SC is associated with AIP as well as other IgG4related diseases such as sialadenitis and retroperitoneal fibrosis at a high prevalence [bib_ref] Nationwide survey for primary sclerosing cholangitis and IgG4-related sclerosing cholangitis in Japan, Tanaka [/bib_ref] , but it is rarely associated with inflammatory bowel disease. Typical imaging findings of biliary trees in PSC include band-like strictures, beaded appearance, prunedtree appearance, and diverticulum-like outpouching [bib_ref] IgG4-related sclerosing cholangitis: all we need to know, Zen [/bib_ref] [bib_ref] Cholangiography can discriminate sclerosing cholangitis with autoimmune pancreatitis from primary sclerosing cholangitis, Nakazawa [/bib_ref]. Differential features on cholangiography include longer strictures in IgG4-SC than in PSC [bib_ref] Diagnostic criteria for IgG4-related sclerosing cholangitis based on cholangiographic classification, Nakazawa [/bib_ref] [bib_ref] Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012, Ohara [/bib_ref] [bib_ref] Schematic classification of sclerosing cholangitis with autoimmune pancreatitis by cholangiography, Nakazawa [/bib_ref] [bib_ref] Cholangiography can discriminate sclerosing cholangitis with autoimmune pancreatitis from primary sclerosing cholangitis, Nakazawa [/bib_ref] [bib_ref] Clinicopathological differentiation between sclerosing cholangitis with autoimmune pancreatitis and primary sclerosing cholangitis, Nishino [/bib_ref]. IDUS findings of irregular inner margins reflecting ductal epithelial damage and diverticulum-like outpouching are significantly more frequent in PSC [bib_ref] Discrimination between sclerosing cholangitis-associated autoimmune pancreatitis and primary sclerosing cholangitis, cancer using..., Kubota [/bib_ref] [bib_ref] Comparison of intraductal ultrasonography findings between primary sclerosing cholangitis and IgG4-related sclerosing..., Naitoh [/bib_ref]. This is in contrast to the findings of homogenous thickening of the inner low-echoic layer without destruction of the three-layer structure frequently observed in IgG4-SC. Typical POCS findings in PSC include multiple lesions involving scarring and pseudodiverticula [bib_ref] The role of peroral video cholangioscopy in patients with IgG4-related sclerosing cholangitis, Itoi [/bib_ref] [bib_ref] Diagnostic utility of single-user peroral cholangioscopy in sclerosing cholangitis, Kalaitzakis [/bib_ref]. Important liver histology findings in PSC include periductal onion-skin fibrosis and fibrous obliterative cholangitis [bib_ref] Manifestations of nonsuppurative cholangitis in chronic hepatobiliary diseases: morphologic spectrum, clinical correlations..., Ludwig [/bib_ref] , although these are not specific for PSC. For the differential diagnosis of IgG4-SC from PSC, fibrous cholangitis is a potential finding of PSC, whereas abundant IgG4-positive plasma cell infiltration in portal areas is suggestive of IgG4-SC. With regard to medical treatment, patients with IgG4-SC are treated effectively with corticosteroids, whereas extensive evidence suggests there are no satisfactory agents for treating PSC. Although ursodeoxycholic acid is widely used in patients with PSC, guidelines in Western countries indicate that its clinical benefit is uncertain. In addition, high-dose ursodeoxycholic acid reportedly has no beneficial effect [bib_ref] Bile acids for primary sclerosing cholangitis, Poropat [/bib_ref] [bib_ref] Meta-analysis: ursodeoxycholic acid for primary sclerosing cholangitis, Triantos [/bib_ref] [bib_ref] Urosdeoxycholic acid in primary sclerosing cholangitis: a meta-analysis and systematic review, Othman [/bib_ref]. PSC leads to liver failure via cholestatic cirrhosis with disease duration of more than 10 years and occasionally leads to cholangiocarcinoma, suggesting poor prognosis. Hence, liver transplantation remains the only established therapy. CQI-9) Is bile duct biopsy recommended for diagnosing IgG4-SC? - We suggest performing bile duct biopsy for the diagnosis of IgG4-SC (Recommendation 2, level D). - We suggest performing bile duct biopsy for differential diagnosis from cholangiocarcinoma (Recommendation 2, level D). Comment: The diagnosis of IgG4-SC warrants bile duct biopsy to differentiate it from other diseases, particularly cholangiocarcinoma. However, definitive diagnoses of IgG4-SC by bile duct biopsy are sporadic. The histopathology of IgG4-SC is characterized by diffuse lymphoplasmacytic infiltration extending from the bile duct mucosa to the serous membrane, storiform fibrosis, obstructive phlebitis, and eosinophilic infiltration, whereas the histopathology of the bile duct epithelium is often normal. In other words, histopathologically, a definitive diagnosis of IgG4-SC by bile duct biopsy, requires the collection of samples containing the bile duct stroma. Ghazale et al. reported pathologic diagnosis of IgG4-SC in 14 of 16 patients (88%) by bile duct biopsy [bib_ref] Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy, Ghazale [/bib_ref]. In contrast, Kawakami et al. [bib_ref] IgG4-related sclerosing cholangitis and autoimmune pancreatitis: histological assessment of biopsies from Vater's..., Kawakami [/bib_ref] , Naitoh et al. [bib_ref] Endoscopic transpapillary intraductal ultrasonography and biopsy in the diagnosis of IgG4-related sclerosing..., Naitoh [/bib_ref] , and Hirano et al. [bib_ref] Endoscopic evaluation of factors contributing to intrapancreatic biliary stricture in autoimmune pancreatitis, Hirano [/bib_ref] reported diagnosis of IgG4-SC by bile duct biopsy in 15 of 29 patients (52%), 3 of 17 patients (18%), and 0 of 5 patients (0%), respectively, which cannot be considered as good outcomes [fig_ref] Table 5: Usefulness of bile duct biopsy for the diagnosis of IgG4-SC [/fig_ref]. The poor ability to diagnose IgG4-SC by bile duct biopsy may be attributed to the fact that the endoscopic bile duct samples are often small, and collecting samples containing the bile duct stroma using biopsy forceps is challenging. Although immunostaining for IgG4 is performed to more effectively use the small samples collected, satisfactory results have yet to be obtained. When we observe localized stenosis, excluding cholangiocarcinoma is necessary. Refer to CQI-7 for differential diagnosis from cholangiocarcinoma. CQI-10) Are endoscopic biopsy samples taken from the ampulla of Vater useful for diagnosing IgG4-SC? - Histopathology of endoscopic biopsy samples taken from the ampulla of Vater for IgG4-immunostaining can be useful as a supplemental tool for the diagnosis of IgG4-SC. We suggest this technique for use in cases involving a swollen ampulla associated with pancreatic head involvement due to AIP in particular (Recommendation 2, level D). ## Comment: Supplemental endoscopic biopsy histopathology using IgG4-immunostaining could contribute to the diagnosis of IgG4-SC in cases in which the ampulla of Vater is swollen [bib_ref] Usefulness of endoscopic observation of the main duodenal papilla in the diagnosis..., Unno [/bib_ref] [fig_ref] Figure 2: Histological findings of transmural inflammatory cell infiltration and fibrosis in the bile... [/fig_ref] and there is positive histopathologic evidence of infiltration (i.e. >10 IgG4-positive plasma cells per HPF) [bib_ref] Usefulness of biopsying the major duodenal papilla to diagnose autoimmune pancreatitis: a..., Kamisawa [/bib_ref] [fig_ref] Figure 2: Histological findings of transmural inflammatory cell infiltration and fibrosis in the bile... [/fig_ref]. Features such as swollen ampulla and abundant infiltration of IgG4-positive plasma cells are regarded as indicative of pancreatic head involvement associated with AIP rather than diagnostic of IgG4-SC [bib_ref] IgG4 + to IgG+ plasma cells ratio of ampulla can help differentiate..., Sepehr [/bib_ref]. There is no consensus criterion regarding endoscopic biopsy in the diagnosis of IgG4-related disease. Additionally, endoscopic biopsy histopathology of samples taken from the ampulla of Vater is regarded as an option in the diagnosis of AIP as proposed in the international consensus diagnostic criteria [bib_ref] International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association..., Shimosegawa [/bib_ref]. Supplemental endoscopic biopsy samples taken from the ampulla of Vater are useful for differential diagnosis of IgG4-SC from PSC [bib_ref] Differentiating sclerosing cholangitis caused by autoimmune pancreatitis and primary sclerosing cholangitis according..., Kubota [/bib_ref] ; however, endoscopic biopsy histopathology itself should not be relied on for final diagnosis of IgG4-related diseases. One case report described isolated-type IgG4-related disease of the ampulla of Vater [bib_ref] Lymphoplasmacytic granuloma localized to the ampulla of Vater: an ampullary lesion of..., Hisa [/bib_ref]. Although there are no consensus diagnostic criteria available regarding the ampulla of Vater in IgG4-related disease, it could be considered in diagnosis if there are typical endoscopic findings such as swollen ampulla of Vater associated with hooding-fold bulging [bib_ref] Usefulness of endoscopic observation of the main duodenal papilla in the diagnosis..., Unno [/bib_ref] and biopsy histopathologic results indicating infiltration with abundant IgG4-positive plasma cells [bib_ref] Usefulness of biopsying the major duodenal papilla to diagnose autoimmune pancreatitis: a..., Kamisawa [/bib_ref]. Endoscopic findings such as a swollen ampulla of Vater and endoscopic biopsy results showing abundant IgG4-positive plasma cell infiltration were noted in 40-80% of patients with IgG4-SC associated with AIP [bib_ref] Clinical significance of swollen duodenal papilla in autoimmune pancreatitis, Kubota [/bib_ref] [bib_ref] Major duodenal papilla in autoimmune pancreatitis, Kim [/bib_ref] [bib_ref] Major and Minor Papillae in autoimmune pancreatitis, Chiba [/bib_ref]. On the other hand, it would be almost impossible for the use of endoscopic biopsy histopathology to reveal stromal features of IgG4-SC, including storiform fibrosis and obliterative phlebitis. Isolated IgG4-SC not associated with AIP is rare [bib_ref] IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitisassociated..., Zen [/bib_ref]. Furthermore, Matsubayashi reported that only 1 of 7 isolated IgG4-SC patients presented with a swollen ampulla of Vater. That author also described the usefulness of characterizing ampulla features in diagnosing IgG4-SC [bib_ref] IgG4-related sclerosing cholangitis without obvious pancreatic lesion: difficulty in differential diagnosis, Matsubayashi [/bib_ref]. Additionally, as the tissue acquisition from the affected bile ducts in IgG4-SC patients are challenging at poor outcomes [fig_ref] Table 5: Usefulness of bile duct biopsy for the diagnosis of IgG4-SC [/fig_ref] , the feasible result taken from the ampulla, which anatomically connected to the bile duct, could be a surrogate to attest it [bib_ref] Japanese consensus guidelines for management of autoimmune pancreatitis: II. Extrapancreatic lesions, differential..., Kawa [/bib_ref]. Therefore, the biopsy of the ampulla is useful. For the aforementioned reasons, ampullary features such as typical endoscopic findings indicative of pancreatic head lesions in AIP can potentially contribute to the diagnosis of IgG4-SC; such findings would also be positive in patients with isolated-type IgG4-SC. CQI -11) Is IDUS recommended for diagnosing IgG4-SC? - We suggest IDUS for the differential diagnosis from cholangiocarcinoma or PSC (Recommendation 2, level D). Comment: Endoscopic transpapillary IDUS is a reliable procedure to obtain high-resolution images of the bile duct wall after ERCP. IDUS is performed by inserting a small-caliber ultrasonic probe into the bile duct. IDUS is widely used for evaluation of bile duct stones, differential diagnosis of indeterminate biliary strictures, and superficial spread of cholangiocarcinoma. IDUS should be performed before biliary drainage, as such drainage often causes mechanical inflammation of the bile duct. IDUS findings of IgG4-SC include circular-symmetrical wall thickening, smooth outer and inner margins, and homogeneous internal echo in the biliary stricture [fig_ref] Figure 2: Histological findings of transmural inflammatory cell infiltration and fibrosis in the bile... [/fig_ref] [bib_ref] Endoscopic transpapillary intraductal ultrasonography and biopsy in the diagnosis of IgG4-related sclerosing..., Naitoh [/bib_ref] [bib_ref] Ultrasonographic evaluation in patients with autoimmune-related pancreatitis, Hyodo [/bib_ref]. The most characteristic IDUS finding of IgG4-SC is wall thickening in non-strictures of the bile duct, which appears normal on a cholangiogram [fig_ref] Figure 2: Histological findings of transmural inflammatory cell infiltration and fibrosis in the bile... [/fig_ref] [bib_ref] Endoscopic transpapillary intraductal ultrasonography and biopsy in the diagnosis of IgG4-related sclerosing..., Naitoh [/bib_ref]. IDUS findings of IgG4-SC reflect pathologic changes of the bile duct in which fibro-inflammation is primarily observed in the stroma of the bile duct walls, whereas the bile duct epithelium remains intact [bib_ref] Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012, Ohara [/bib_ref]. IDUS findings in strictures and non-strictures of the bile duct differ between IgG4-SC and cholangiocarcinoma [bib_ref] Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012, Ohara [/bib_ref] [bib_ref] Endoscopic transpapillary intraductal ultrasonography and biopsy in the diagnosis of IgG4-related sclerosing..., Naitoh [/bib_ref] [bib_ref] The role of endoscopy in the diagnosis of autoimmune pancreatitis, Moon [/bib_ref] [bib_ref] Differentiating immunoglobulin g4-related sclerosing cholangitis from hilar cholangiocarcinoma, Tabata [/bib_ref] [bib_ref] Difference from bile duct cancer and relationship between bile duct wall thickness..., Kuwatani [/bib_ref] [bib_ref] Role of endoscopic retrograde cholangiography in autoimmune pancreatitis, Kamisawa [/bib_ref] [bib_ref] Small bile duct involvement in IgG4-related sclerosing cholangitis: liver biopsy and cholangiography..., Naitoh [/bib_ref]. IDUS findings of cholangiocarcinoma include asymmetric wall thickening, notched outer margins, rough inner margins, and homogeneous internal echo in the biliary stricture. The most characteristic IDUS finding of IgG4-SC is wall thickening in non-strictures of the bile duct, as mentioned above. By contrast, bile duct wall thickening is not observed in non-stricture sites in cholangiocarcinoma due to the absence of cancer there. One study revealed that a bile duct wall thickness of 0.8 mm is the optimal cut-off for differentiating IgG4-SC from cholangiocarcinoma, according to receiver operating characteristic curve analysis [bib_ref] Endoscopic transpapillary intraductal ultrasonography and biopsy in the diagnosis of IgG4-related sclerosing..., Naitoh [/bib_ref]. In that study [bib_ref] Endoscopic transpapillary intraductal ultrasonography and biopsy in the diagnosis of IgG4-related sclerosing..., Naitoh [/bib_ref] , no cholangiocarcinoma cases exhibiting a bile duct wall thickness greater than 1 mm were noted; therefore, this cut-off can be used to completely exclude cholangiocarcinoma from IgG4-SC diagnoses. The most useful IDUS finding for differentiating between IgG4-SC and cholangiocarcinoma is that wall thickness continuously spreads from the lower bile duct to the upper bile duct in most IgG4-SC cases. Most cases of IgG4-SC with intrapancreatic bile duct strictures exhibit bile duct wall thickening. This IDUS finding is useful in the differential diagnosis from pancreatic cancer because intrapancreatic bile duct strictures are considered to be caused primarily by extrinsic compression due to pancreatic enlargement [bib_ref] Endoscopic evaluation of factors contributing to intrapancreatic biliary stricture in autoimmune pancreatitis, Hirano [/bib_ref] [bib_ref] Mechanisms of lower bile duct stricture in autoimmune pancreatitis, Watanabe [/bib_ref]. Both intrapancreatic bile duct thickening and extrinsic compression due to pancreatic enlargement influence intrapancreatic bile duct strictures. The degree of influence produced by these two factors might differ in each IgG4-SC case. Upstream (middle and upper) bile duct thickening is often observed in IgG4-SC but not in pancreatic cancer. An IDUS finding of upstream bile duct thickening is useful in the differential diagnosis between AIP (IgG4-SC) and pancreatic cancer. Typical IDUS findings of PSC include circular-asymmetric wall thickening, irregular inner margins, unclear outer margins, diverticulum-like outpouching, heterogeneous internal echo, and the disappearance of three layers. These findings differ from those of IgG4-SC [bib_ref] Discrimination between sclerosing cholangitis-associated autoimmune pancreatitis and primary sclerosing cholangitis, cancer using..., Kubota [/bib_ref] [bib_ref] Comparison of intraductal ultrasonography findings between primary sclerosing cholangitis and IgG4-related sclerosing..., Naitoh [/bib_ref]. Irregular inner margins, diverticulum-like outpouching, and the disappearance of three layers are specific findings for distinguishing IgG4-SC from PSC according to IDUS. Diverticulum-like outpouching is considered to be the most objective finding on ERCP [bib_ref] Comparison of intraductal ultrasonography findings between primary sclerosing cholangitis and IgG4-related sclerosing..., Naitoh [/bib_ref]. IDUS is more useful than ERCP for the early detection of diverticulum-like outpouching, which is specific to PSC. IDUS is recommended for the differential diagnosis of IgG4-SC from cholangiocarcinoma, pancreatic cancer, or PSC, especially in patients undergoing ERCP, because IDUS can be performed after ERC. CQI-12) Is a liver biopsy recommended for diagnosing IgG4-SC? - Lesions of IgG4-SC may be obtained by liver biopsy, but specific histologic features are rarely observed (Recommendation 2, level D). Comment: Lesional tissues are obtained by liver biopsy in about 25% of IgG4-SC cases [bib_ref] Small bile duct involvement in IgG4-related sclerosing cholangitis: liver biopsy and cholangiography..., Naitoh [/bib_ref] [bib_ref] Inflammatory disease of the bile ductscholangiopathies: liver biopsy challenge and clinicopathological correlation, Portmann [/bib_ref]. This happens more frequently in cases with intrahepatic bile duct involvement using a 14-G needle [bib_ref] Small bile duct involvement in IgG4-related sclerosing cholangitis: liver biopsy and cholangiography..., Naitoh [/bib_ref]. In most cases, however, the obtained tissues reveal non-specific histologic findings, such as lymphoplasmacytic and occasional eosinophilic infiltration in the peripheral portal regions, sometimes with periportal, intralobular, and central perivenular inflammatory cell infiltration [bib_ref] Clinicopathological differentiation between sclerosing cholangitis with autoimmune pancreatitis and primary sclerosing cholangitis, Nishino [/bib_ref] [bib_ref] Small bile duct involvement in IgG4-related sclerosing cholangitis: liver biopsy and cholangiography..., Naitoh [/bib_ref] [bib_ref] IgG4-associated cholangitis: a comparative histological and immunophenotypic study with primary sclerosing cholangitis..., Deshpande [/bib_ref] [bib_ref] Diagnostic utility of biopsy specimens for autoimmune pancreatitis, Hirano [/bib_ref]. Cholangitis similar to that in the large bile ducts, storiform fibrosis, and obliterative phlebitis are usually absent. The presence of portal-based fibro-inflammatory nodules in the portal tracts, resembling the findings of IgG4-related inflammatory pseudotumors, is pathognomonic [bib_ref] IgG4-associated cholangitis: a comparative histological and immunophenotypic study with primary sclerosing cholangitis..., Deshpande [/bib_ref] but rarely observed in liver biopsies. The standard for increased IgG4-positive cells in the liver biopsy is >10 cells per HPF in the clinical diagnostic criteria for IgG4-SC [bib_ref] Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012, Ohara [/bib_ref] and consensus statement on the pathology of IgG4-related disease [bib_ref] Consensus statement on the pathology of IgG4-related disease, Deshpande [/bib_ref] ; in the latter, an IgG4/IgG-positive cell ratio >40% also needs to be satisfied. IgG4-positive cells in the liver biopsy are significantly more numerous in IgG4-SC compared with PSC and cholangiocarcinomas [bib_ref] Clinicopathological differentiation between sclerosing cholangitis with autoimmune pancreatitis and primary sclerosing cholangitis, Nishino [/bib_ref] [bib_ref] Clinical clues to suspicion of IgG4-associated sclerosing cholangitis disguised as primary sclerosing..., Oh [/bib_ref]. In one study, >10 IgG4-positive cells per HPF was reported in 6 of 10 IgG4-SC cases but in none of 16 PSC cases [bib_ref] IgG4-associated cholangitis: a comparative histological and immunophenotypic study with primary sclerosing cholangitis..., Deshpande [/bib_ref]. The IgG4-positive/mononuclear cell ratio and IgG4/IgG-positive cell ratio were reported to be significantly higher in IgG4-SC than PSC [bib_ref] Distinct clinicopathological entity 'autoimmune pancreatitis-associated sclerosing cholangitis, Uehara [/bib_ref]. Although not previously studied with liver biopsy specimens, numerous IgG4-positive cells may also be observed in cholangiocarcinomas; therefore, sufficient attention should be paid to incorrectly diagnose false-negative samples of cholangiocarcinoma as IgG4-SC based solely on IgG4-immunostaining. In terms of distinguishing IgG4-SC from PSC in a liver biopsy sample, advanced fibrosis corresponding to stages 3 and 4 would be observed only in PSC and not in IgG4-SC [bib_ref] Clinical differences between primary sclerosing cholangitis and sclerosing cholangitis with autoimmune pancreatitis, Nakazawa [/bib_ref] [bib_ref] Clinicopathological differentiation between sclerosing cholangitis with autoimmune pancreatitis and primary sclerosing cholangitis, Nishino [/bib_ref]. Fibrous cholangitis is significantly more frequent in PSC but can be detected in IgG4-SC as well [bib_ref] Clinicopathological differentiation between sclerosing cholangitis with autoimmune pancreatitis and primary sclerosing cholangitis, Nishino [/bib_ref] [bib_ref] Small bile duct involvement in IgG4-related sclerosing cholangitis: liver biopsy and cholangiography..., Naitoh [/bib_ref] [bib_ref] IgG4-associated cholangitis: a comparative histological and immunophenotypic study with primary sclerosing cholangitis..., Deshpande [/bib_ref]. Complications, such as severe pain, vasovagal syncope, and hemorrhage, occur infrequently after a liver biopsy. ## Cqi-13) is pocs recommended for diagnosing igg4-sc? - We suggest the use of POCS for differentiating between cholangiocarcinoma and PSC (Recommendation 2, level D). Comment: The detailed structure of the surface of the bile duct mucous membrane can be macroscopically observed using POCS. When combined with narrow-band imaging, observation of blood vessels using POCS is useful as a diagnostic aid [bib_ref] The role of peroral video cholangioscopy in patients with IgG4-related sclerosing cholangitis, Itoi [/bib_ref]. According to a report comparing POCS images of IgG4-SC, cholangitis, and PSC [bib_ref] Peroral cholangioscopic diagnosis of biliary-tract diseases by using narrow-band imaging (with videos), Itoi [/bib_ref] , a small number of cases of IgG4-SC characteristically exhibited a high frequency of dilated and tortuous vessels, and in many instances, there was no fibrous scar tissue [fig_ref] Figure 2: Histological findings of transmural inflammatory cell infiltration and fibrosis in the bile... [/fig_ref]. In IgG4-SC, inflammation is primarily submucosal [bib_ref] IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitisassociated..., Zen [/bib_ref] ; therefore, it is said that the appearance of congestion in the mucosal veins, where there is relatively little inflammation, can be perceived macroscopically. By contrast, in PSC, blood vessel distribution is poor, and scarring with pseudodiverticulum-like changes is often seen. In cholangiocarcinoma, irregular mucosal changes and large new blood vessels (particularly enlarged vessels) are often observed. However, differentiation based on POCS images alone can be difficult. In the diagnosis of cholangiocarcinoma, when bile duct biopsy under fluoroscopic guidance is difficult, specimens can be collected with greater reliability by POCS biopsy. ## Cqi-14) Are steroid trials recommended for diagnosing IgG4-SC? - We suggest that steroid trials should be carried out only by experts familiar with AIP and IgG4-SC or in patients with diagnostically challenging cases of IgG4-SC without AIP or other organ involvement only after exclusion of cholangiocarcinoma (Recommendation 2, level D). - The effectiveness of steroid trials for diagnosing IgG4-SC should be assessed by confirming resolution of findings on bile duct images obtained using ERCP/MRCP after 1 or 2 weeks of steroid administration at a dose of 0.4-0.6 mg/kg. In the absence of amelioration, we suggest re-evaluation, including resection of cases suspicious for cancer (Recommendation 2, level D). Comment: There are no reports of randomized controlled steroid trials for the diagnosis for IgG4-SC. Only one paper regarding AIP and a few case reports have been published [bib_ref] Is a 2-week steroid trial after initial negative investigation for malignancy useful..., Moon [/bib_ref] [bib_ref] Presentation and management of post-treatment relapse in autoimmune pancreatitis/immunoglobulin G4-associated cholangitis, Sandanayake [/bib_ref]. A steroid trial conducted for differential diagnosis of AIP and pancreatic cancer stated that steroid trials should be carried out only by pancreatobiliary subspecialists after the exclusion of potential malignancy [bib_ref] International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association..., Shimosegawa [/bib_ref]. This would also apply to the use of steroid trials in the diagnosis of IgG4-SC, which should be attempted only after excluding biliary malignancy. Steroid trials would be appropriate for use by pancreatobiliary subspecialists in diagnostically challenging cases mimicking PSC and/or cholangiocarcinoma. Almost all cases of IgG4-SC are associated with AIP, and cases that are not associated with AIP are often accompanied by involvement of other organs. These diagnostic clues could facilitate a correct diagnosis of IgG4-SC without evaluation of histopathologic evidence in bile duct samples [bib_ref] IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitisassociated..., Zen [/bib_ref]. However, a steroid trial would be acceptable in diagnostically challenging patients with IgG4-SC with a slight relationship with AIP and/or patients with isolated-type IgG4-SC without other organ involvement. Steroid trials might also be appropriate in patients with elevated serum IgG4 levels who present with typical cholangiogram results indicative of IgG4-SC [bib_ref] Schematic classification of sclerosing cholangitis with autoimmune pancreatitis by cholangiography, Nakazawa [/bib_ref]. The effectiveness of steroid trials for diagnosing IgG4-SC should be assessed by confirming resolution of findings on bile duct images obtained using ERCP/MRCP after 1 or 2 weeks of steroid administration at a dose of 0.4-0.6 mg/kg [bib_ref] Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy, Ghazale [/bib_ref] [bib_ref] Assessment in steroid trial for IgG4-related sclerosing cholangitis, Iwaski [/bib_ref]. The Mayo Clinic group [bib_ref] Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy, Ghazale [/bib_ref] and Iwasaki et al. [bib_ref] Assessment in steroid trial for IgG4-related sclerosing cholangitis, Iwaski [/bib_ref] validated the use of steroid trials for diagnosing IgG4-SC. The efficacy of steroid treatment should be evaluated within a week or so using serum data, and CT and MRCP or ERCP imaging findings should be assessed 1 to 2 weeks after the trial. In the absence of amelioration, re-evaluation, including resection of cases suspicious for cancer, should be proposed. Treatment CQII-1) What are the recommendations for steroid therapy in IgG4-SC patients? - We recommend steroid therapy for almost all IgG4-SC patients. Immediate steroid therapy should be considered for IgG4-SC patients with obstructive jaundice, acute cholangitis, and symptomatic extrabiliary IgG4related diseases (Recommendation 1, level D). Comment: Steroid therapy is recommended as the standard treatment for IgG4-related disease [bib_ref] IgG4-related disease, Kamisawa [/bib_ref] [bib_ref] IgG4-related sclerosing cholangitis, Nakazawa [/bib_ref] [bib_ref] International consensus guidance statement on the management and treatment of IgG4-related disease, Khosroshahi [/bib_ref]. According to a nationwide survey in Japan, about 88% of IgG4-SC patients receive steroid therapy [bib_ref] Clinical features, response to treatment, and outcomes of IgG4-related sclerosing cholangitis, Tanaka [/bib_ref]. The steroid-treated IgG4-SC remission rate is 90% [bib_ref] Clinical features, response to treatment, and outcomes of IgG4-related sclerosing cholangitis, Tanaka [/bib_ref]. According to the Japanese consensus guidelines for AIP, the indications for steroid therapy in AIP are the presence of symptoms (e.g. obstructive jaundice, abdominal pain, and back pain) and the presence of symptomatic extrapancreatic lesions [bib_ref] Amendment of the Japanese consensus guidelines for management of autoimmune pancreatitis, 2013...., Kamisawa [/bib_ref]. Furthermore, based on the international consensus guidance statement on the management and treatment of IgG4-related disease, proximal biliary strictures as well as associated symptomatic IgG4related diseases, including aortitis, retroperitoneal fibrosis, tubulointerstitial nephritis, pachymeningitis, pericarditis, and diffuse pancreatic enlargement, have been reported as indications for urgent steroid therapy, which may include combination therapy consisting of higher steroid doses and other mechanical interventions, such as biliary stenting [bib_ref] International consensus guidance statement on the management and treatment of IgG4-related disease, Khosroshahi [/bib_ref]. Thus, it is recommended that almost all IgG4-SC patients receive steroid therapy. Immediate steroid therapy should be considered in IgG4-SC patients with obstructive jaundice, acute cholangitis, and symptomatic extrabiliary IgG4-related diseases [bib_ref] International consensus guidance statement on the management and treatment of IgG4-related disease, Khosroshahi [/bib_ref]. It was reported that jaundice in some IgG4-SC cases without acute cholangitis can be safely treated and effectively managed with steroid therapy alone, without any need for biliary stenting [bib_ref] Obstructive jaundice in autoimmune pancreatitis can be safely treated with corticosteroids alone..., Yan [/bib_ref]. However, biliary drainage should be considered in IgG4-SC cases with acute cholangitis diagnosed based on the 2013 Tokyo Guidelines [bib_ref] Differentiating immunoglobulin g4-related sclerosing cholangitis from hilar cholangiocarcinoma, Tabata [/bib_ref] [bib_ref] TG13 flowchart for management of acute cholangitis and cholecystitis, Miura [/bib_ref] [bib_ref] Role of endoscopy in the diagnosis of autoimmune pancreatitis and immunoglobulin G4-related..., Kamisawa [/bib_ref]. Biliary stricture relapse has been reported in IgG4-SC patients during steroid tapering or after withdrawal of steroid treatment, and development of new biliary strictures has been reported in untreated IgG4-SC patients [bib_ref] Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy, Ghazale [/bib_ref] [bib_ref] Biliary tract involvement in autoimmune pancreatitis, Nishino [/bib_ref] [bib_ref] Clinical factors predictive of spontaneous remission or relapse in case of autoimmune..., Kubota [/bib_ref] [bib_ref] Long-term prognosis of autoimmune pancreatitis with and without corticosteroid treatment, Hirano [/bib_ref]. Relapse rates reportedly range from 16% [bib_ref] Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy, Ghazale [/bib_ref] to 53% [bib_ref] Long-term prognosis of autoimmune pancreatitis with and without corticosteroid treatment, Hirano [/bib_ref]. Bile duct strictures reportedly improve to varying degrees after steroid treatment, but mild bile duct strictures can persist in some IgG4-SC patients [bib_ref] Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy, Ghazale [/bib_ref] [bib_ref] Biliary tract involvement in autoimmune pancreatitis, Nishino [/bib_ref]. Consequently, steroid treatment is also recommended for asymptomatic IgG4-SC patients with elevated serum hepatobiliary enzyme levels. Differential diagnosis between cholangiocarcinoma and pancreatic cancer should be made before starting steroid therapy in IgG4-SC patients. CQII-2) Is biliary drainage recommended before initiating steroid therapy for IgG4-SC? - We suggest performing biliary drainage in cases involving obstructive jaundice due to biliary stenosis (Recommendation 2, level D). - Steroid therapy can be initiated without biliary drainage in cases involving mild jaundice without cholangitis in patients for whom the diagnosis is definite and pathologic approaches to the biliary stenosis are unnecessary (Recommendation 2, level D). Comment: In IgG4-SC, it is important to differentiate bile duct invasion by pancreatic cancer or lower bile duct cancer in cases involving stenosis of the lower bile duct and to differentiate from hilar cholangiocarcinoma in cases involving stenosis of the upper or hilar bile duct. Regarding differential diagnosis, ERCP and related procedures play an important role. Many IgG4-SC patients undergo ERCP, IDUS, transpapillary bile duct biopsy, and/or bile cytology with/without brushing, with ultimate insertion of an endoscopic nasobiliary drainage tube or plastic stent to relieve cholestasis and prevent cholangitis in a single session [bib_ref] International consensus guidance statement on the management and treatment of IgG4-related disease, Khosroshahi [/bib_ref] [bib_ref] Role of endoscopy in the diagnosis of autoimmune pancreatitis and immunoglobulin G4-related..., Kamisawa [/bib_ref] [bib_ref] Role of endoscopy in diagnosis and treatment, Moon [/bib_ref]. According to one Japanese study [bib_ref] Standard steroid therapy for autoimmune pancreatitis, Kamisawa [/bib_ref] and an international survey [bib_ref] Long-term outcomes of autoimmune pancreatitis: a multicentre, international analysis, Hart [/bib_ref] , biliary drainage before starting steroids were underwent in 77% and 71% of AIP patients who presented with obstructive jaundice, respectively. On the other hand, in a study of 15 AIP patients, Bi et al. of the Mayo Clinic [bib_ref] Obstructive jaundice in autoimmune pancreatitis can be safely treated with corticosteroids alone..., Yan [/bib_ref] reported that obstructive jaundice was safely and effectively treated with steroids alone without biliary stenting. Follow-up serum liver tests at a mean of 4 days (range 1-14 days) after starting steroids showed rapid reduction in all measures: 54.9% decrease in aspartate aminotransferase (AST), 51.6% decrease in alanine aminotransferase (ALT), 33% decrease in alkaline phosphatase (ALP), and 47.2% decrease in total bilirubin (TB). By 15 to 45 days after steroid treatment, all patients had normal AST, three patients had ALT more than 1.5 9 ULN (upper limit of normal), one patient had ALP more than 1.5 9 ULN, and only one patient had TB more than 1.5 9 ULN. No patients showed any infectious complications such as cholangitis during steroid treatment. Therefore, steroid therapy alone in a closely monitored setting under the guidance of an experienced pancreatologist is recommended for AIP patients with obstructive jaundice whose diagnosis is certain, thereby avoiding ERCP and its potential complications such as pancreatitis. Iwasaki et al. [bib_ref] Assessment in steroid trial for IgG4-related sclerosing cholangitis, Iwaski [/bib_ref] reported 75%, 89%, and 83% decreases in serum levels of ALT, ALP, and TB, respectively, around 5 days after starting steroids in 19 patients with IgG4-SC who were treated with steroids without biliary drainage, and the levels were halved in 63%, 89%, and 67% around 10 days after starting steroids. Bile duct stenosis improved in all patients except one on ERC performed 1-4 weeks after starting steroids. The above data suggest that as IgG4-SC improves rapidly with steroids, steroid therapy can be initiated without ERC or biliary drainage in cases involving mild jaundice without cholangitis in patients for whom the diagnosis is definite and pathologic approaches to the biliary stenosis are unnecessary, such as in cases of stenosis of the lower bile duct associated with elevated serum IgG4 levels and diffuse enlargement of the pancreas [bib_ref] Mechanisms of lower bile duct stricture in autoimmune pancreatitis, Watanabe [/bib_ref] [bib_ref] International consensus for the treatment of autoimmune pancreatitis, Okazaki [/bib_ref]. ## Cqii-3) how is steroid therapy for igg4-sc performed? - We suggest oral prednisolone at 0.6 mg/kg/day (usual dose: 30-40 mg/day) for 2-4 weeks for initial remission-induction therapy (Recommendation 2, level D). - We suggest that the dose of prednisolone is reduced by 5 mg every 1-2 weeks after induction of remission, while confirming the response to steroid therapy by laboratory tests and imaging studies (e.g. ultrasonography, CT, or MRCP), and then gradually tapered further to the maintenance level by 2-3 months (Recommendation 2, level D). - Although the recommended maintenance dose is 5 mg/day, adjusting the dose within the range of approximately 5 mg/day based on the patient's response is suggested (Recommendation 2, level D). - After remission has been maintained for 3 years, it is possible to consider further reducing or discontinuing steroid therapy, but we suggest that this should be done carefully because there is a high risk of relapse (Recommendation 2, level C). - We recommend periodic assessment of symptoms, analysis of objective findings such as jaundice, and biochemistry tests, serum IgG/IgG4 levels, and imaging findings after the initiation of steroid therapy as well as after discontinuation of therapy. Care should be taken to identify relapse, exclude malignancy, and control adverse reactions to steroid therapy while managing the clinical course of these patients (Recommendation 1, level D). Comment: 1) Initial remission induction There have been few studies on steroid therapy for IgG4-SC. Steroid therapy is indicated for patients who have AIP with symptoms, jaundice, and bile duct involvement. The standard treatment schedule recommended by the Japanese clinical guidelines for AIP [bib_ref] Amendment of the Japanese consensus guidelines for management of autoimmune pancreatitis, 2013...., Kamisawa [/bib_ref] and the international consensus diagnostic criteria [bib_ref] International consensus for the treatment of autoimmune pancreatitis, Okazaki [/bib_ref] is oral prednisolone (0.6 mg/kg/day) for 2-4 weeks as initial remission-induction therapy, with subsequent tapering by 5 mg/day every 1-2 weeks and reduction to the maintenance dose by 2-3 months after the start of treatment, observing the patient's response throughout [bib_ref] Standard steroid therapy for autoimmune pancreatitis, Kamisawa [/bib_ref] [bib_ref] Treatment for autoimmune pancreatitis: consensus on the treatment for patients with autoimmune..., Ito [/bib_ref]. The Mayo Clinic also proposed a treatment schedule that starts with 4 weeks of oral prednisone at 40 mg/day, followed by tapering at 5 mg/week until discontinuation at 11 weeks [bib_ref] Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy, Ghazale [/bib_ref] [bib_ref] Optimising corticosteroid treatment for autoimmune pancreatitis, Ghazale [/bib_ref]. In a Japanese multicenter study, biliary drainage was performed in 242/314 patients who had obstructive jaundice among 563 patients with AIP in order to compare a starting dose of 40 mg/day or 30 mg/day of oral prednisolone in 459 patients treated with steroids, but there was no difference of the time to remission or the relapse rate [bib_ref] Standard steroid therapy for autoimmune pancreatitis, Kamisawa [/bib_ref]. Although there are reports of an observable effect even at low steroid doses (≤20 mg/day) in diabetic patients who are at risk of exacerbation of diabetes by steroid therapy [bib_ref] Clinical features, response to treatment, and outcomes of IgG4-related sclerosing cholangitis, Tanaka [/bib_ref] [bib_ref] Comparable efficacy of low-versus high-dose induction corticosteroid treatment in autoimmune pancreatitis, Buijs [/bib_ref] , patient selection bias cannot be ruled out in retrospective studies. It was also reported that steroid pulse therapy is more effective for improving early bile duct lesions compared with oral steroids when it is desirable to obtain a response in a short period [bib_ref] Effective steroid pulse therapy for the biliary stenosis caused by autoimmune pancreatitis, Matsushita [/bib_ref] [bib_ref] Comparison of steroid pulse therapy and conventional oral steroid therapy as initial..., Sugimoto [/bib_ref]. 2) Dose reduction after remission induction After induction of remission, the response to steroids is confirmed by laboratory tests and imaging studies. Steroid therapy is continued, with the dose gradually being tapered if other diseases are excluded, including cholangiocarcinoma, pancreatic cancer, and PSC. If improvement is not achieved by steroid therapy and the possibility of another disease is considered to be high, it is necessary to promptly review the diagnosis. After induction of remission with steroid therapy, the standard method is to reduce the dose of prednisolone by 5 mg every 1-2 weeks until the maintenance dose (5-10 mg/day) is finally reached at 2-3 months after starting treatment. Since it has been reported that there is a risk of relapse of SC, the steroid dose should be reduced while regularly checking for recurrence by monitoring symptoms and signs, biochemistry data, IgG/IgG4 levels, and imaging findings (e.g. ultrasonography, CT, MRCP, or ERCP). After prednisolone is reduced to 15 mg/day, the dose is reduced further at longer intervals in some cases [bib_ref] Standard steroid therapy for autoimmune pancreatitis, Kamisawa [/bib_ref]. While pancreatic enlargement associated with AIP almost always improves after remission is achieved by steroid therapy, bile duct stenosis persists in 58% of patients with persistent elevation of IgG4 versus 27% of patients with normal IgG4 levels [bib_ref] Standard steroid therapy for autoimmune pancreatitis, Kamisawa [/bib_ref]. 3) Maintenance therapy A randomized controlled trial of steroid maintenance therapy was performed in 49 Japanese patients with AIP after induction of remission to compare maintenance therapy (5-7.5 mg/day) between a group treated for 3 years and a group in which therapy was discontinued at 26 weeks. It was found that the relapse rate up to 3 years was 23.3% in the former group versus 57.9% in the latter, and the long-term maintenance therapy group had a significantly lower risk of relapse, with no serious steroidrelated adverse events [bib_ref] Randomised controlled trial of long-term maintenance corticosteroid therapy in patients with autoimmune..., Masamune [/bib_ref]. In a retrospective multicenter study of 510 patients with AIP [bib_ref] Low-dose maintenance steroid treatment could reduce the relapse rate in patients with..., Kubota [/bib_ref] , the relapse rate achieved with standard steroid therapy for AIP [bib_ref] Amendment of the Japanese consensus guidelines for management of autoimmune pancreatitis, 2013...., Kamisawa [/bib_ref] was 10% at 1 year, 11% at 2 years, 25.8% at 3 years, 30.9% at 4 years, and 35.1% at 5 years, finally reaching a plateau at 43% after 7 years. When maintenance therapy was performed with a steroid dose of 2.5-10 mg/day, the relapse rate was significantly lower in the group that received ongoing maintenance therapy than in the group with withdrawal of therapy (30.3% vs. 45.2%). Also, when administration of oral prednisolone at various doses (0, 2.5, 5, 7.5, or 10 mg/day) was compared, the risk of relapse was the lowest at 5 mg/day (26.1%), and there were no significant differences between 5 mg, 7.5 mg, and 10 mg/day. Discontinuing steroid therapy in the short term has been the general policy in other countries. However, a retrospective study of 30 patients with SC performed at the Mayo Clinic showed that starting oral prednisone at 40 mg/day with tapering by 5 mg/week until discontinuation at 11 weeks resulted in a recurrence rate of 53% after a median of 3 months and 71% within 6 months [bib_ref] Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy, Ghazale [/bib_ref]. In a prospective study of IgG4-SC performed in the United Kingdom, oral prednisolone was initiated at 30 mg/day for 2 weeks and then reduced by 5 mg every 2 weeks, resulting in a remission rate of 82%. However, 18% of the patients had no response to steroid therapy, and 35% developed recurrence after a median of 4 months [bib_ref] Presentation and management of post-treatment relapse in autoimmune pancreatitis/immunoglobulin G4-associated cholangitis, Sandanayake [/bib_ref]. From these results, the consensus in Japan is that continuing long-term maintenance therapy at a dose of approximately 5 mg/day for 3 years is desirable to prevent recurrence [bib_ref] Amendment of the Japanese consensus guidelines for management of autoimmune pancreatitis, 2013...., Kamisawa [/bib_ref] [bib_ref] Standard steroid therapy for autoimmune pancreatitis, Kamisawa [/bib_ref] , but there is no agreement regarding discontinuation of steroid therapy or further dose reduction after 3 years. Hirano et al. [bib_ref] Outcome of long-term maintenance steroid therapy cessation in patients with autoimmune pancreatitis...., Hirano [/bib_ref] performed a prospective trial in 21 patients with AIP who discontinued maintenance therapy after 3 years, and they found relapse in 48% of the patients during follow-up for 43 months. Based on these results, they recommended that long-term maintenance therapy should be continued beyond 3 years. A Japanese multicenter study of adverse events associated with steroid therapy reported an area under the curve of 0.717 when the cut-off value for the total steroid dose was set at 6,405 mg [bib_ref] Low-dose maintenance steroid treatment could reduce the relapse rate in patients with..., Kubota [/bib_ref]. To avoid adverse reactions caused by long-term administration of corticosteroids, the standard recommendation is to consider continuation of therapy, dose reduction, or discontinuation after 3 years, as the risk of infection increases with long-term administration at 10 mg/day, and the risk of steroid-associated osteoporosis is significantly increased when the total steroid dose reaches or exceeds 6,405 mg. In IgG4-SC patients, we should carefully consider steroid dose reduction, maintenance therapy, and the duration of treatment for those with SC, as it has a high risk of relapse. CQII-4) How should relapse be treated? - We recommend both re-administration and increasing the dose of steroids for treating relapse in IgG4-SC patients (Recommendation 1, level D). - Immunomodulatory drugs and rituximab are useful in some relapse cases. However, treatment with these drugs is not covered by the medical insurance system in Japan (level C). Comment: Relapse of IgG4-SC is generally defined as a reappearance of symptoms after remission (during maintenance steroid therapy or after steroid withdrawal), with the development or aggravation of bile duct strictures, and/or other organ involvement (e.g. AIP, IgG4-related dacryoadenitis/sialadenitis, IgG4-related retroperitoneal fibrosis) with abnormalities on imaging, and/or elevation of serum IgG4 levels [bib_ref] Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic..., Hart [/bib_ref] [bib_ref] The treatment of IgG4-related diseases in the hepatobiliary-pancreatic system, Kamisawa [/bib_ref]. Re-elevation of serum IgG4 levels alone without symptoms or with the presence of bile duct strictures is not considered to be relapse [bib_ref] Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic..., Hart [/bib_ref] [bib_ref] The treatment of IgG4-related diseases in the hepatobiliary-pancreatic system, Kamisawa [/bib_ref]. Disease relapse occurs in 30-57% of IgG4-SC patients either during maintenance steroid therapy or after the discontinuation of steroids, particularly in the first couple of years [bib_ref] Type 1 autoimmune pancreatitis and IgG4-related sclerosing cholangitis is associated with extrapancreatic..., Huggett [/bib_ref] [bib_ref] Long-term outcomes of autoimmune pancreatitis: a multicentre, international analysis, Hart [/bib_ref]. Relapse rates after steroid therapy are similar to those reported after surgery [bib_ref] Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy, Ghazale [/bib_ref]. In a retrospective cohort study of 507 patients with IgG4-SC in Japan, relapse with restenosis of the bile ducts was noted in 104 patients (19%), and the cumulative rate of relapse was 1.6%, 7.6%, and 16.5% at 1, 3, and 5 years after diagnosis, respectively [bib_ref] Clinical features, response to treatment, and outcomes of IgG4-related sclerosing cholangitis, Tanaka [/bib_ref]. Known risk factors predictive of a relapse include high serum IgG4 level at diagnosis, the presence of proximal extrahepatic/intrahepatic or multiple bile duct strictures, and thicker bile duct walls during the initial attack [bib_ref] Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy, Ghazale [/bib_ref] [bib_ref] Long-term outcomes of autoimmune pancreatitis: a multicentre, international analysis, Hart [/bib_ref] [bib_ref] Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic..., Hart [/bib_ref] [bib_ref] Relapse of IgG4-related sclerosing cholangitis after steroid therapy: imaging findings and risk..., You [/bib_ref]. Both re-administration and increasing the dose of steroids have been shown to be effective in treating relapse patients [bib_ref] Amendment of the Japanese consensus guidelines for management of autoimmune pancreatitis, 2013...., Kamisawa [/bib_ref] [bib_ref] Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic..., Hart [/bib_ref]. In Western countries, in addition to the re-administration of steroids, immunomodulatory drugs such as azathioprine, 6-mercaptopurine, mycophenolate mofetil, and methotrexate have been administered as steroid-sparing agents for treating relapse in IgG4-SC patients [bib_ref] Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy, Ghazale [/bib_ref] [bib_ref] Type 1 autoimmune pancreatitis and IgG4-related sclerosing cholangitis is associated with extrapancreatic..., Huggett [/bib_ref] [bib_ref] Presentation and management of post-treatment relapse in autoimmune pancreatitis/immunoglobulin G4-associated cholangitis, Sandanayake [/bib_ref] [bib_ref] TG13 flowchart for management of acute cholangitis and cholecystitis, Miura [/bib_ref] [bib_ref] Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic..., Hart [/bib_ref]. However, the benefits of the additional immunomodulators in reducing time to further relapse are uncertain, and as these drugs are associated with serious side-effects, their use should be considered with caution [bib_ref] Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic..., Hart [/bib_ref]. Rituximab, a monoclonal anti-CD20 antibody leading to B-cell depletion, is reportedly effective for treatment of IgG4-SC resistant to steroid and immunomodulator therapy. According to the limited data available, disease response is obtained in 80-90% of IgG4-SC patients, including many with difficult-to-treat disease [bib_ref] Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic..., Hart [/bib_ref] [bib_ref] Rituximab therapy for refractory biliary strictures in immunoglobulin G4-associated cholangitis, Topazian [/bib_ref] [bib_ref] Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt..., Khosroshahi [/bib_ref] [bib_ref] Takahiro Nakazawa (Department of Gastroenterology, Japanese Red Cross Nagoya Daini Hospital, Carruthers [/bib_ref]. In international consensus statements for the treatment of AIP, immunomodulatory drugs or rituximab is recommended for relapse AIP as steroid-sparing agents. However, treatment with these drugs for IgG4-related diseases including IgG4-SC is not covered by the medical insurance system in Japan [bib_ref] International consensus for the treatment of autoimmune pancreatitis, Okazaki [/bib_ref]. [fig] Figure 2: Histological findings of transmural inflammatory cell infiltration and fibrosis in the bile duct of IgG4-SC (arrow). (Scale: 100 lm) [/fig] [fig] Figure 3: Histological findings of storiform fibrosis in the bile duct of IgG4-SC. (Scale: 100 lm) Fig. 4 Histological findings of obliterative phlebitis (arrows) in the bile duct of IgG4-SC. (Scale: 100 lm) [/fig] [fig] Figure 5: Immunohistochemical findings of infiltration of numerous IgG4-positive cells in the bile duct of IgG4-SC. IgG4-immunostaining. (Scale: 100 lm) [/fig] [fig] Figure 6: Algorithm for diagnosis and treatment of IgG4-SC referred from Reference 18Fig. 8 Algorithm for diagnosis and treatment of IgG4-SC referred from Reference 18 [/fig] [fig] Figure 7: Algorithm for diagnosis and treatment of IgG4-SC referred from Reference 18 [/fig] [fig] Figure 11: Schematic illustration of treatment of IgG4-SC Fig. 10 Summary of imaging findings suggestive of IgG4-SC [/fig] [fig] Figure 12: Ultrasonographic image of IgG4-SC. Ultrasonography detects marked wall thickening in the extrahepatic bile duct (arrows) Fig. 13 EUS image of IgG4-SC. EUS shows a homogeneous, highlow-high echo of the bile duct wall thickening (arrows) [/fig] [fig] Figure 14, Figure 15: CT image of IgG4-SC. Contrast-enhanced CT (delayed image) demonstrates concentric wall thickening of the hilar bile duct (arrows) CT and MRCP images of IgG4-SC. (a) In CT, the hilar bile duct shows marked thickening (arrow). (b) MRCP demonstrates bile duct strictures in the hilar bile duct (arrows) [/fig] [fig] Figure 16: ERCP image of a patient with AIP in which the lesion was limited to the pancreatic head. Narrowing of the main pancreatic duct in the head (arrows) and strictures of the lower bile ducts are recognized [/fig] [fig] Figure 17: IgG4-related dacryoadenitis. Swelling of right and left lacrimal glands (right > left) is recognized (arrows) Fig. 18 CT image of IgG4-related retroperitoneal fibrosis. Soft-tissue mass surrounding the abdominal aorta is recognized (arrow) CQI-5) Is consideration of other associated diseases useful for diagnosing IgG4-SC? [/fig] [table] Table 1: Comparison of clinical features of IgG4-related sclerosing cholangitis [/table] [table] Table 2: Comparison of treatment and prognosis of IgG4-related sclerosing cholangitis [/table] [table] Table 3: Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012 [3] 1. Diagnostic items (1) Biliary tract imaging reveals diffuse or segmental narrowing of the intrahepatic and/or extrahepatic bile duct associated with the thickening of bile duct wall. (2) Hematological examination shows elevated serum IgG4 concentrations (≥135 mg/dl). (3) Coexistence of autoimmune pancreatitis, IgG4-related dacryoadenitis/sialadenitis, or IgG4-related retroperitoneal fibrosis. [/table] [table] Table 4: Differential characteristics of IgG4-SC and PSC [/table] [table] Table 5: Usefulness of bile duct biopsy for the diagnosis of IgG4-SC [/table]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/jhbp.596	IgG4‐related sclerosing cholangitis (IgG4‐SC) is a distinct type of cholangitis frequently associated with autoimmune pancreatitis and currently recognized as a biliary manifestation of IgG4‐related disease. Although clinical diagnostic criteria of IgG4‐SC were established in 2012, differential diagnosis from primary sclerosing cholangitis and cholangiocarcinoma is sometimes difficult. Furthermore, no practical guidelines for IgG4‐SC are available. Because the evidence level of most articles retrieved through searching the PubMed, Cochrane Library, and Igaku Chuo Zasshi databases was below C based on the systematic review evaluation system of clinical practice guidelines MINDS 2014, we developed consensus guidelines using the modified Delphi approach. Three committees (a guideline creating committee, an expert panelist committee for rating statements according to the modified Delphi method, and an evaluating committee) were organized. Eighteen clinical questions (CQs) with clinical statements were developed regarding diagnosis (14 CQs) and treatment (4 CQs). Recommendation levels for clinical statements were set using the modified Delphi approach. The guidelines explain methods for accurate diagnosis, and safe and appropriate treatment of IgG4‐SC.
696740ef5d7668729fa74b01e0999470359df8e5	pubmed	7th Brazilian Guideline of Arterial Hypertension: Chapter 9 - Arterial Hypertension in pregnancy	7th Brazilian Guideline of Arterial Hypertension: Chapter 9 - Arterial Hypertension in pregnancy EpidemiologyThe hypertensive syndromes of pregnancy cause expressive maternal and fetal morbidity and mortality. There is no accurate information on the incidence of preeclampsia (PE), but it is estimated to affect 4% of gestations. In Brazil, the incidence of PE is 1.5 %, while the incidence of eclampsia is 0.6%. 1 More developed areas have an incidence of eclampsia of 0.2%, with a maternal death rate of 0.8%, while for less favored regions those indices are 8.1% and 22%, respectively. 2 A population-based study shows AH in 7.5% of the gestations in Brazil, with 2.3% of PE and 0.5% of superimposed PE. 3 Arterial hypertension during pregnancy accounts for 20% to 25% of all causes of maternal death, and data from SUS show a trend towards stagnation. 4 Preeclampsia is defined as the presence of AH after the 20th gestational week, associated with significant proteinuria. In the absence of significant proteinuria, the diagnosis can be based on the presence of: headache, blurred vision, abdominal pain, low blood platelet count (< 100,000/mm³), elevation of liver enzymes (twice the baseline level), kidney impairment (creatinine > 1.1 mg/dL or twice the baseline level), pulmonary edema, visual or cerebral disorders, scotomas, and seizure. Eclampsia is defined as the presence of grand mal seizure in a pregnant woman with PE. Chronic AH is defined by the detection of AH prior to pregnancy or before the 20th week of gestation. Preeclampsia might overlap. Gestational hypertension is characterized by AH after the 20th week of gestation without proteinuria. Some clinical conditions increase the risk of PE dramatically. Severe PE should be considered in the presence of: SBP ≥ 160 or DBP ≥ 110 mm Hg; low blood platelet count; TGP twice the baseline level; persistent epigastric or right hypochondrial pain; acute kidney injury (AKI -creatinine > 1.1 mg/dL or twice the baseline level); pulmonary edema; visual or cerebral symptoms. 5 ## Preeclampsia prevention Regarding PE prevention, there is no unequivocally effective strategy for all pregnant women. Calcium supplementation (> 1 g/day) is not recommended for pregnant women with normal intake of that ion 6 (GR: III; LE: A), but to those with low calcium intake and at intermediate and increased risk for PE. 6 (GR: I; LE: A). Low doses of acetylsalicylic acid (75-150 mg/day) at the end of the first gestational trimester can be useful for primary prevention of PE in pregnant women at intermediate and increased risk for PE. 7,8 (GR: IIa; LE: B). That use, however, is not recommended in the absence of risk. 8 (GR: III; LE: A). Calcium supplementation (> 1 g/day) is associated with a reduction in the risk for PE, prematurity and a lower risk of gestational-hypertension-related death, particularly in women with a low-calcium diet (< 600 g). [bib_ref] CLASP: a randomized trial of low-dose aspirin for the prevention and treatment..., Hofmeyr [/bib_ref] For women at risk for PE, clinical trials have suggested a significant protective effect of the daily acetylsalicylic acid use. 7 Low acetylsalicylic acid doses reduce the risk of PE by 17%, with a decrease in the fetal death risk of 14% and in the prematurity risk of 8%. Daily doses of 75-150 mg seem safe.Acetylsalicylic acid at low doses should be considered for primary prevention of women at high risk and should be initiated at the end of the first trimester. 9 ## Nonpharmacological treatment For persistent AH > 150 mm Hg for more than 15 minutes, NPT alone should not be used to prevent irreversible neurological damage. 10 (GR: III; LE: B). Systolic BP > 155 mm Hg, especially > 160 mm Hg, is detected immediately before stroke. [bib_ref] Stroke and severe preeclampsia and eclampsia: a paradigm shift focusing on systolic..., Martin [/bib_ref] Severe diastolic AH (DAH: > 105 or 110 mm Hg) does not develop before most strokes of pregnant women with severe PE. [bib_ref] Stroke and severe preeclampsia and eclampsia: a paradigm shift focusing on systolic..., Martin [/bib_ref] To avoid maternal deaths, SBP > 150-160 mm Hg should indicate urgent treatment. [bib_ref] Saving Mothers' Lives: reviewing maternal deaths to make motherhood safer: 2006-2008. The..., Cantwell [/bib_ref] Relative rest at hospital or day-hospital with monitoring is suggested for PE. (GR: IIa; LE: B). Hospitalization should be indicated to pregnant patients with severe AH. (GR: I; LE: B). A systematic review has shown no difference in outcomes between strict rest and relative rest for pregnant women with AH and proteinuria. Relative rest at hospital, as compared with routine house activity, reduces the risk for severe AH; however, data do not support a clear recommendation. Rest is not routinely indicated for gestational hypertension.Prenatal care units and hospitals have similar clinical outcomes for mothers and newborns, but women might prefer day-hospitals.Although there is no indication for specific care during hospitalization, maternal and fetal monitoring is required. Blood pressure should be periodically measured, with daily weight and diuresis assessment, and patients should be instructed about premonitory signs. Laboratory tests, such ## Chart 1 -classification of hypertension in pregnancy. ## Preeclampsia -eclampsia Chronic AH (any etiology) Chronic AH with overlapping PE Gestational hypertension as hemogram with platelet count, liver enzymes, uric acid, creatinine and proteinuria, should be performed once to twice a week. Fetal follow-up comprises assessment of growth, movements, well-being and biophysical profile, as well as US. ## Expectant management Expectant management is not recommended after the 36th gestational week for women with gestational hypertension. [bib_ref] HYPITAT study group. Induction of labour versus expectant monitoring for gestational hypertension..., Koopmans [/bib_ref] (GR: III; LE: B). Expectant management is suggested between the 34th and 36th gestational weeks for stable women, without clinical worsening or severe hypertension. [bib_ref] HYPITAT-II study group. Immediate delivery versus expectant monitoring for hypertensive disorders of..., Broekhuijsen [/bib_ref] (GR: IIa; LE: B). Premature delivery for patients with PE can be associated with decreased mortality. The ideal delivery time, before the 32nd-34th weeks, is a dilemma because of the uncertainty in the balance between maternal safety (end of pregnancy) and fetal maturity (expectant). [bib_ref] Quantifying the fall in mortality associated with interventions related to hypertensive diseases..., Ronsmans [/bib_ref] After the 34th week, survival is high and the baby and placenta delivery is effective in developed countries. [bib_ref] Quantifying the fall in mortality associated with interventions related to hypertensive diseases..., Ronsmans [/bib_ref] The HYPITAT study has compared delivery induction versus expectant monitoring for severe AH or mild PE after the 36th week. [bib_ref] HYPITAT study group. Induction of labour versus expectant monitoring for gestational hypertension..., Koopmans [/bib_ref] Women in the intervention group had a 29% lower risk of worse maternal outcome, without affecting neonatal outcome, suggesting that expectant treatment after 36 weeks is not indicated. [bib_ref] HYPITAT study group. Induction of labour versus expectant monitoring for gestational hypertension..., Koopmans [/bib_ref] In the HYPTAT-II study, with non-severe AH between the 34 th and 37 th weeks, expectant management increased maternal risk as compared to immediate delivery, but decreased the occurrence of neonatal respiratory distress syndrome. In that situation, immediate delivery is not justified, and expectant monitoring until the clinical situation worsens should be considered. [bib_ref] HYPITAT-II study group. Immediate delivery versus expectant monitoring for hypertensive disorders of..., Broekhuijsen [/bib_ref] ## Pharmacological treatment Urgent pharmacological treatment is indicated in severe AH (SBP > 155-160 mm Hg) [bib_ref] Stroke and severe preeclampsia and eclampsia: a paradigm shift focusing on systolic..., Martin [/bib_ref] and presence of premonitory signs. (GR: I; LE: B). The treatment of severe AH in emergency situations can be performed with intravenous (IV) hydralazine (5 mg, repeat 5-10 mg IV every 30 minutes until the maximum of 20 mg). In exceptional situations, such as acute pulmonary edema (APE) and refractory severe SAH, the use of sodium nitroprusside (SNP) should be the preferential option for urgent BP control. [bib_ref] Does sodium nitroprusside kill babies? A systematic review, Sass [/bib_ref] Oral administration of rapid-acting nifedipine (5 mg every 30 minutes) is an alternative, but associated complications have been reported. [bib_ref] Severe hypotension and fetal distress following sublingual administration of nifedipine to a..., Impey [/bib_ref] Although sublingual nifedipine is not indicated in other forms of hypertensive crisis (HC), it is an alternative in gestational hypertension. Its use for hypertensive emergency (HE), however, has been considered bad practice, harmful to the patient in a report by the São Paulo Regional Medical Board. Pharmacological treatment should be initiated whenever BP is > 150/100 mm Hg, [bib_ref] Saving Mothers' Lives: reviewing maternal deaths to make motherhood safer: 2006-2008. The..., Cantwell [/bib_ref] aiming at maintaining it 130-150/80-100 mm Hg. (GR: IIa; LE: B). For stable patients with PE, not requiring immediate delivery, oral antihypertensive treatment is indicated. Treatment with antihypertensive agents reduces the risk for severe AH, but not the risk for PE, restricted intrauterine growth, placental abruption and neonatal outcomes.Treatment to meet the DBP target of 85 mm Hg as compared to 100 mm Hg showed neither maternal nor obstetric benefit, except for the less frequent occurrence of severe AH in the group with stricter control. [bib_ref] Less-tight versus tight control of hypertension in pregnancy, Magee [/bib_ref] The choice of the antihypertensive drug depends on the attending physician's experience and familiarity with the drug chosen and its possible side effects.(GR: IIb; LE: B). The use of ACEIs, ARBs and direct renin inhibitors is contraindicated in pregnancy (GR: I; LE: B), and atenolol and prazosin should be avoided.(GR: IIa; LE: B). In Brazil, the available oral drugs usually used are methyldopa, BBs (except atenolol), hydralazine and CCBs (nifedipine, amlodipine and verapamil). Atenolol is associated with a reduction in fetal growth, and prazosin can cause natimortality. [bib_ref] Treatment of hypertension in pregnancy: effect of atenolol on maternal disease, preterm..., Easterling [/bib_ref] [bib_ref] Prevention of preeclampsia: a randomized trial of atenolol in hyperdynamic patients before..., Easterling [/bib_ref] [bib_ref] Nifedipine or prazosin as a second agent to control early severe hypertension..., Hall [/bib_ref] For PE, the prescription of a DIU is usually avoided; thiazide DIUs, however, can be continued in pregnant women with chronic AH (CAH), [bib_ref] Effects of diuretics on plasma volume in pregnancies with long-term hypertension, Sibai [/bib_ref] as long as they do not cause volume depletion. Magnesium sulfate is recommended for eclampsia prevention and treatment. (GR: I; LE: B). In case of HE or of hypertensive urgency (HU) requiring hospitalization, intensive monitoring, preterm delivery and parenteral administration of antihypertensive drugs, the IV administration of magnesium sulfate, considered the drug of choice to prevent and treat eclampsia, is recommended. 5,28-30 Magnesium sulfate is administered at an attack dose of 4-6 g IV for 10-20 minutes, followed by infusion of 1-3 g/h, usually for 24 hours. If the seizure reoccurs, 2-4 g can be administered IV. Deep intramuscular administration of 10 g (5 g in each gluteus), followed by intramuscular 5 g every 4 hours for 24 hours is an alternative. Magnesium sulfate is indicated during labor for patients with severe PE. Magnesium sulfate administration should continue for up to 24 hours after seizure, imminent eclampsia signs and delivery. Its administration should be generous to patients with PE, preferably before the administration of rapid-acting antihypertensive drugs to patients, in whom the possibility of eclampsia cannot be ruled out. ## Other important aspects Severe AH, per se, is not an indication for C section. In the presence of stable maternal clinical findings, good fetal vitality and lack of other C section indications, pregnancy termination can occur by delivery induction, always considering maternal clinical condition and fetal vitality during the procedure.Labor analgesia is recommended with local-regional techniques (peridural or combined analgesia). Severe thrombocytopenia contraindicates anesthesia with lumbar puncture, and, if C section is required, it should be performed under general anesthesia. Invasive central monitoring is reserved to cases with hemodynamic instability (respiratory failure, disseminated intravascular coagulation related to placental abruption, or HELLP syndrome).Antihypertensive treatment in lactating women Chart 2 shows the antihypertensive drugs available in Brazil considered safe, moderately safe and not recommended. [bib_ref] Medicines and breastfeeding: update and revision applied to mother and baby care, Chaves [/bib_ref] (GR: IIb, LE: C).	None	None	The hypertensive syndromes of pregnancy cause expressive maternal and fetal morbidity and mortality. There is no accurate information on the incidence of preeclampsia (PE), but it is estimated to affect 4% of gestations. In Brazil, the incidence of PE is 1.5 %, while the incidence of eclampsia is 0.6%.1 More developed areas have an incidence of eclampsia of 0.2%, with a maternal death rate of 0.8%, while for less favored regions those indices are 8.1% and 22%, respectively.2 A population-based study shows AH in 7.5% of the gestations in Brazil, with 2.3% of PE and 0.5% of superimposed PE.3 Arterial hypertension during pregnancy accounts for 20% to 25% of all causes of maternal death, and data from SUS show a trend towards stagnation.4
5ca2cacb7f4d8ca64dd496795a5f2f565f5e7f73	pubmed	Management of patients with acute leukemia during the COVID-19 outbreak: practical guidelines from the acute leukemia working party of the European Society for Blood and Marrow Transplantation	Management of patients with acute leukemia during the COVID-19 outbreak: practical guidelines from the acute leukemia working party of the European Society for Blood and Marrow Transplantation [bib_ref] Critical care utilization for the COVID-19 outbreak in Lombardy, Italy: early experience..., Grasselli [/bib_ref] [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref] [bib_ref] Covid-19 in critically ill patients in the Seattle region-case series, Bhatraju [/bib_ref] [bib_ref] Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China, Liang [/bib_ref] [bib_ref] Management of patients with multiple myeloma during the COVID-19 outbreak, Malard [/bib_ref] [bib_ref] Index to predict invasive mold infection in high-risk neutropenic patients based on..., Portugal [/bib_ref] [bib_ref] Association of risk factors, mortality, and care costs of adults with acute..., Halpern [/bib_ref] ## General principle Patients should be aware of their frailty to COVID-19 infection and specific hygiene measures and importance of social distancing should be explained. All journeys outside the hematological department should be discussed and adapted for the situation. For example, it should be ensured that outpatient transportation services bring patients to the scheduled time of their consultation, in order to minimize the time spent in the waiting area. For those requiring oral or subcutaneous treatment administration, one needs to minimize hospital visits. Possible strategies for this are offering telephone or video consultations, cutting nonessential face-to-face follow-up, using home-delivery services for medicines, and using local services for blood tests. ## Screening Given that percentage of asymptomatic cases of COVID-19 can be high [bib_ref] Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board..., Mizumoto [/bib_ref] , all newly diagnosed patients with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) should be screened for COVID-19 infection by PCR and high-resolution thoracic computerized tomography scan before initiating chemotherapy [bib_ref] Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19)..., Ai [/bib_ref] [fig_ref] Table 1: Recommendation for management of patients with acute leukemia during the COVID-19 outbreak [/fig_ref]. The screening should be repeated before each course of chemotherapy. If positive, the decision to initiate or continue the treatment needs to made on a case-by-case basis. ## Clinical research In terms of clinical research, most clinical trials have been suspended during the pandemic. However, in some cases, clinical trials allow access to off-label drugs or combinations which can be highly beneficial. For patients already included in clinical trials, their participation should, in principle, continue. Nevertheless, the patients' safety must remain the priority and, similarly to the recommendation for those treated outside clinical trials, outpatient visits must be replaced by e-health assessment whenever possible. Furthermore, for those receiving oral treatment in the frame of a clinical trial, most clinical research organizations now organize home delivery of the investigated medication to ## General points - Screening for COVID-19 infection before initiating chemotherapy. - Cytogenetics and molecular biology should be awaited before starting treatment. - MRD molecular remission should be useful to consider omitting one cycle of consolidation. - Outpatient visits should be as much as possible deferred or substituted with telemedicine visites. ## Allo-hsct Discuss indication for allo-HCT on case-by-case. Nonurgent allo-HCT should be deferred as much as possible. High-risk allo-HCT such as for refractory AL or patient with a high risk of NRM should not proceed. ALL acute lymphoblastic leukemia, Allo-HSCT allogeneic stem cell transplantation, AML acute myeloid leukemia, MRD measurable/minimal residual disease, "3 + 7" daunorubicin and cytarabine. avoid hospital visits. Alternatively, hospital pharmacies should be authorized to deliver 2 or 3 months' worth of medication, rather than the standard one. Whenever possible, follow-up by e-health assessment should be preferred to avoid hospital visits. ## Acute myeloid leukemia Patients fit to receive intensive therapy For patients with favorable or intermediate risk acute myeloid leukemia (AML) [bib_ref] Diagnosis and management of AML in adults: 2017 ELN recommendations from an..., Dohner [/bib_ref] who are fit to receive intensive chemotherapy, the standard "3 + 7" induction should be considered [bib_ref] Cytarabine dose for acute myeloid leukemia, Lowenberg [/bib_ref]. For AML with FLT3ITD mutation, midostaurin may be added to induction and consolidation as it prolongs OS and EFS [bib_ref] Midostaurin in FLT3-mutated acute myeloid leukemia, Stone [/bib_ref]. For consolidation, the dose of cytarabine could be reduced to 1.5 g/m 2 instead of 3 g/m 2 for all patients. Indeed, prospective studies showed that consolidation, in association with anthracycline, with either intermediate or high dose of cytarabine, did not result in significant differences in the 5-year overall survival, whereas prolongation of neutropenia and higher transfusion demands were observed in the high dose cytarabine arm [bib_ref] Cytarabine dose of 36 g/m(2) compared with 12 g/m(2) within first consolidation..., Schaich [/bib_ref] [bib_ref] Attempts to optimize induction and consolidation treatment in acute myeloid leukemia: results..., Burnett [/bib_ref] [bib_ref] A randomized trial of high-versus conventional-dose cytarabine in consolidation chemotherapy for adult..., Bradstock [/bib_ref]. The use of G-CSF should be recommended after each cycle to reduce the duration of neutropenia. In patients who have negative measurable/minimal residual disease (MRD) after two cycles of chemotherapy, omission of the fourth cycle of consolidation should be discussed. In this case, the MRD should be very closely monitored, and maintenance therapy considered, especially in those cases. Patients with an adverse cytogenetic risk should receive intensive therapy if a real chance of going to allogeneic stem cell transplantation exists. In the case of acute promyelocyte leukemia (APL), chemotherapy should be initiated without delay. Patients with standard-risk APL (white blood cells <10 × 10 9 /L) should receive all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) as frontline following the standard guideline for APL management (i.e., avoidance of G-CSF for the risk of differentiation syndrome). For high-risk APL, induction should be performed with idarubicine, ATRA, and ATO. ## Patients unfit to receive intensive therapy Newly diagnosed patients with AML, who are unfit for intensive treatment, hypomethylating agents (HMA) or lowdose cytarabine monotherapy (LDAC) could be given in the case of no-proliferative disease. The addition of venetoclax should be discussed on a case-by-case basis, considering the positive impact on CR rate and OS in combination with HMA or LDAC, but also the risk of tumor lysis syndrome and myelosuppression (https://www.fda.gov/drugs/fda-a pproves-venetoclax-combination-aml-adults). After the first cycle with this combination, if medullary blast infiltration is <5%, dose adjustments, duration of venetoclax, and/or the use of G-CSF are recommended to avoid prolonged cytopenia. Taking into account age, comorbidities, and disease characteristics, patients could also be managed with supportive care and, possibly, eventually hydroxycarbamide. For patients with relapsed or refractory AML, each team should carefully assess the risks and benefits of pursuing a curative approach on a case-by-case basis. Molecular targeted therapy (e.g., enasidenib, ivosidenib, sorafenib, gilteritinib, etc.) should be discussed, considering the rate of complete remission and the duration of the response that can be expected, with a view to postponing an intensive treatment or allogeneic hematopoietic cell transplantation (allo-HCT). ## Acute lymphoblastic leukemia In ALL, one major question is the use of glucocorticoids, as they remain essential components of ALL therapy. They appeared to be effective in reducing immunopathological damage [bib_ref] High-dose hydrocortisone reduces expression of the pro-inflammatory chemokines CXCL8 and CXCL10 in..., Cinatl [/bib_ref] , but there are concerns about their possible promotion of viral rebound and adverse events. Taking into account the major role of glucocorticoids in the treatment of ALL, and the paucity of information on their potential negative role in COVID-19 infections, physicians should use the recommended dose of glucocorticoids, especially during, the prephase, induction, and consolidation, with a major concern on preventing bacterial and fungal infections. The use of asparaginase should be carefully monitored considering the inherent risk of thrombotic complications of this drug, especially knowing that COVID-19 can lead to systemic coagulation disorders, and thrombotic complications. The use of blinatumomab or inotuzumab should not be delayed as their benefit in terms of survival has been established. For Philadelphia-chromosome positive ALL, inhibitors of tyrosine kinase should be maintained considering their positive impact on OS and EFS. ## Stem cell transplantation The EBMT recommendations for management of allo-HCT during the COVID-19 outbreak have been recently published [bib_ref] The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management..., Ljungman [/bib_ref]. Nonurgent allo-HCT procedures should be deferred as much as possible. Due to the rapidly changing situation, access to a stem cell donor may be restricted by the fact that the donor may become infected at the harvest centers in the middle of a strained health care system, or by travel restrictions across international borders. It is, therefore, strongly recommended to have secured stem cell product access, by cryopreserving the product before the start of conditioning. In situations when this is not possible, an alternative back-up donor should be identified. The impact of COVID-19 on a timely graft availability, on cellular therapy unit organization, and on ICU capacity should be considered for each patient with allo-HCT indication. It is necessary to highlight the yet unknown impact of COVID-19 infection on outcomes, when counseling patients on the benefits and risks of the allo-HCT procedure. All patients who have a high risk of disease progression without allo-HCT should still be considered candidates for the procedure according to standard clinical practice. More controversial allo-HCT indications such as refractory AL, or patients with a high risk of non-relapse mortality should be avoided. Overall, the management of patients with AL in the COVID-19 outbreak is a major challenge, as this hematological malignancy requires rapid treatment, which may result in a requirement for admission to an ICU unit. Physicians should therefore carefully balance the risk of COVID-19 infection itself against the benefit of antileukemic intensive treatment on a case-by-case basis, within the individual resources of each medical institution. [table] Table 1: Recommendation for management of patients with acute leukemia during the COVID-19 outbreak. [/table]	None	https://www.nature.com/articles/s41409-020-0970-x.pdf	None
0ba795336f718df23ada281dd0c55a7cab017211	pubmed	Controversies in the treatment of RAS wild-type metastatic colorectal cancer	Controversies in the treatment of RAS wild-type metastatic colorectal cancer Objective To provide guidance for the management of RAS wild-type (wt) metastatic colorectal cancer (mCRC) in daily practice. Methods Nominal group and Delphi techniques were used. A steering committee of seven experts analyzed the current management of RAS wt mCRC, through which they identified controversies, critically analyzed the available evidence, and formulated several guiding statements for clinicians. Subsequently, a group of 30 experts (the expert panel) was selected to test agreement with the statements, through two Delphi rounds. The following response categories were established in both rounds: 1 = totally agree, 2 = basically agree, 3 = basically disagree, 4 = totally disagree. Agreement was defined if ≥ 75% of answers were in categories 1 and 2 (consensus with the agreement) or 3 and 4 (consensus with the disagreement). Results Overall, 71 statements were proposed, which incorporated the following areas: (1) overarching principles; (2) tumor location; (3) triplets; (4) maintenance; (5) second-line and beyond treatments; (6) Rechallenge and liquid biopsy. After the two Delphi rounds, only six statements maintained a lack of clear consensus. Conclusions This document aims to describe the expert's attitude when dealing with several common clinical questions regarding patients with RAS wt mCRC. # Introduction Colorectal cancer (CRC) is the fourth most commonly diagnosed malignancy and the second-leading cause of global cancer-related deaths. Approximately 20-25% of patients exhibit metastatic disease (mCRC) at disease onset and 50% of patients will eventually develop metastases. The prognosis of mCRC has dramatically improved in recent decades, due to a range of factors, including improvements in treatment strategies and new biological agents. Another factor that has contributed to this improvement is biomarker-based patient selection. RAS mutations have been associated with a lack of response to anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapies, which are used in mCRC treatment. Based on these data, guidelines from the European Society for Medical Oncology (ESMO) note that expanded RAS analyses should be conducted on all patients at the time of diagnosis of mCRC, as well as on all patients that are eligible or Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s1209 4-020-02475 -8) contains supplementary material, which is available to authorized users. ## 3 being considered for anti-EGFR therapy. However, this requirement has increased the need for more information about clinical and tumor characteristics based on RAS mutational status. For example, in RAS wild-type (wt) mCRC patients, published data suggest that primary tumor location might have a predictive effect, depending on the treatment applied. Consequently, oncologists may face different questions in daily practice, when considering the best treatment option to manage RAS wt mCRC patients. Therefore, the aim of this consensus document was to provide a guide to managing RAS wt mCRC patients, focusing on those areas that might generate clinical questions or controversies. # Methodology Nominal group and Delphi techniques were used, and a comprehensive narrative review supported the statements. ## Expert panel selection and clinical statement generation A steering committee of seven experts on mCRC was established, who were responsible of:The expert panel comprised 30 experts that were selected according to the following criteria. Experts must be medical oncologists, specialize in mCRC, have clinical experience ≥ 8 years or ≥ 5 publications, and be members of the Sociedad Española de Oncología Médica (SEOM) or Grupo Español de Tratamiento de Tumores Digestivos (TTD). ## Delphi process The expert panel completed two Delphi rounds using an online platform. After each round, a facilitator provided an anonymous summary of the experts' forecasts as well as the individual responses of each expert from the previous round. In the first round, the panelists voted using the following options: 1 = totally agree, 2 = basically agree, 3 = basically disagree, 4 = totally disagree. Consensus was defined if there were ≥ 75% of answers in categories 1 or 2 or 3 or 4. Any statement that reached consensus in this round did not proceed to a second round. The rest of the statements were analyzed by the steering committee, who reformulated the statement or maintained the original statement for the next Delphi round. In the second round, votes for statements employed the same categories. However, in this stage, "consensus" was defined if ≥ 75% of responses in categories 1 and 2 (sum of the responses of both categories), consensus in the agreement, or in categories 3 and 4 (sum of the responses of both categories), consensus in the disagreement. When the rate of sum of responses in categories 1 and 2 or 3 and 4 was 60%-75%, this was considered "majority" and when it was < 60%, this was considered "dissent." Finally, if this rate was 100%, this was considered "unanimous." # Results ## Delphi process Overall, 71 statements were generated. After the first Delphi round, 13 reached consensus and three were rephrased. After the second round, the grade of the agreement was 8 "unanimous," 47 "consensus," 10 "majority," and 6 "dissent" statements. Please see the supplementary material (tables a to f) for more details of the Delphi results. Tables 1, 2, 3, 4, 5 and 6 summarize the main conclusions of the sections described below. Overarching principlesThe experts agreed (100%, "unanimous") the following statements regarding mCRC patients. First, RAS/BRAF mutational status and the microsatellite instability (MSI) assessment are strongly recommended to appropriately select a treatment. Second, the best first-line treatment option is the combination of CT and biologic therapy, in fit patients. Third, care should be provided by a multidisciplinary team. These Delphi results are depicted inof the supplementary material. In mCRC, to select a treatment appropriately, the assessment of RAS/BRAF mutational status and the MSI is strongly recommended 2 In mCRC patients, I consider the best treatment option in first-line the combination of CT and biologic therapy in fit patients 3 In mCRC patients, I consider a multidisciplinary team necessary for the treatment of patients with mCRC In RAS wt mCRC patients, primary tumour location (right or left colon) is a factor to be taken into account when selecting a treatment. However, the molecular characteristics of the primary tumour are the most important factor 2 Treatment goal (response vs. survival) in another factor to be considered when selecting a treatment 3 In relation to the first-line treatment in RAS wt mCRC patients: In right-sided primary tumors, when treatment goal is response, and in the absence of contraindications, the preferred treatments are CT triplets + bevacizumab In right-sided primary tumors, when treatment goal is survival, and in the absence contraindications, the preferred treatments are CT doublets + bevacizumab In left-sided primary tumors, when treatment goal is response, and in the absence contraindications, the preferred treatments are Ct doublets + anti-EGFR therapy In left-sided primary tumors, when treatment goal is survival, and in the absence contraindications, the preferred treatments are Ct doublets + anti-EGFR therapy CT triplets + antiangiogenic therapy in right-sided primary tumors potentially resectables In left-sided primary tumors potentially resectables, CT doublets + anti-EGFR therapy is more appropriate than CT triples + anti-EGFR or antiangiogenic therapy In BRAF mt mCRC patients, CT triplet + antiangiogenic drugs is the preferred option 3 It can be considered in second-line treatment: The use of anti-EGFR drugs after progression to a first-line CT triplet + anti-angiogenic drugs The use of CT + anti-angiogenic drugs after progression to a first-line CT triplet + anti-EGFR therapy 1 Maintenance in the first-line treatment of unresectable mCRC patients is a treatment standard in clinical practice 2 Complete cessation of first-line CT and biologicals (once the maximum response is achieved), and intermittent treatment with pre-established periods of rest (for CT and biologicals), are not a preferred alternative to maintenance 3 Induction first-line treatment of unresectable mCRC patients should be maintained until the maximum response is achieved (in the absence of contraindications), adapting the treatment scheme and evaluations to patients and tumor features and local organization 4 In unresectable mCRC patients with first-line CT + bevacizumab treatment, it would be advisable to maintain treatment with fluoropyrimidines + bevacizumab until disease progression 5 In unresectable RAS wt mCRC patients with first-line CT + anti-EGFR therapy, EGFR inhibitors (in the absence of unmanageable toxicity) should be maintained until disease progression 6 Anti-EGFR or antiangiogenic monotherapy is not recommended as maintenance therapy in unresectable mCRC 7 At disease progression after maintenance treatment, the first option is the reintroduction of initial induction therapy (in the absence of relevant residual toxicity) 1 3 ## Primary tumor sidedness (table 2) Experts considered (90% agreement, "consensus") that primary tumor location should be taken into account in first-line treatment selection for RAS wt mCRC. However, the differences described between the right and left colon may determine treatment approaches. The treatment goal was also considered relevant, but the molecular profile was deemed the most crucial factor for treatment selection, as expounded by the guidelines. In patients with right-sided mCRC, when the treatment goal was response, and in the absence of contraindications, the panelists preferred first-line CT triplet + bevacizumab (80% agreement, "consensus"). Sub-analyses in right-sided RAS-BRAF wt mCRC showed no benefit in response rates with FOLFOXIRI + bevacizumab versus FOLFOX + bevacizumab (81.3% vs. 66.7%; p = 0.584). Propensity score-match analyses indicated that adding bevacizumab to FOLFOXIRI provided significant benefits in terms of progression-free survival (PFS) and overall survival (OS) (HR = 0.73; 95% CI 0.55-0.97) without increasing the response rate (HR = 1.29; 95% CI 0.81-2.05). CT doublet + anti-EGFR was selected by 60% of experts for patients with right-sided mCRC when looking for a response. In the PRIME study, there were no differences in the response rates between FOLFOX + panitumumab (42.1%) and FOLFOX (34.8%), while in the PEAK trial, the corresponding response rates were 63.6% for panitumumab + mFOLFOX versus 50% for bevacizumab + mFOLFOX (OR = 1.75; 95% CI 0. . Data from the FIRE-3 study did not reveal any significant differences between FOLFIRI + bevacizumab versus FOL-FIRI + cetuximab in the response rates (OR = 1.11; 95% CI 0.48-2.59). Similar results were observed in the Phase III CALGB/SWOG 80405 trial. With regards to CT triplet + anti-EGFR, right-sided RAS wt mCRC patients in the Phase II VOLFI trial exhibited higher response rates with mFOLFOXIRI + panitumumab versus FOLFOXIRI (70.0% vs. 37.5%; p = 0.345). Several Phase II randomized controlled trials (RCTs) with cetuximab, without specific sub-analyses and based on tumor location, have shown benefits in the response rates. A meta-analysis involving patients with right-sided RAS wt mCRC revealed that CT + anti-EGFR achieved higher response rates than CT + bevacizumab or Main conclusions of second-line treatment and beyond section wt wild-type, mCRC metastatic colorectal cancer, CT chemotherapy, EGFR epidermal growth factor receptor, MSI microsatellite instability # Conclusions 1 The combination of CT + targeted treatment should be a part of the second-line treatment in most of RAS wt fit mCRC patients, and the oncology treatment is a reality in the third-line treatment and beyond 2 The response rate for possible resectability or for symptom control is a treatment goal to be considered when selecting treatment in second line 3 Primary tumor sidedness does not influence the selection of treatment in the second line 4 In RAS wt mCRC who have received first-line anti-EGFR therapy, the preferred treatment in second line is an antiangiogenic drug 5 In RAS wt mCRC who have not received anti-EGFR treatment in first or second line, the preferred option in the third line and beyond is anti-EGFR therapy ± CT 6 Toxicity is the most important factor in the selection of treatment mCRC patients beyond second line 7 It would be important to have in clinical practice MSI and HER2 data for the treatment decision making in the third line and beyond Main conclusions of the rechallenge and liquid biopsy section wt wild-type, mCRC metastatic colorectal cancer, CT chemotherapy, EGFR epidermal growth factor receptor, MAF mutant allele fraction # Conclusions 1 In RAS wt mCRC patients the assessment of RAS mutational status (exons 2, 3, 4 of KRAS and NRAS) using liquid biopsy is a STANDARD alternative comparable to paraffin 2 The detection sensitivity of the liquid biopsy technique is a decisive factor in the decision-making process of RAS wt mCRC patients 3 Currently (in the absence of more robust data), rechallenge with anti-EGFR therapies is generally not considered to be a comparable alternative to approved standard therapies in patients who have received all therapies considered standard in RAS wt disease. But if rechallenge is considered, liquid biopsy should be used to make this decision 4 Reintroduction of anti-EGFR therapies could be a comparable alternative to approved standard therapies in patients who have received all therapies considered standard in RAS wt disease 5 It is important to define the exact cut-off for clinically relevant RAS-mutant allele frequencies in liquid biopsy, i.e. the MAF below which the patient is considered to still benefit from anti-EGFR treatment 1 3 CT alone (OR = 0.56; 95% CI 0.40-0.79 and OR = 0.56; 95% CI 0.36-0.87, respectively). However, it must be noted that these estimates are based on relatively small sample sizes. In right-sided mCRC, when the treatment goal was survival, the panelists preferred first-line CT doublets + bevacizumab (93% agreement, "consensus"). CT triplets + bevacizumab was chosen by 70% of experts ("majority"). In the TRIBE trial, the median OS in RAS and BRAF wt right-sided mCRC patients was 31.5 months for FOLFOX-IRI + bevacizumab versus 22.3 months for FOLFIRI + bevacizumab (p = 0.165), while the median PFS was 13.4 versus 10.1 months (p = 0.292). Adverse events were significantly higher in the CT-triplet group. Furthermore, a meta-analysis suggests that right-sided RAS wt mCRC patients achieve higher OS and PFS with CT, with or without bevacizumab, compared to CT + anti-EGFR. However, these data are similarly based on small sample sizes. Panelists did not recommend CT doublets (87%, "consensus") or triplets (93%, "consensus") + anti-EGFR in rightsided RAS wt mCRC when the treatment goal was survival. In the PRIME study, patients with these features depicted a median OS of 11.1 months with FOLFOX + panitumumab, compared to 15.4 months with FOLFOX (HR = 0.87; 95% CI 0.55-1.37; p = 0.539). Median PFS was 7.5 months versus 7 months (HR = 0.80; 95% CI 0.51-1.26; p = 0.328). The PEAK study, as well as the FIRE-3 and CALGB/ SWOG 80405 studies both of which concerned cetuximab, all reported similar results. The above-mentioned meta-analysis suggested better OS and PFS for CT + bevacizumab, compared to CT + anti-EGFR. The VOLFI trial demonstrated 6.3 months PFS for CT triplet + panitumumab versus 8.5 months for CT triplet (p = 0.338). Moreover, the panelists recognized the toxicity of CT + anti-EGFR, while evidence from another Phase II trial for the triplet could limit these therapeutic options. In patients with left-sided RAS wt mCRC, 60% of the experts ("majority") considered that selecting a treatment should consider the treatment goal and tumor's molecular profile. Nevertheless, with regards to treatment goal, the experts preferred (93% agreement, "consensus") CT doublet + anti-EGFR for first-line treatment. Response rates in the PRIME study of this population were higher with FOLFOX + panitumumab than with FOLFOX (OR = 1.91; 95% CI 1.18-3.07). Similarly, median OS and PFS were higher for CT doublet + panitumumab, at 32.5 months versus 23.6 months (p < 0.001), and 12.9 months versus 9.3 months (p = 0.002), respectively. In the PEAK study, the median OS favored CT + panitumumab over CT + bevacizumab (HR = 0.77; 95% CI 0.46-1.28). Additionally, in the FIRE-3 study, the response rate for FOLFIRI + cetuximab was higher than for FOLFIRI + bevacizumab, at 61.7% versus 68.8% (HR = 1.37; 95% CI 0.85-2.19). In this and the CALGB/SWOG 80405 studies, OS was significantly higher for cetuximab. When the treatment goal was the response, CT triplets + anti-EGFR or bevacizumab were not the preferred options (53% and 57% of experts, respectively). The response rate in left-sided RAS wt mCRC patients from the VOLFI trial was higher with mFOLFOXIRI + panitumumab than with FOLFOXIRI (OR = 4.52; 95% CI 1.30-15.72). Other Phase II studies have analyzed CT triplet + cetuximab, which suggest clinical benefit, whereas no statistically significant differences have been demonstrated in the response rates between FOLFOXIRI + bevacizumab (63.8%), compared to FOLFIRI + bevacizumab (65.4%), in left-sided RAS and BRAF wt mCRC. However, propensity score-match analysis showed that bevacizumab + FOL-FOXIRI did not increase the response rates. In patients with left-sided RAS wt mCRC, when the treatment goal was survival, CT doublet + bevacizumab and CT triplet + anti-EGFR or bevacizumab were not the preferred option in the first-line setting (90%, "consensus"). Toxicity and the current evidence may limit these options. Finally, a meta-analysis has revealed better results in this patient group for the combination of CT + anti-EGFR, compared to CT + bevacizumab, in terms of both OS (HR = 0.75; 95% CI 0.67-0.84) and PFS (HR = 0.78; 95% CI 0.70-0.87). Full Delphi results are presented inof the supplementary material. ## Triplets (table 3) With regards to the first-line treatment of patients with RAS wt mCRC, the panel considered that, in general, CT triplets + targeted therapy is not more effective than the sequential approach of CT doublets + targeted therapy. No studies have been specifically designed to analyze this question for RAS wt patients. A sub-analysis of the TRIBE-1 studyrevealed a median OS in RAS wt mCRC patients of 26.8 months with FOLFIRI + bevacizumab, compared to 37.1 months with FOLFOXIRI + bevacizumab (HR = 0.78; p = 0.66). The TRIBE-2 study was designed to compare whether three CT + bevacizumab, followed by maintenance strategy with 5-FU/bevacizumab and their reintroduction after the progression (Arm B), was more effective than a preplanned use of the same agents in consecutive therapy lines (Arm A). The primary outcome was PFS2, defined as the time from randomization to progression on any treatment given after first progression or death. Using triplets/bevacizumab was statistically significantly associated with PFS2 improvement (19.1 vs. 16.4 months, p < 0.001), response rate (62% vs. 50%, p = 0.002), first PFS (12.0 vs. 9.8 months, p < 0.001), and OS (27.6 vs. ## 3 22.6 months, p = 0.033). However, no specific sub-analysis for the RAS wt population is available. Similarly, most experts agreed that the first-line use of triplet CT + targeted therapy is conditioned by hard-tohandle toxicity (73%, "majority") since this would limit the therapeutic options of second-line treatment (70%, "majority"). In clinical trials, using triplet CT is associated with a significant increase in Grade 3-4 toxicity. FOLFOXIRI + bevacizumab has been associated with a significantly higher rate of serious adverse events, including neutropenia (50%), febrile neutropenia (8.8-7.2%), and diarrhea (17%). Reported rates with FOLFOXIRI + cetuximab were 31% for neutropenia, 3% for fever, 18% for diarrhea, and 16% for skin toxicity. In the VOLFI trial's, under FOL-FOXIRI + panitumumab, Grade 3-4 events were observed in 80.3% of patients. Many experts agreed that using triplet CT + biologic therapies in first-line treatment might limit the use of active therapies in subsequent treatment lines. A limited number of first-line cycles, as in the TRIBE and TRIBE-2 trials, along with the use of maintenance therapy, facilitates the availability of effective second-line treatments. In the TRIBE study, 76% of patients in both treatment arms received second-line treatment at disease progression (p = 0.92). In the TRIBE-2 trial, 86% of patients treated in Arm A received second-line treatment, of whom 78% were treated with FOLFIRI + bevacizumab, according to the study design. In Arm B, 81% of patients received second-line treatment at first disease progression. There was a broad consensus among experts about the appropriate use of anti-EGFR drugs in the second-line setting (93%, "consensus"), following triplet CT triplet + bevacizumab in RAS wt. Experts also broadly agreed on using antiangiogenic drugs following progression to first-line treatment with triplet CT + anti-EGFR therapy (97%, "consensus"). However, efficacy data have not been published for either strategy. In the TRIBE trial, 29% of patients on firstline triplet CT triplet + bevacizumab received an anti-EGFR agent in the second-line setting, and 29% of patients continued with bevacizumab at disease progression. In 13% of patients, anti-EGFR therapy was administered in the thirdline setting. In the TRIBE-2 trial, 59% of patients in Arm B received the pre-planned reintroduction of FOLFOX-IRI + bevacizumab in the second-line setting. Overall, 9% received triplet CT without biologic therapy, and only 4% received CT with anti-EGFR drugs. Both studies included patients irrespective of their RAS mutational status. Moreover, the rate of RAS wt patients on anti-EGFR therapy was not reported. Most experts (93%) asserted that treatment goal influences the use of CT triplets + targeted therapy in the first line for patients with RAS wt mCRC, particularly when the goal is response or tumor resectability. A pooled analysis of mCRC patients with unresectable liver-limited metastases was subsequently performed. A total of 42% of patients were RAS wt that had been treated with first-line FOLFOXIRI + bevacizumab. The objective response rate (ORR) was 69%, and a R0/R1 surgical resection of metastases was possible in 36.1% of patients. The mPFS in resected patients was 18.1 months and the mOS 44.3 months. The Phase II OLIVIA trialrandomized patients with unresectable liver metastases into FOLFOX-IRI + bevacizumab or mFOLFOX-6 + bevacizumab, in the context of conversion to surgery. The RAS mutational status was not evaluated. The authors reported a response rate of 81%, and 49% of R0 resection rates in the CT triplet + bevacizumab group, compared to 23% of R0 in the other group. In a single-arm Phase II study, the combination of FOL-FIRINOX + cetuximab in the first line showed ORR of 70% in unresectable mCRC patients and an R0 conversion rate of 37% in KRAS wt patients < 70 years with a PS0-1. The response rate of FOLFOXIRI + panitumumab versus FOLFOXIRI was the main outcome of the VOLFI trial, which included patients with unresectable RAS wt mCRC. This trial also reported significantly higher ORR in the FOL-FOXIRI + panitumumab group (87.3% vs. 60.6%; p = 0.004). The rate of secondary resection of metastases, as a secondary outcome, was also significantly higher (33% vs. 12.1%; p = 0.02) in the full analysis set, which increased to 75% (vs. 36.4%) in patients with a chance of secondary resection with curative intent. As discussed in the previous section, with regards to tumor location, the experts considered the use of a triplet CT with antiangiogenic drugs to be the main treatment option in the first line (80%, "consensus") for RAS wt mCRC patients with a right-sided primary tumor, and potentially resectable disease. Conversely, 57% considered CT triplets + anti-EGFR agents to be an acceptable first option in this subgroup of patients. Likewise, for RAS wt mCRC patients with a left-sided primary tumor and potentially resectable disease, in the absence of contraindications, the experts asserted that the combination of a CT triplet with anti-EGFR in the firstline setting was not more appropriate than using a doublet CT + anti-EGFR therapy. This reinforces the messages proposed in the tumor-location section. Most of the experts (83%, "consensus") considered triplet CT with antiangiogenic drugs in the first line to be the preferential treatment for BRAF-mutated (mt) mCRC patients. The BRAF V600 mt is an essential prognosis marker in mCRC patients, as it has been associated with poor response to conventional treatments. The estimated OS rates of BRAF V600 mt patients is around 11 months, compared to an average of 35 months in BRAF wt patients. Data on the efficacy 1 3 of anti-EGFR therapy in RAS wt/BRAF mt mCRC patients were shown worse than those in RAS wt/BRAF wt patients. These observations encourage a discussion about whether BRAF mt is a predictive biomarker of poor response to anti-EGFR therapy. The TRIBE-1 trial included 28 BRAF V600E mt patients. Compared to RAS/BRAF wt patients, BRAF mt patients showed significant lower OS (HR = 2; p = 0.003). Additionally, those on FOLFOXIRI + bevacizumab (n = 16) reported better OS (19 vs. 10.7 months), PFS (7.5 months vs 5.5 months), and response rate (56% vs 46%) than those on FOLFIRI + bevacizumab (n = 12). The results of this sub-analysis positioned FOLFOXIRI + bevacizumab as the clinical guidelines' first choice for first-line treatment of patients with BRAF mt mCRC. The TRIBE-2 trialshowed no statistically significant differences in PFS2 between the groups of BRAF mt patients. Similarly, in 33 BRAF mt patients in the VISNU-1 trial, no statistically significant differences in PFS were reported, when comparing FOLFOXIRI + bevacizumab and FOLFOX + bevacizumab. Conversely, 93% of experts did not consider triplet CT + anti-EGFR therapy to be the preferred option for BRAF mt patients, which aligns with the clinical guidelines. There is currently no published data from Phase III RCTs that assess CT triplets with anti-EGFR therapy. The VOLFI trialdemonstrated a significant increase for mFOL-FOXIRI + panitumumab in the ORR (p = 0.04) of 16 BRAF mt mCRC patients. Full Delphi results are presented inof the supplementary material. ## Maintenance (table 4) Maintenance treatment is defined as the continuation of part of the CT and/or biological treatment that was initially used in the first-line treatment of the mCRC. There was consensus among experts (97%) that maintenance in the first-line setting for unresectable mCRC patients is standard practice. It is, therefore, recommended in the main clinical guidelines. Several studies have demonstrated the efficacy of maintenance therapy in mCRC patients, mainly using combinations of fluoropyrimidines and bevacizumab. The Phase III CAIRO3 trial demonstrated the benefit of maintenance treatment with capecitabine + bevacizumab after six cycles of CAPOX, compared to total treatment suspension, in terms of PFS2 (which was the study's primary endpoint). In an update, this benefit continued in the whole population and across all mutational subgroups (RAS/BRAF/MSI). Results from Phase II and III trials comparing maintenance therapy with bevacizumab or complete discontinuation of treatment, compared to maintenance with fluoropyrimidines and bevacizumab, showed improved PFS and a trend toward better OS for the latter strategy. This option would also be possible following FOLFOXIRI + bevacizumab. Several trials have also analyzed maintenance with anti-EGFR agents in RAS wt mCRC. The MACRO-2 trial found no significant differences in PFS between maintenance with cetuximab and the continuation of mFOLFOX and cetuximab after induction therapy with eight cycles of mFOLFOX + cetuximab. In the SAPPHIRE trial, after six cycles of mFOLFOX + panitumumab, patients were randomized into mFOLFOX + panitumumab or 5-FU/leucovorin + panitumumab, without any differences in PFS and OS observed. In the VALENTINO phase II trial of non-inferiority, maintenance therapy with 5-FU/leucovorin + panitumumab after eight cycles with FOLFOX + panitumumab demonstrated superiority to panitumumab monotherapy in PFS. Conversely, experts did not recommend anti-EGFR (80%) or antiangiogenic (97%) monotherapy as a maintenance treatment in unresectable mCRC. According to the experts, induction therapy in the firstline treatment for patients with unresectable mCRC should be maintained until the maximum response is achieved (87%, "consensus"). However, this does not mean that the number of cycles should always be pre-set. Instead, the experts asserted that, in clinical practice, each case must be individualized, and the treatment scheme should be adapted to the patient's features, treatment goal, response, and toxicity. Finally, 87% of the experts agreed that the first option in mCRC patients at disease progression after maintenance treatment is the reintroduction of the initial treatment, in the absence of relevant residual toxicity. Full Delphi results are presented inof the supplementary material. ## Second-line treatment and beyond (table 5) One of this section's most essential conclusions is that there is consensus among the experts that the combination of CT + targeted therapy should be part of the second-line treatment of most fit patients with RAS wt mCRC, which is also recommended in the main clinical guidelines. The use of targeted therapy at disease progression to the first line was evaluated by meta-analysis and shown associated with improved outcomes. These data, together with those from Phase III trials, have demonstrated the efficacy of this combination, both for antiangiogenic and anti-EGFR treatment, which supports using second-line targeted therapies. When selecting a second-line treatment, the experts emphasized that the resectability of the metastatic disease should be a treatment goal throughout the disease course, based on published data that confirm the conversion to resectable disease after second-line treatment. Conversely, 87% of experts did not consider the primary tumor location to be a factor in the selection of secondline treatment. Data from the VELOUR trial, which evaluated the efficacy of FOLFIRI + aflibercept in second-line treatment, showed the same benefit in terms of OS in a left-sided primary tumor and right-sided primary tumor. In the Phase III 181 trial, the combination of FOLFIRI + panitumumab demonstrated no differences in response rate, SLP, or OS according to the primary tumor location. However, the results were generally worse in the right-sided tumors, which probably reflects the alreadyacknowledged worse prognosis of right-sided primary tumors. With regard to treatment sequence, the experts primarily indicated that the optimal sequence is yet to be elucidated, due to a lack of data from RCTs. Ongoing studies (CR-SEQUENCE and STRATEGIC-1) are currently providing new insights into this context. Until they yield more results, treatment selection in the second line is largely determined by the first-line treatment, the patient's features, and the tumor's characteristics and molecular profile. When experts were asked about the preferred sequence for RAS wt mCRC patients that had received a first-line anti-EGFR treatment, there was unanimity (100% agreement) about considering an antiangiogenic drug. Three Phase III trials on second-line antiangiogenic treatments are currently being conducted, but none of them include patients with first-line anti-EGFR treatments. Retrospective analyses of the FIRE III study support the sequence of anti-EGFR therapy followed by antiangiogenic treatment, while other exploratory and pre-clinical data also support this sequence. However, for RAS wt mCRC patients that have received first-line antiangiogenic treatment, there was no consensus about second-line treatment among the experts. While 60% of experts did not support the sequence of antiangiogenic-antiangiogenic therapy, 56% supported the sequence of antiangiogenic-anti-EGFR therapy as a preferred option. These results align with some available data from Phase III studies in second-line treatment. The VELOUR and TML trials (ML18147)also support the antiangiogenic-antiangiogenic sequence of treatment. The 181 study showed benefits in both response rate and PFS with FOLFIRI + panitumumab in the second-line setting, but not in OS. However, only a small number of patients received first-line antiangiogenic treatment. Data from trials such as FIRE-3, as well as observational and in vitro studies, suggest that using first-line antiangiogenic drugs for RAS wt mCRC patients would negatively impact the efficacy of anti-EGFR agents in the second-line setting. Moreover, pooled exploratory data from the PRIME, PEAK, and 181 trials depicted a trend (not statistically significant) toward an improved median OS for panitumumab in the firstline treatment, followed by an antiangiogenic therapy in the second-line (36.8 months), compared to first-line bevacizumab and second-line anti-EGFR therapy (27.8 months). All these controversial data would explain the lack of consensus about the appropriate sequence after antiangiogenic treatment in the first-line. The use of oncological treatments in the third-line and beyond is a reality for RAS wt mCRC patients (100% agreement). Experts considered the cost-benefit balance to be present in the choice of treatment for patients with mCRC beyond the second-line (93% agreement). There was agreement (80%) that, in RAS wt mCRC patients, drug toxicity is the most crucial factor when selecting treatment beyond the second-line. Regorafenib and TAS 102 have demonstrated benefits in terms of OS without impairment to quality of life when compared with best supportive care beyond the second line. Furthermore, a broad consensus was reached (97%) concerning RAS wt mCRC patients that have received first-and second-line antiangiogenic treatments. In these patients, the preferred option was anti-EGFR therapy with or without CT. Both cetuximab and panitumumab have demonstrated benefits in terms of response rate and PFS without impairment to quality of life, compared with best supportive care. More recently, an updated retrospective analysis from ASPECCT and WJOG6510G has concluded that, even in multivariate analysis, panitumumab was superior to cetuximab in terms of OS for patients that had previously received bevacizumab (HR = 0.69; 95% CI 0.54-0.87). Finally, the experts also considered (93% agreement) it important to have MSI and HER2 data in clinical practice, for patients with RAS wt mCRC, to aid treatment decision making in the third-line and beyond. Molecular studies suggest that amplification of the HER2 gene may be involved in resistance to anti-EGFR antibodies in patients with RAS or BRAF wt mCRC. Other studies have shown the benefits of immunotherapy in patients with high MSI. Although these drugs are not approved in mCRC, analysis of the molecular profile is necessary because these patients might benefit from their inclusion in clinical trials. Full Delphi results are shown in of the supplementary material. ## Retreatment and liquid biopsy (table 6) Rechallenge with anti-EGFR therapies was defined as the re-use of these agents after a period of time without them (ideally more than 6 months), provided that the patient has shown previous benefits and has progressed on treatment with anti-EGFR antibodies. Reintroduction with anti-EGFR therapies was defined as the re-use of these treatments in patients that have not developed resistance to them or have not progressed during their use. The experts noted that, for patients with RAS wt mCRC, assessment of RAS mutational status (exons 2, 3, and 4 of KRAS and NRAS) by liquid biopsy is a standard alternative that is comparable to paraffin (80% of agreement). Moreover, 100% considered it a standard alternative in the case of insufficient availability of paraffin material. Several studies have been published that have analyzed the validity of liquid biopsy and its possible utility when a rechallenge with anti-EGFR antibodies is considered. There was unanimity (100% agreement) that the sensitivity of the technique used for the liquid biopsy is a critical decision-making factor in RAS wt mCRC. Several similar studies have compared the ability of liquid biopsy to establish the RAS mutational state, compared to solid biopsy. Depending on the technique used, the sensitivity of the liquid biopsy varied from 85% to 94%, with a specificity of approximately 90% and high concordance (even higher than 90%). The panel also agreed (87%) that, in patients with RAS wt mCRC, liquid biopsy determinations should be performed exclusively in experienced reference centers (87%). Conversely, 67% of experts did not consider rechallenge with anti-EGFR therapies a comparable alternative to approved standard therapies in patients that have received all therapies considered standard in RAS wt disease. The Phase II CRICKET trialevaluated 28 RAS and BRAF wt mCRC patients that were initially sensitive to and later resistant to first-line irinotecan-and cetuximab-based therapy, followed by second-line oxaliplatin-and bevacizumabbased treatment. The efficacy of the rechallenge of a regimen that included cetuximab and irinotecan was subsequently tested. The overall response was 21%, and 46% of patients progressed. The PFS was significantly higher in the RAS wt subgroup of patients, compared to the mutated patients, but there were no significant differences in terms of OS between the groups. Pooled data from the PEAK and PRIME studies of RAS wt mCRC patients that had undergone EGFRinhibitor rechallenge had a median OS after rechallenge of 14.2 months and a median OS from the start of treatment of more than 45 months. According to the experts, this evidence is only preliminary. However, if rechallenge with anti-EGFR therapies is considered for patients that have received all therapies that are considered standard, 90% of the experts asserted that liquid biopsy should be used to make the final decision. With regards to anti-EGFRs reintroduction, 70% of experts considered this a comparable alternative to approved standard therapies for patients that have received all therapies that are considered standard in RAS wt disease. Furthermore, 90% noted that liquid biopsy should be used for decision making when considering anti-EGFR reintroduction. Finally, 97% of the experts agreed on the importance of defining the exact cut-off for clinically relevant RAS-mutant allele frequencies in liquid biopsy; that is to say, the mutant allele fraction (MAF) below which a patient is understood to still benefit from anti-EGFR treatment. Although robust and definitive evidence is lacking, the panel recognized the clinical significance of the cut-off points. PERSEIDA was an observational prospective study in patients with RAS wt mCRC, most of whom were on panitumumab. In this study, liquid biopsies were collected at 20 ± 2 weeks and at disease progression. MAF cut-offs of ≥ 1%, ≥ 0.1%, and ≥ 0.02% were considered, whose negative correlations with tumor tissue biopsy were 97.5%, 95%, and 87.4%, respectively. Full Delphi results are presented in of the supplementary material. # Discussion This consensus reinforces and complements recommendations provided by ESMO and SEOM guidelines regarding the management of RAS wt mCRC patients. We identified the most relevant questions and controversies in this field, critically evaluated the available evidence, and provided oncologists with specific information in the form of several statements that had undergone a Delphi process. We would like to highlight several points. First, tumor sidedness should be taken into account when selecting a first-line treatment. Evidence indicates that first-line CT + anti-EGFR therapy is a preferred option in left-sided primary tumors of RAS wt mCRC patients, but the effect of this treatment strategy in right-sided primary tumors remains unclear. Subsequently, the use of triplet CT is definitively influenced by treatment goal (particularly when respectability is considered), as well as toxicity and the impact of this strategy on second-line treatment options. Similarly, tumor location led to a specific treatment proposal in the first line when using triplet CT, as previously explained. However, we would like to note that, although the available evidence from triplet CT + anti-EGFR therapy in the first-line is promising, it is still only initial. With regards to maintenance, containing targeted therapies in the first-line treatment of unresectable mCRC patients is considered standard in clinical practice, which is also supported by evidence. However, conversely, a complete cessation of first-line CT, biologicals, and intermittent schemes are not preferred alternatives to maintenance. It should also be noted that, in the second line, anti-EGFR drugs can be considered after progression to a first-line triplet CT triplet + antiangiogenic therapy, as well as antiangiogenic drugs after progression to a triplet + antiEGFR. Nevertheless, the best treatment strategy and sequence are currently unknown. In the second-line and beyond, the experts would like to encourage oncologists to include many (but not all) factors in their decision making that are considered in the first-line. This includes response as a treatment goal, particularly in fit patients. This is also true of CT plus targeted therapy, as robust evidence supports their efficacy in this context. Additionally, new molecular evidenceencourages including assessment of MSI and HER2 mutational status in treatment decision making for the third-line and beyond. Finally, although liquid biopsy is an emerging technique, the experts declared that the assessment of RAS mutational status in mCRC using liquid biopsy is a standard alternative that is comparable to paraffin. Moreover, although more research is needed, a liquid biopsy should be performed, when anti-EGFR therapy rechallenge is considered. In summary, although new and robust evidence is needed to definitively clarify some of the issues that are developed in the present document, we believe that the practical framework provided in this document will help oncologists manage RAS wt mCRC patients. Ethical approval This study did not involve humans, thus it was not necessary the approval of an Ethical Committee. This study was conducted in accordance with Good Clinical Practice and the current version of the revised Declaration of Helsinki (World Medical Association Declaration of Helsinki). Informed consent This study did not involve humans, thus informed consent was not necessary. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/.	None	https://link.springer.com/content/pdf/10.1007/s12094-020-02475-8.pdf	None
a81eb739e18c60e42b76e4c7819d7692e86579ea	pubmed	Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy alone for management of cryptogenic stroke? A clinical practice guideline	Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy alone for management of cryptogenic stroke? A clinical practice guideline We recommend PFO closure followed by antiplatelet therapy over antiplatelet therapy alone.This recommendation is for patients to whom anticoagulants are contraindicated, unacceptable, or unavailable.Key InfoRationaleWe issue a strong recommendation for PFO closure followed by antiplatelet therapy because we believe that the probable substantial benefit in stroke reduction, an outcome of very high importance to patients, clearly outweighs the undesirable consequences when compared to antiplatelet therapy alone, in patients to whom anticoagualants are contraindicated or unacceptable.Benefits and harmsThe panel agrees that PFO closure followed by antiplatelet therapy versus antiplatelet therapy alone probably has a large decrease in ischemic stroke (8.7% absolute risk reduction over 5 years, moderate quality evidence), carries a risk of device or procedure related adverse events (3.6% absolute risk, high quality evidence) and probably has an increase in persistent atrial fibrillation (1.8% absolute risk increase, moderate quality evidence) and transient atrial fibrillation (1.2% absolute risk increase, moderate quality evidence). There probably is little or no difference in death, major bleeding, pulmonary embolism, TIA and systemic embolism (moderate to high quality evidence).Substantial net benefits of the recommended alternativeQuality of evidenceWe had moderate certainty in a decrease in ischemic stroke, high certainty in an increase in device or procedure related adverse events and moderate certainty in an increase in persistent atrial fibrillation. We were moderate certainty that there were little or no difference in death, major bleeding, pulmonary embolism, recurrent TIA and systemic embolism.ModeratePreference and valuesOur strong recommendation for PFO closure reflects patients' high value on avoiding an ischemic stroke. The panel, including the patient representatives, felt that that the probable absolute reduction of stroke with PFO closure over 8.7% in 5 years is extremely important. We were concerned about the 3.6% incidence of serious device or procedure related adverse events following PFO closure. However, these events, in contrast to stroke, do not usually result in long term disability, and so, we felt, are much less important.We were also concerned about the 1,8% absolute increase in incidence of persistent atrial fibrillation following the PFO closure procedure. The main adverse consequence of atrial fibrillation is increased stroke risk, and stroke risk was substantially lower in patients randomized to PFO closure.No substantial variability expectedResources and other considerationsThe panel focused on the patient-perspective rather than that of society when formulating the recommendation. Implementation of this recommendation is likely to have an important impact on the costs for health funders which warrants cost-effectiveness data. Over the short term PFO closure is associated with higher costs related to the procedure; however in the long term PFO closure may reduce costs as a result of reduced stroke rates and reduction in the long-term costs of care for stroke patients. [1] No important issues with the recommended alternative Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy for management of cryptogenic stroke -WikiRecs group 8 of 28 Clinical Question/ PICO Population: Patients with cryptogenic stroke Intervention: PFO closure plus antiplatelet therapy Comparator: Antiplatelet therapy Weak RecommendationWe suggest PFO closure followed by antiplatelet therapy over anticoagulation therapy. Discuss both options with each patient.This recommendation is for patients to whom all options are acceptable. ## Summary The panel agreed that PFO closure followed by antiplatelet therapy versus antiplatelet therapy alone: - probably has a large decrease in ischemic stroke (8.7% absolute risk reduction over 5 years, moderate quality evidence) - carries a risk of device or procedure related adverse events (3.6% absolute risk, high quality evidence) - probably has an increase in persistent atrial fibrillation ## Procedure and device The PFO device will be implanted using a catheter (long, thin, flexible, hollow tube), inserted through a small cut made at the inner thigh (groin), with local anasthesia and moderate sedation or under general anaesthesia. The procedure takes under 2 hours. In-hospital stay is usually one day. ## Recovery and adaptation Most activities can be resumed within a few days, with full recovery within a few weeks. ## Costs and access Most can take a low-cost medication available without a prescription. Most can take a low-cost medication available without a prescription. Exercise and activities Need to avoid strenuous activity during recovery. Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy for management of cryptogenic stroke -WikiRecs group Work and education Time to return to work depends on speed of recovery. Travel and driving Driving may be limited during recovery. ## Benefits and harms The panel agreed that PFO closure followed by antiplatelet therapy versus anticoagulation may have little or no difference in ischaemic stroke (1.6% absolute risk reduction over 5 years, low quality evidence), probably decreases major bleeding (2.0% absolute risk reduction over 5 years, moderate quality evidence), has a risk of device or procedure related adverse events (3.6% absolute risk, high quality evidence) and probably has an increase in persistent atrial fibrillation (1.8% absolute risk increase, moderate quality evidence) and transient atrial fibrillation (1.2% absolute risk increase, moderate quality evidence). There probably is little or no Small net benefit, or little difference between alternatives Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy for management of cryptogenic stroke -WikiRecs group ## Rationale We issue a weak recommendation for PFO closure versus anticoagulation because of the large uncertainty and possibly little or no difference in ischemic stroke between PFO closure and anticoagulation. In addition to the low certainty in the estimates of effect -that most panel members felt that whereas most serious complications of PFO closure are usually short-term, anticoagulation imposes a lifelong increased risk of major bleeding. The panel felt that the majority of fully informed patients would accept the mostly transient risk of major adverse events rather than the long-term bleeding risk, but that a substantial minority would choose anticoagulation. difference in death, pulmonary embolism, TIA and systemic embolism (moderate quality evidence). ## Quality of evidence There is low certainty that there is little or no difference in ischemic stroke, moderate certainty for a decrease in major bleeding and an increase in persistent atrial fibrillation. There is high certainty in a risk of device or procedure related adverse events. There is moderate certainty that there is little or no difference in death, recurrent TIA, systemic embolism, pulmonary embolism. ## Low ## Preference and values The weak recommendation for PFO closure versus anticoagulation reflects -in addition to the low certainty in the estimates of effect -that most panel members felt that whereas most serious complications of PFO closure are usually short-term, anticoagulation imposes a lifelong increased risk of major bleeding. The panel felt that the majority of fully informed patients would accept the mostly transient risk of major adverse events rather than the long-term bleeding risk, but that a substantial minority would choose anticoagulation. Substantial variability is expected or uncertain ## Resources and other considerations The panel focused on the patient-perspective rather than that of society when formulating the recommendation. Implementation of this recommendation is likely to have an important impact on the costs for health funders which warrants cost-effectiveness data. Over the short term PFO closure is associated with higher costs related to the procedure; however in the long term PFO closure may reduce costs as a result of reduced stroke rates and reduction in the long-term costs of care for stroke patients. No important issues with the recommended alternative Medication routine One or two doses per day. ## Tests and visits Initial frequent testing required to achieve appropriate dose. Periodic testing required while taking medication. May include 1 or 2 visits to the cardiologist in the first 6 months followed by an appointment every 1-2 years. ## Procedure and device The PFO device will be implanted using a catheter (long, thin, flexible, hollow tube), inserted through a small cut made at the inner thigh (groin), with local anasthesia and moderate sedation or under general anaesthesia. The procedure takes under 2 hours. In-hospital stay is usually one day. ## Recovery and adaptation Most activities can be resumed within a few days, with full recovery within a few weeks. ## Adverse effects, interactions and antidote Certain medicines may increase one's risk of bleeding, and some may increase the risk of stroke, by reducing the effect of the anticoagulan. ## Pregnancy and nursing Women who are pregnant or considering pregnancy may need to change their medication, and may face considerable complications of pregnancy and birth being on anticoagulation or heparine during pregnancy. Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy for management of cryptogenic stroke -WikiRecs group ## Benefits and harms The panel agreed that anticoagulation versus antiplatelet therapy may decrease ischaemic stroke (7.1% absolute risk reduction over 5 years, low quality evidence), probably increases major bleeding (1.2% absolute risk increase over 5 years, moderate quality evidence) and probably has little or no difference in death, pulmonary embolism, TIA and systemic embolism (moderate quality evidence). ## Small net benefit, or little difference between alternatives ## Quality of evidence There is low certainty that there was a decrease in ischemic stroke, moderate certainty for an increase in major bleeding. There is moderate certainty that there is little or no difference in death, pulmonary embolism, TIA and systemic embolism. ## Low ## Preference and values A typical patient places a high value in a possible absolute reduction of stroke with anticoagulation of 7.1% in 5 years and would therefore value the possible benefit in stroke reduction higher than the probable increased risk of major bleeding. A systematic review and a primary study regarding values and preferences on thromboprophylaxis treatment of patients with atrial fibrillation were highly variable, however both strongly suggest that patients value preventing strokes considerably more than they are concerned with increased risk of bleeding. However, there is substantial uncertainty in our estimates for stroke reduction -how this uncertainty would influence decisions is likely to vary substantially. Therefore we issue a weak recommendation for anticoagulation. Both options need to be discussed with the patients, ideally in a process of shared decision making. ## Substantial variability is expected or uncertain ## Resources and other considerations The panel focused on the patient-perspective rather than that of society when formulating the recommendation. Implementation of this recommendation is likely to have an important impact on the costs for health funders which warrants cost-effectiveness data. No important issues with the recommended alternative Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy for management of cryptogenic stroke -WikiRecs group benefit of anticoagulation on ischemic stroke, an outcome we feel a typical patient places a high value on. Another reason that drove this weak recommendation is anticoagulation probably increases major bleeding. Therefore we feel the possible benefit less clearly outweighs the undesirable consequences of antigoagulation versus antiplatelet therapy. ## Clinical question/ pico ## Population: Patients with cryptogenic stroke ## Intervention: anticoagulation Comparator: Antiplatelet ## Summary The panel agreed that anticoagulation versus antiplatelet therapy: - may decrease ischaemic stroke (7.1% absolute risk reduction over 5 years, low quality evidence) - probably increases major bleeding ( ## Tests and visits Initial frequent testing required to achieve appropriate dose. Periodic testing required while taking medication. ## Adverse effects, interactions and antidote Certain medicines may increase one's risk of bleeding, and some may increase the risk of stroke, by reducing the effect of the anticoagulan. ## Pregnancy and nursing Women who are pregnant or considering pregnancy may need to change their medication, and may face considerable complications of pregnancy and birth being on anticoagulation or heparine during pregnancy. ## Costs and access Most can take a low-cost medication available without a prescription. Newer medications cost more, but require less monitoring. Food and drinks Dietary restrictions may apply. Exercise and activities May need to limit activities with high injury risk. Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy for management of cryptogenic stroke -WikiRecs group . ## -bmj rapid recommendations methods and process about bmj rapid recommendations Translating research to clinical practice is challenging. Trustworthy clinical practice recommendations are one useful knowledge translation strategy. Organisations creating systematic reviews and guidelines often struggle to deliver timely and trustworthy recommendations in response to potentially practice-changing evidence. BMJ Rapid Recommendations aims to create trustworthy clinical practice recommendations based on the highest quality evidence in record time. The project is supported by an international network of systematic review and guideline methodologists, people with lived experience of the diseases or conditions, clinical specialists, and front-line clinicians. This overview is one of a package that includes recommendations and one or more systematic reviews published by the BMJ group and in MAGICapp (http://www.magicapp.org). The goal is to translate evidence into recommendations for clinical practice in a timely and transparent way, minimizing bias and centred around the experience of patients. BMJ Rapid Recommendations will consider both new and old evidence that might alter established clinical practice. The RapidRecs executive team and editors at The BMJ choose which clinical questions to pursue among the identified potentially-practice changing evidence, based on relevance to a wide audience, widespread interest, and likelihood to change practice. 3. We incorporate the evidence into the existing body of evidence and broader context of clinical practice via: ## Process overview - A rapid and high-quality systematic review and meta-analysis on the benefits and harms with a focus on the outcomes that matter to patients - Parallel rapid recommendations that meet the standards for trustworthy guidelines 1 by an international panel of people with relevant lived experience, front-line clinicians, clinical content experts, and methodologists. - The systematic review and the recommendation panel will apply standards for trustworthy guidelines. 1,2 They use the GRADE approach, which has developed a transparent process to rate the quality (or certainty) of evidence and grade the strength of recommendations. - Further research may be conducted including: Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy for management of cryptogenic stroke -WikiRecs group - A systematic review of observational studies to identify baseline risk estimates that most closely represent the population at the heart of the clinical question, a key component when calculating the estimates of absolute effects of the intervention. - A systematic review on the preferences and values of patients on the topic. ## Disseminate the rapid recommendations through: - publication of the research in bmj journals - short summary of recommendations for clinicians published in the bmj - Press release and/or marketing to media outlets and relevant parties such as patient groups - Links to BMJ group's Best Practice point of care resource - MAGICapp which provides recommendations and all underlying content in digitally structured multilayered formats for clinicians and others who wish to re-examine or consider national or local adaptation of the recommendations. ## Who is involved? Researchers, systematic review and guideline authors, clinicians, and patients often work in silos. Academic journals may publish work from any one or combinations of these groups of people and findings may also be published in the media. But it is rare that these groups work together to produce a comprehensive package. BMJ-RapidRecs circumvents organisational barriers in order to provide clinicians with guidance for potentially practice-changing evidence. Our collaboration involves: 1. The RapidRecs group with a designated Executive team responsible for recruiting and coordinating the network of researchers who perform the systematic reviews and the recommendation panels.. The RapidRecs group is part of MAGIC (www.magicproject.org), a non for profit organization that provides MAGICapp (www.magicapp.org) an authoring and publication platform for evidence summaries, guidelines and decision aids, which are disseminated online for all devices. 2. The BMJ helps identifiying practice-changing evidence on key clinical questions, coordinates the editorial process and publishes the package of content linking to the MAGICapp that is presented in a user-friendly way. ## Methods for the rapid recommendations The formation of these recommendations adheres to standards for trustworthy guidelines with an emphasis on patient involvement, strict management of conflicts of interests, as well as transparent and systematic processes for assessing the quality of evidence and for moving from evidence to recommendations. Guidance on how the panel is picked and how they contribute ## How the panel meets and works Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy for management of cryptogenic stroke -WikiRecs group - The RapidRecs group will aim to include representation from most or every major geographic region in the world, with specific efforts made achieve gender-balance. - We will facilitate patient and public involvement by including patient experience, via patient-representatives and systematic reviews addressing values and preferences to guide outcome choices and relative weights of each outcome, where available. - Patient-representatives will be given priority during panel meetings and will have an explicit role in vetting the panel's judgements of values and preferences. ## Clinical practice guideline-systematic review Intersection "CPG developers should use systematic reviews that meet standards set by the IOM. Guideline development group and systematic review team should interact regarding the scope, approach, and output of both processes." - Each rapid recommendation will be based on one or more high-quality SRs either developed and published in parallel with our BMJ Rapid Recommendations or produced by other authors and available at the time of making the recommendaiton. - The recommendation panel and SR teams will interact, with up to three members participating in both teams to facilitate communication and continuity in the process. - The GRADE approach will provide the framework for establishing evidence foundations and rating strength of recommendations. For each recommendation systematic and transparent assessments are made across the following key factors: ## Establishing evidence foundations for and rating strength of recommendations - Absolute benefit and harms for all patient-important outcomes through structured evidence summaries (e.g. GRADE Summary of Findings tables) 4 - Quality of the evidence - Values and preferences of patients - Resources and other considerations (e.g. feasibility, applicability, equity) - Each outcome will -if data are available through systematic reviews -include an effect estimate and confidence interval, with a measure of certainty in the evidence, as presented in Summary of Findings tables. If such data are not available narrative summaries will be provided. - A summary of the underlying reasoning and all additional information (e.g. key factors, practical advice, references) will be available online in an interactive format at www.magicapp.org. This summary will include descriptions of how theory (e.g. pathophysiology) and clinical experience played into the evidence assessment and recommendation development. - Recommendations will be rated either weak or strong, as defined by GRADE. [bib_ref] GRADE guidelines: 15. Going from evidence to recommendation-determinants of a recommendation's direction..., Andrews [/bib_ref] - If the panel members disagree regarding evidence assessment or strength of recommendations, we will follow a structured consensus proce customized to the GRADE system and report any final differences in opinion, with their rationale, in the online supplement and online at www.magicapp.org. ## Articulation of recommendations "recommendations should be articulated in a standardized form detailing precisely what the recommended action is, and under what circumstances it should be performed, and so that compliance with the recommendation(s) can be evaluated." - Each recommendation will appear at the top of the guideline infographic, published in The BMJ, and will be available in standardised formats MAGICapp, articulated to be actionable based on best current evidence on presentation formats of guidelines. [bib_ref] Development of a novel, multilayered presentation format for clinical practice guidelines, Kristiansen [/bib_ref] - There will be a statement included in each summary article in The BMJ and in the MAGICapp that these are recommendations to provide clinicians with guidance. They do not form a mandate of action and should be contextualised in the healthcare system a clinician's works in, and with an individual patient. ## 7. External review "External reviewers should comprise a full spectrum of relevant stakeholders...., authorship should be kept confidential....., all reviewer comments Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy for management of cryptogenic stroke -WikiRecs group should be considered....a rationale for modifying or not should be recorded in writing.... a draft of the recommendation should be made available t general public for comment..." - At least two external peer-reviewers and one patient reviewer will review the article for The BMJ and provide open peer review. Each will have access to all the information in the package. They will be asked for general feedback as well as to make an overall judgement on whether they view the guidelines as trustworthy. - A BMJ series adviser with methodological and/or statistical expertise will review the BMJ Rapid Recommendations publication and the systematic reviews. - The RapidRecs panel will be asked to read and respond to the peer review comments and make amendments where they judge reasonable. - The BMJ and RapidRecs executive team may, on a case-by-case basis, choose to invite key organizations, agencies, or patient/public representatives to provide and submit public peer-review. - There will be post-publication public review process through which people can provide comments and feedback through MAGICapp (or through The BMJ). The Chair will, on behalf of panel authors, aim to respond to each publicly-available peer-review within 30 days, for a period o six months after publication. ## Updating "The date for publication, systematic review and proposed date for future review should be documented, the literature should be monitored regularly and the recommendation should be updated when warranted by new evidence." - The RapidRecs panel will, through monitoring of new research evidence for published BMJ Rapid Recommendations, aim to provide updates the recommendations in situations in which the evidence suggests a change in practice. These updates will be initially performed in MAGICapp and submitted to The BMJ for consideration of publication of a new Rapid Recommendation. [fig] 1: On a daily basis, we monitor the literature for practice-changing evidence: • Formal monitoring through McMaster Premium LiteratUre Service (PLUS) • Informal monitoring the literature by BMJ Rapid Recommendations expert groups, including clinician specialists and patients 2. [/fig] [fig] ": For each recommendation: explain underlying reasoning, including a clear description of potential benefits and harms, a summary of relevant available evidence and description of the quality., explain the part played by values, opinion, theory, and clinical experience in deriving the recommendation, provide rating of strength of recommendations. [/fig]	None	https://www.bmj.com/content/bmj/362/bmj.k2515.full.pdf	### What you need to know Options for the secondary prevention of stroke in patients younger than 60 years who have had a cryptogenic ischaemic stroke thought to be secondary to patent foramen ovale (PFO) include PFO closure (with antiplatelet therapy), antiplatelet therapy alone, or anticoagulants. International guidance and practice differ on which option is preferable. The BMJ Rapid Recommendations panel used a linked systematic review1 triggered by three large randomised trials published in September 2017 that suggested PFO closure might reduce the risk of ischaemic stroke more than alternatives.234 The panel felt that the studies, when considered in the context of the full body of evidence, might change current clinical practice.5 The linked systematic review finds that PFO closure prevents recurrent stroke relative to antiplatelet therapy, but possibly not relative to anticoagulants, and is associated with procedural complications and persistent atrial fibrillation.1 The review also presents evidence regarding the role of anticoagulants or antiplatelet therapy when PFO closure is not acceptable or is contraindicated. This expert panel make a
06df5df3bbbed82976a0707f9e1c6f37585fcb7b	pubmed	Central European Vaccination Advisory Group (CEVAG) guidance statement on recommendations for influenza vaccination in children	Central European Vaccination Advisory Group (CEVAG) guidance statement on recommendations for influenza vaccination in children Background: Influenza vaccination in infants and children with existing health complications is current practice in many countries, but healthy children are also susceptible to influenza, sometimes with complications. The underrecognised burden of disease in young children is greater than in elderly populations and the number of paediatric influenza cases reported does not reflect the actual frequency of influenza. # Background Influenza is a serious infectious disease that continues to contribute to significant morbidity and mortality worldwide. The WHO estimates up to five million cases annually with mortality between 250,000 and 500,000 in the industrialised world. In Europe excess deaths due to influenza are estimated to be between 40,000 and 220,000 per season. Yearly influenza vaccination benefits have been demonstrated and vaccination for high-risk groups is well recognised in Europe and the rest of the world as a means of preventing infection and the complications that develop from influenza such as pneumonia [bib_ref] Effectiveness of influenza vaccine in the community-dwelling elderly, Nichol [/bib_ref] [bib_ref] A cohort study of the effectiveness of influenza vaccine in older people,..., Mangtani [/bib_ref] [bib_ref] Economic evaluation of strategies for the control and management of influenza in..., Scuffham [/bib_ref]. Highrisk groups include infants and children with existing health complications as well as the elderly (>65 years of age) and vaccination of these groups is current practice in many countries. Within the member states of the Euro-pean Union there is an objective to achieve over 75% vaccination coverage in elderly populations. However, there are no such objectives in paediatric populations within Europe despite the evidence that healthy children are susceptible to influenza, sometimes with complications [bib_ref] Impact of influenza infection in healthy children examined as outpatients and their..., Tsolia [/bib_ref]. The burden of disease in infants is greater than in elderly populations [bib_ref] Influenza virus infections in infants, Glezen [/bib_ref] [bib_ref] Acute respiratory illness in the community. Frequency of illness and the agents..., Monto [/bib_ref] and rates of hospitalisation attributable to influenza are similar to those in older adults. To reflect this morbidity, universal influenza vaccination in all children from the age of 6 months up to 18 years is current practice in the USA and from 6 to 23 months in Canada [bib_ref] Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory..., Fiore [/bib_ref]. Universal vaccination of healthy children is not widespread in Europe despite clear demonstration of the benefits of vaccination in reducing the large health and economic burden of influenza [bib_ref] National seasonal influenza vaccination survey in Europe, Mereckiene [/bib_ref]. In Central Europe guidelines on paediatric influenza immunisation have not been made to date and the current report represents a summary of evidence and the formulation of advisory guidelines to help decision-making about paediatric influenza immunisation. # Discussion ## The under-recognised burden of influenza in children The burden of influenza in children is under-recognised [bib_ref] Burden of influenza in children in the community, Heikkinen [/bib_ref] [bib_ref] Should healthy children be vaccinated against influenza? A consensus report of the..., Heikkinen [/bib_ref] [bib_ref] The underrecognized burden of influenza in young children, Poehling [/bib_ref]. The incidence of influenza in children under 5 years of age is far greater than in the elderly, with estimates showing an attack rate of 30% and respiratory illnesses peaking in the age group at 1-2 years [bib_ref] Acute respiratory illness in the community. Frequency of illness and the agents..., Monto [/bib_ref]. Although overall influenza-associated mortality rates in children were not high, a US study showed 63% of the 153 reported influenza-associated paediatric deaths during the 2003-04 influenza season were less than 5 years of age [bib_ref] Influenza-associated deaths among children in the United States, Bhat [/bib_ref]. In this study 33% had an underlying condition known to increase the risk of influenza-related complications and 20% had other chronic conditions; however, 47% had previously been healthy. Children under 2 years of age are at highest risk of influenza and are most likely to develop serious complications such as pneumonia, secondary bacterial infection, and sepsis [bib_ref] Burden of interpandemic influenza in children younger than 5 years: a 25-year..., Neuzil [/bib_ref]. Excess hospitalisations are high in young children, particularly those younger than 12 months of age. Healthy children under one year of age are hospitalised for influenza-associated illnesses at similar rates to those for adults in high-risk groups [bib_ref] The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics..., Neuzil [/bib_ref]. The high rate of hospitalisation in children was largely responsible for introduction of universal vaccination in the USA. Despite high rates of hospitalisation, influenza cases are generally under-reported and it is likely that the number of notified cases does not reflect the real-life frequency of influenza. Influenza infections are frequently unrecognised clinically despite contributing to significant numbers of hospitalisation (annual rate 0.9 per 1000 children) [bib_ref] The underrecognized burden of influenza in young children, Poehling [/bib_ref]. The largest proportion of paediatric influenza-related illness is associated with the outpatient setting [bib_ref] Impact of influenza infection in healthy children examined as outpatients and their..., Tsolia [/bib_ref]. Outpatient visits associated with influenza in young children are 10-to 250-fold more common than hospitalised cases [bib_ref] The underrecognized burden of influenza in young children, Poehling [/bib_ref]. Children between the ages of 6 and 23 months have the highest rates of visits to clinics and emergency departments attributable to influenza [bib_ref] The underrecognized burden of influenza in young children, Poehling [/bib_ref]. These medically-attended influenza cases are also under-reported due to the potential for incorrect diagnosis and lack of laboratory confirmation. Laboratory confirmation is frequently not used to diagnose influenza in young children and rarely used in the outpatient setting. The diagnosis of influenza is usually made on the basis of patient history, clinical signs and symptoms and knowledge of the local epidemiological situation. Due to overlap of symptoms with other respiratory disease infection, influenza in children is easily misdiagnosed [bib_ref] The underrecognized burden of influenza in young children, Poehling [/bib_ref]. Typical symptoms of early influenza include mainly sudden high fever, cough and absence of rhinitis. Children do not always show these symptoms. Whilst high fever is a prominent sign of influenza, unlike adults, many children treated for influenza in the outpatient setting present with rhinitis during the early phase of the illness, making clinical distinction from a 'cold' difficult in this age group [bib_ref] Clinical presentation of influenza in unselected children treated as outpatients, Silvennoinen [/bib_ref]. In young children the clinical presentations of influenza-related illness can consist of pneumonia, croup, bronchitis and sepsis, and these conditions might not be attributed to influenza if laboratory-confirmed data are not available [bib_ref] Burden of interpandemic influenza in children younger than 5 years: a 25-year..., Neuzil [/bib_ref]. Several rapid antigen detection tests are available and provide results in 10-30 min but with reduced sensitivity (70%-90% in children) compared with RT-PCR and with viral culture. Accuracy of these assays depends greatly on patient age, length of illness, sample type, and possibly viral type [bib_ref] Seasonal influenza in adults and children--diagnosis, treatment, chemoprophylaxis, and institutional outbreak management:..., Harper [/bib_ref]. Our understanding of the clinical presentation of paediatric influenza is based only on studies examining hospitalised children with severe forms of influenza which may alter our perception concerning the signs and symptoms of influenza in children [bib_ref] Clinical presentation of influenza in unselected children treated as outpatients, Silvennoinen [/bib_ref]. It has been shown that for children with laboratory-confirmed influenza, only 28% of hospitalised children and 17% of children seen in the clinic are correctly diagnosed by their treating physicians [bib_ref] The underrecognized burden of influenza in young children, Poehling [/bib_ref]. The accuracy of diagnosis is poor, particularly in the early and late phases of outbreaks [bib_ref] Accuracy of clinical diagnosis of influenza in outpatient children, Peltola [/bib_ref]. Clinical diagnosis is poorest in children under 3 years of age, the group that has the greatest burden of disease from influenza. In this group a clinical diagnosis sensitivity of 21% and positive predictive value of 16% were observed [bib_ref] Accuracy of clinical diagnosis of influenza in outpatient children, Peltola [/bib_ref]. One result of low diagnosis is that the number of cases reported does not reflect the actual frequency of influenza. The use of rapid testing for influenza may enhance the precision of the influenza diagnosis but the reduced sensitivity of these tests means that negative test results should be confirmed with RT-PCR and/or viral culture [bib_ref] Seasonal influenza in adults and children--diagnosis, treatment, chemoprophylaxis, and institutional outbreak management:..., Harper [/bib_ref] [bib_ref] Vaccine effectiveness against medically attended, laboratory-confirmed influenza among children aged 6 to..., Shuler [/bib_ref]. ## Influenza vaccine The efficacy and effectiveness of trivalent inactivated vaccine (TIV) in healthy children (under 19 years of age) has been examined in a number of meta-analyses, overall vaccine efficacy estimates were similar for laboratoryconfirmed influenza (59-63%) and clinical cases (36-45%) [bib_ref] Vaccines for preventing influenza in healthy children, Jefferson [/bib_ref] [bib_ref] The efficacy of influenza vaccine for healthy children: a meta-analysis evaluating potential..., Manzoli [/bib_ref]. Lower estimates for clinically diagnosed cases are possibly due to inclusion of misdiagnosed non-influenza cases and a proportion of cases that would not be prevented even with a totally efficacious vaccine [bib_ref] The efficacy of influenza vaccine for healthy children: a meta-analysis evaluating potential..., Manzoli [/bib_ref]. All three meta-analysis studies highlight a lack of extensive data for children less than 2 years of age that preclude meaningful analysis. For children aged less than 5 years the vaccine efficacy against influenza is broad ranging, from 12 to 83% [bib_ref] Safety and efficacy of trivalent inactivated influenza vaccine in young children: a..., Zangwill [/bib_ref]. The efficacy and effectiveness of influenza vaccinations depends on several factors, most importantly on the age and immunocompetence of the recipient, the similarity between the viruses in the vaccine and in circulation for a given influenza season, and the study design and outcome measured [bib_ref] Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory..., Fiore [/bib_ref]. A recent case-control study over eight consecutive influenza seasons from 1999-2000 through 2006-07 has shown that TIV is highly effective in preventing laboratory-confirmed influenza in children <5 years of age when given as recommended by the American Academy of Pediatrics and the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC), with effectiveness estimates of 86% [bib_ref] Effectiveness of inactivated influenza vaccine in children less than 5 years of..., Joshi [/bib_ref]. Relatively few studies on influenza vaccine efficacy and effectiveness have been conducted in children aged between 6 and 23 months [bib_ref] Effectiveness of inactivated influenza vaccine in preventing acute otitis media in young..., Hoberman [/bib_ref] [bib_ref] Effectiveness of the 2003-2004 influenza vaccine among children 6 months to 8..., Ritzwoller [/bib_ref] [bib_ref] Influenza vaccine effectiveness in healthy 6-to 21-month-old children during the 2003-2004 season, Allison [/bib_ref]. In one randomised clinical study in this age group, vaccine efficacy against culture-confirmed influenza was 66% during the 1999-2000 influenza season; however there was no significant reduction of culture-confirmed influenza during the 2000-01 season. It was noted that the attack rate was higher (15.9%) in the first season compared to the second (3.3%) [bib_ref] Effectiveness of inactivated influenza vaccine in preventing acute otitis media in young..., Hoberman [/bib_ref]. In a retrospective cohort study in children 6 to 23 months of age, vaccine effectiveness was 25% against influenza-like illnesses and 49% against pneumonia or influenza during the 2003-04 influenza season [bib_ref] Effectiveness of the 2003-2004 influenza vaccine among children 6 months to 8..., Ritzwoller [/bib_ref]. In another retrospective study examining healthy children aged 6-21 months, vaccine effectiveness after two doses was estimated to be 87% against pneumonia or influenza-related office visits [bib_ref] Influenza vaccine effectiveness in healthy 6-to 21-month-old children during the 2003-2004 season, Allison [/bib_ref]. The influenza cases in both studies were not laboratory-confirmed. The influenza vaccines currently approved for children and adults in Europe contain three strains of influenza viruses that are recommended annually by the WHO based on global surveillance. The vaccine contains one influenza A(H3N2) strain, one influenza A(H1N1) strain, and one influenza B strain and may change each year to reflect the most recent circulating forms of the virus. TIV is approved for use in children aged 6 months or more, as well as adults, and includes populations who have chronic medical conditions and women who are pregnant. There is currently no vaccine recommended for children less than 6 months of age. An annual booster of influenza vaccine is recommended for all age groups. The TIV is injected into the deltoid muscle and does not cause influenza although minor side effects are noted. Inactivated influenza vaccines contain trace levels of egg protein so that individuals with allergies to egg protein should not receive the vaccine. The inactivated influenza vaccine is safe and well-tolerated in children [bib_ref] Safety of the trivalent inactivated influenza vaccine among children: a population-based study, France [/bib_ref] [bib_ref] Efficacy of inactivated and cold-adapted vaccines against influenza A infection, 1985 to..., Neuzil [/bib_ref]. It very rarely causes immediate allergic reactions and there is no evidence of an increase in asthma exacerbations. The risk of developing Guillain-Barré syndrome following influenza vaccination is at most one in 1,000,000 [bib_ref] Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory..., Fiore [/bib_ref]. There is no evidence of any preventive effects of homeopathic supplements against influenza [bib_ref] Preventing influenza: an overview of systematic reviews, Van Der Wouden [/bib_ref]. Influenza vaccines are the mainstay of efforts to reduce the substantial global health burden that influenza poses. In the USA influenza vaccination is recommended for all children six months of age or older, adults 50 years old or older, all individuals with chronic medical conditions and pregnant women, as well as people in contact with susceptible groups, such as health-care professionals. Given the global disease burden of influenza, the WHO has indicated that member states should evaluate the costeffectiveness of introducing influenza vaccination into national immunisation programmes [bib_ref] Seasonal influenza vaccines, Fiore [/bib_ref]. In Europe two doses of trivalent inactivated influenza vaccine are recommended in previously unvaccinated infants and children. The two doses are administered at least one month apart for children aged 6 months to 8 or 9 years (depending on manufacturer's recommendations) who either receive an influenza vaccine for the first time or have not been exposed to influenza previously. Despite recommendations of multiple doses, young children often only receive one injection of influenza vaccine for primary vaccination. For children under 3 years of age a half dose is required per injection. For older children receiving the seasonal influenza vaccine for the first time, a single dose of the vaccine is appropriate. However, optimal dosage and scheduling in infants and children is currently not well established. In the USA the number of influenza vaccine doses administered is age-dependent [bib_ref] Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory..., Fiore [/bib_ref]. Children who are 9 years old or older who have not been vaccinated previously require one dose in their first season of immunisation. Children under the age of 9 years being vaccinated for the first time receive a second dose at least 4 weeks after the first. Children younger than 9 years of age who received only one dose of vaccine in the first season they were vaccinated should receive two doses of influenza vaccine the following season; this applies only to the influenza season that follows the first year that the child receives influenza vaccine. In Canada children under 9 years of age who have never received an influenza vaccine require two doses administered 4 weeks apart. Those who have been vaccinated with one dose in the previous year require two doses, while those who received two doses in the previous year would only require one dose. Children receiving vaccine for the third year or longer would only require one dose. Before implementing any universal vaccination scheme it is vital to consider in addition to disease burden the safety of the vaccine to the recipient and to the whole population and the expectation of significant public health benefits with a demonstration of cost-effectiveness. The indirect benefit to the community of vaccinating healthy children, mostly of school age, has been evaluated in a systematic review and found to be potentially beneficial to the children and capable of generating significant health benefits and cost saving for the wider community [bib_ref] Universal vaccination of children against influenza: are there indirect benefits to the..., Jordan [/bib_ref]. In Europe the prevailing immunisation strategy is to prevent seasonal influenza primarily by protecting vulnerable (those at high risk) individuals as opposed to achieving herd immunity and reduce transmission in the community via universal vaccination. There is increasing support for immunising healthy children against influenza with the appreciation that children bear the vast burden of disease. Vaccination of children will protect against viral infection but will also protect against two common bacterial complications: otitis media and pneumonia. In addition to the direct benefit of reducing the burden of disease in children there is the indirect effect of reducing transmission by protecting unvaccinated adults against infection. Children are the main transmitters of the influenza virus during local outbreaks as they shed greater quantities of the virus and for longer periods of time than adults [bib_ref] Should healthy children be vaccinated against influenza? A consensus report of the..., Heikkinen [/bib_ref] [bib_ref] Patterns of shedding of myxoviruses and paramyxoviruses in children, Frank [/bib_ref] [bib_ref] Viral shedding patterns of children with influenza B infection, Hall [/bib_ref] [bib_ref] Human influenza, Nicholson [/bib_ref]. Universal vaccination of infants and children could result in decreased morbidity and mortality in other high-risk groups in the community [bib_ref] Universal vaccination of children against influenza: are there indirect benefits to the..., Jordan [/bib_ref]. As long ago as 1970 Monto et al. showed that indirect protection of adults was achieved by vaccinating schoolchildren [bib_ref] Modification of an outbreak of influenza in Tecumseh, Michigan by vaccination of..., Monto [/bib_ref]. In Japan the overall influenza-associated mortality rates were lowest during the winters of 1977-87 when influenza vaccination in Japanese schools was compulsory [bib_ref] The Japanese experience with vaccinating schoolchildren against influenza, Reichert [/bib_ref]. With around 60% of Japanese families consisting of grandparents also living in the same household, immunisation of all schoolchildren protected other atrisk members in their family. During the influenza epidemic of 1968-69 in the USA, in which 85% of schoolchildren had been vaccinated, overall respiratory illness rates dropped to one-third of the rates observed in an unvaccinated population [bib_ref] Modification of an outbreak of influenza in Tecumseh, Michigan by vaccination of..., Monto [/bib_ref] while vaccination of day care children (aged 24-60 months) reduced the incidence of febrile respiratory illnesses in unvaccinated family members by 42% [bib_ref] Effectiveness of influenza vaccination of day care children in reducing influenza-related morbidity..., Hurwitz [/bib_ref]. Similar findings were reported in Italy where vaccination of children younger than 14 years significantly decreased the cases of respiratory infections and absenteeism from work among household contacts [bib_ref] Socioeconomic impact of influenza on healthy children and their families, Principi [/bib_ref]. In addition to the community-wide protection against influenza provided by vaccinating children, there are potentially significant cost-related benefits. Indirect costs avoided include parental time costs, absence from work, loss of earnings and time costs among secondary cases. Parents lose an average of 1.3 working days caring for sick children and 0.4 days due to transmission of the infection [bib_ref] Impact of influenza infection in healthy children examined as outpatients and their..., Tsolia [/bib_ref]. A study in Finland showed that for every 100 influenza-infected children younger than 3 years old, 195 days of parental work were lost (mean duration 3.2 days) [bib_ref] Burden of influenza in children in the community, Heikkinen [/bib_ref]. It is estimated that investing 1.7 million Euros in the vaccination of children <5 years of age will save 2.7 million Euros in health care costs [bib_ref] Costeffectiveness of influenza vaccination of healthy children, Salo [/bib_ref]. Vaccination was found to be cost saving even with an assumed vaccine efficacy of 60% [bib_ref] Costeffectiveness of influenza vaccination of healthy children, Salo [/bib_ref]. ## Existing recommendations for vaccinating children against influenza In 2006-07 an independent scientific panel convened by the European Centre for Disease Prevention and Control found that there were insufficient data to support widespread immunisation of children though the vaccines did induce immunity. The review found considerable data from outside Europe but few data relevant to Europe itself and there was a lack of information on the European burden of disease in children. This view has recently been reconfirmed [bib_ref] The scientific basis for offering seasonal influenza immunisation to risk groups in..., Nicoll [/bib_ref]. Although the evidence for immunisation of risk groups such as children and pregnant women is not strong for Europe, it should be noted that there is no evidence against immunisation of these groups [bib_ref] The scientific basis for offering seasonal influenza immunisation to risk groups in..., Nicoll [/bib_ref]. The World Health Organization currently recommends yearly vaccination against seasonal influenza for children 6-23 months of age. The number of countries adopting universal vaccination of infants and children in response to the burden of influenza in this age group is increasing. In Canada the National Advisory Committee on Immunization currently recommends influenza vaccination for all children aged 6-23 months of age. ACIP has continuously updated its recommendations in the USA for influenza vaccination in children of 6-23 months of age (in 2003) to 6-59 months of age (in 2006) and finally extending their recommendation in 2009 to include all children and adolescents under the age of 19 years [bib_ref] Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory..., Fiore [/bib_ref]. Interestingly, 48% of children received the first dose of influenza vaccine in the first year of the ACIP's recommendation for universal influenza vaccination. This vaccination rate was higher than the vaccination rate among older children with high-risk medical conditions, for whom influenza vaccination has been recommended for many years. Universal age-based recommendations are more likely to be successful than risk-based. Health-care professionals and the public find it difficult to decide on eligibility using risk-based recommendations. Vaccination rates for those ≥65 years of age, for whom universal influenza vaccination is recommended, are consistently higher than among adults <65 years old with underlying high-risk conditions [bib_ref] Annual universal influenza vaccination: ready or not?, Abramson [/bib_ref]. A 2008 survey of the 27 EU member states together with Norway and Iceland revealed that all countries recommended seasonal influenza vaccination in the period 2006-07 for older age groups (22 countries for those aged >65 years) [bib_ref] National seasonal influenza vaccination survey in Europe, Mereckiene [/bib_ref]. In Austria the vaccine was recommended for all age groups. In Poland the recommendation is from the age of 50 whilst in Hungary immunisation is recommended from the age of 55. All countries recommended vaccinating high-risk patients and this includes any person irrespective of age with chronic pulmonary and cardiovascular diseases, with haematological or metabolic disorders, immunological disorders and renal disease, as well as residents of long-term care facilities. Within Europe, six countries, in addition to Austria, advise routine vaccination of children. Estonia recommends vaccination of all healthy individuals from the age of 6 months whilst Finland recommends vaccination of healthy children between 1 and 3 years. Latvia, Romania and Slovenia recommend vaccination between 6 months and 2 years whilst Slovakia has a broader age range from 6 months to 5 years for vaccination of healthy children. Whilst these countries recommend vaccination for children, a recent study suggested that the scientific evidence for immunising children in Europe was not strong but acknowledged that there was no evidence against immunisation of this group [bib_ref] The scientific basis for offering seasonal influenza immunisation to risk groups in..., Nicoll [/bib_ref]. [fig_ref] Table 1: Countries with recommendations to vaccinate healthy children according to age [/fig_ref] summarises the current recommendations for vaccination of children according to country. ## Cevag CEVAG consists of regional experts from ten Central European countries: Bulgaria, Croatia, the Czech Republic, Estonia, Hungary, Lithuania, Poland, Romania, Slovakia and Turkey. The aim of CEVAG is to encourage the efficient and safe use of vaccines to prevent, control and if possible eradicate infectious diseases, by raising awareness of immunisation and by the compilation and distribution of appropriate information. # Cevag guidance statement CEVAG recommends the introduction of universal influenza vaccination of all children, including healthy children and those with existing health complications, from the age of 6 months. Special attention is needed for children up to 60 months of age as they are at greatest risk. Individual countries should decide on how best to implement this recommendation based on their circumstances. The CEVAG guidance statement on recommendations for paediatric influenza immunisation is described in [fig_ref] Table 2: Summary of CEVAG guidance statement on recommendations for influenza vaccination of all... [/fig_ref]. ## Strategies for the future Constant review of new immunisation strategies to protect against childhood influenza will be required in [bib_ref] Superior relative efficacy of live attenuated influenza vaccine compared with inactivated influenza..., Ashkenazi [/bib_ref] [bib_ref] Live attenuated versus inactivated influenza vaccine in infants and young children, Belshe [/bib_ref] [bib_ref] Safety, efficacy, and effectiveness of cold-adapted influenza vaccine-trivalent against community-acquired, culture-confirmed influenza..., Vesikari [/bib_ref]. In children aged <24 months one study suggested increased risk of wheezing and increased risk of hospitalisation in children aged between 6 and 11 months [bib_ref] Live attenuated versus inactivated influenza vaccine in infants and young children, Belshe [/bib_ref]. A subsequent smaller study did not find any evidence for these adverse events [bib_ref] Safety, efficacy, and effectiveness of cold-adapted influenza vaccine-trivalent against community-acquired, culture-confirmed influenza..., Vesikari [/bib_ref]. Another strategy for the future is the use of enhanced adjuvants in association with inactivated influenza vaccine. The ability of an influenza vaccine to trigger an immune response against drifted viruses not in the vaccine formulation is of potential clinical benefit in very young children naive to influenza virus exposure. Antigenic drift of influenza viruses requires frequent adaptation of vaccines to accommodate this drift. One of the major challenges faced is to predict the drifts ahead of influenza seasons. Adjuvanted vaccines such as those using MF59 induce significantly higher immune responses against mismatched H3N2 and H1N1 strains than the licensed split vaccine, they have acceptable tolerability and a greater immunogenicity in young children compared with conventional split vaccines [bib_ref] Enhanced Immunogenicity of Seasonal Influenza Vaccines in Young Children Using MF59 Adjuvant, Vesikari [/bib_ref]. Recent development of a vaccine against the pandemic influenza A (H1N1) containing the adjuvant AS03 show high immunogenicity and are well tolerated in children aged 6 to 35 months. Influenza vaccines need to provide sustained protection against illness as well as being effective. Vaccination with LAIV provides prolonged protection against influenza in children between 6 and 18 years of age that lasts 5-12 months after the vaccination is first administered. Multiple studies have shown that LAIV provides sustained protection against influenza caused by antigenically similar strains through a second influenza season in children aged 6 months to 18 years without the need to revaccinate [bib_ref] Duration of protection provided by live attenuated influenza vaccine in children, Ambrose [/bib_ref] [bib_ref] Safety and efficacy of live attenuated influenza vaccine in children 2-7 years..., Belshe [/bib_ref]. No such protection data exist for adult populations. The introduction of universal influenza vaccination for all children is clearly desirable but continued education for health-care professionals and the public on the bene-fits of immunisation and paediatric influenza is likely to increase acceptance of vaccination. A stronger motivation on the part of health-care professionals would also enhance the vaccination of children. Vaccine uptake in children across 11 European countries ranged from 4.2% in Ireland to 19.3% in Germany with two countries of the CEVAG region, the Czech Republic and Poland, showing intermediate rates of 7.6 and 9.2% respectively [bib_ref] Vaccination coverage rates in eleven European countries during two consecutive influenza seasons, Blank [/bib_ref]. There is little doubt that increased awareness will overcome many of the barriers to vaccination. ## Summary - The under-recognised burden of disease in children under 5 years is far greater than in elderly populations - The number of paediatric influenza cases reported does not reflect the actual frequency of influenza with clinical diagnosis poorest in children under 3 years of age - Universal vaccination of infants and children could result in decreased morbidity and mortality in other high-risk groups in the community - CEVAG recommends the introduction of universal influenza vaccination for all children from the age of 6 months. Special attention is needed for children up to 60 months of age as they are at greatest risk. Individual countries should decide on how best to implement this recommendation based on their circumstances. ## Competing interests VU has been the principal investigator in clinical studies supported by GlaxoS-mithKline (GSK), Novartis, and Wyeth-Lederle Vaccines. He has also been a scientific consultant to Aventis Pasteur, Baxter, GSK, Merck, and Wyeth-Lederle Vaccines and has received sponsorship from these companies to attend scientific meetings. IA has been the principal investigator in clinical studies supported by GSK. She has also been a scientific consultant to GSK and Wyeth and has received sponsorship from these companies to attend scientific meetings. RC has been the principal investigator in clinical studies supported by GSK, Novartis. He has also been a scientific consultant to Baxter, GSK, Novartis, Aventis Pasteur and Pfizer and received sponsorship from the GSK and Aventis Pasteur to attend scientific meetings. II has been a scientific consultant to Baxter, GSK, Merck, and Wyeth-Lederle Vaccines and has received sponsorship from these companies to attend scientific meetings. AM has been a scientific consultant to Wyeth, GSK, Aventis Pasteur, Solvey Pharma and has received sponsorship from these companies to attend scientific meetings. RP is a member of advisory boards for GSK, MSD, Wyeth, Baxter, Aventis Pasteur and has received research grants and honoraria from GSK, Wyeth, Baxter, Aventis Pasteur, Novartis. PS has received consulting fees and lecture fees from GSK, Wyeth and Merck Sharp & Dohme (MSD). ET has received sponsorship from the GSK and PharmaSwiss to attend scientific meetings. GT has received sponsorship from GSK, MSD and Wyeth to attend scientific meetings. FA and ZM have no competing interests. Authors' contributions RP highlighted the need for such recommendations for Central Europe that were discussed by all authors at the CEVAG meeting in May 2009. VU conceived the outline and produced the first draft of the manuscript. All authors were actively involved in the selection and review of all content and had full editorial control during the writing of the manuscript. All authors read and approved the final manuscript. [table] Table 1: Countries with recommendations to vaccinate healthy children according to age [/table] [table] Table 2: Summary of CEVAG guidance statement on recommendations for influenza vaccination of all children [/table]	None	https://bmcinfectdis.biomedcentral.com/counter/pdf/10.1186/1471-2334-10-168	None
54953b6c42cf118168c47d099ebf865c715b64d4	pubmed	Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III)	Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III) The Billroth III guidelines were developed during a consensus meeting of the Austrian Society of Gastroenterology and Hepatology (ÖGGH) and the Austrian Society of Interventional Radiology (ÖGIR) held on 18 February 2017 in Vienna. Based on international guidelines and considering recent landmark studies, the Billroth III recommendations aim to help physicians in guiding diagnostic and therapeutic strategies in patients with portal hypertension. ## I. Definitions of portal hypertension II. Diagnosis and screening of portal hypertension III. Preprimary prophylaxis and prevention of decompensation IV. Primary prophylaxis of variceal bleeding V. Acute variceal bleeding VI. Secondary prophylaxis of variceal bleeding VII. Measurement of the hepatic venous pressure gradient (HVPG) VIII. Portal hypertensive gastropathy IX. Gastric varices X. Management of ascites XI. Spontaneous bacterial peritonitis (SBP) The strength of the underlying evidence and the recommendations were based on a modified version of the GRADE system I. Definitions of portal hypertension [bib_ref] for the GRADE Working Group. GRADE: an emerging consensus on rating quality..., Guyatt [/bib_ref]. The term compensated advanced chronic liver disease (cACLD) may be used similar to cirrhosis and is defined as confirmed liver stiffness >15 kPa on transient elastography [bib_ref] Non invasive evaluation of portal hypertension using transient elastography, Castera [/bib_ref]. Diagnosis of cACLD should trigger screening for clinically significant portal hypertension (CSPH) [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop:..., De Franchis [/bib_ref]. (A1) 2. CSPH is defined as an increase of the hepatovenous pressure gradient (HVPG) to values of ≥10 mm Hg. (A1) [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop:..., De Franchis [/bib_ref] 3. Normal portal pressure is defined as HVPG of ≤5 mm Hg, while subclinical portal hypertension is defined as HVPG 6-9 mm Hg. (A1) 4. CSPH might already be present in compensated patients (without ascites, without varices). (A1) 5. The presence of gastroesophageal varices (GOVs), variceal hemorrhage, ascites (in the absence of significant cardiac, malignant, peritoneal or renal comorbidities) and/or the presence of large portosystemic collaterals on imaging studies are indicative of the presence of CSPH [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop:..., De Franchis [/bib_ref]. (A1) 6. Assessing the four Baveno stages of portal hypertension is clinically useful to quickly assess the prognosis of patients with liver cirrhosis: Baveno-I compensated, no varices, Baveno-II compensated, presence of GOVs, Baveno-III decompensated with ascites and Baveno-IV decompensated, history of variceal bleeding [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop:..., De Franchis [/bib_ref] [bib_ref] Natural history and prognostic indicators of survival in cirrhosis: A systematic review..., D'amico [/bib_ref]. (B1) 1. Patients with cirrhosis (or cACLD) should be screened for CSPH [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop:..., De Franchis [/bib_ref] (see Billroth-III screening algorithm in [fig_ref] Figure 1: Flow chart for screening of varices in cirrhotic patients [/fig_ref]. (A2) 2. After the initial diagnosis of cirrhosis (or cACLD) screening endoscopy may be performed at least once if the patient never had an upper GI endoscopy before. (C1) 3. In cirrhotic patients with a platelet count >150 G/L and liver stiffness <15 kPa on transient elastography screening endoscopy can be safely deferred [bib_ref] Noninvasive tools and risk of clinically significant portal hypertension and varices in..., Abraldes [/bib_ref] [bib_ref] Liver stiffness plus platelet count can be used to exclude high-risk oesophageal..., Ding [/bib_ref] [bib_ref] Elastography, spleen size, and platelet count identify portal hypertension in patients with..., Berzigotti [/bib_ref]. (B1) 4. Esophageal varices (EV) should be graded as absent, small (<5 mm of diameter), or large (≥5 mm). The presence of red spots should be indicated for risk stratification. (A2) 5. Gastric varices should be described as GOV-1 (continued varices on minor curvature), GOV-2 (continued varices on larger curvature extending to the fundus) or isolated gastric varices (IGV-1) isolated fundal varices or IGV-2 ectopic varices in the stomach. The presence of red spots should be indicated for risk stratification [bib_ref] Prevalence, classification and natural history of gastric varices: A long-term follow-up study..., Sarin [/bib_ref]. (B2) 6. In patients without varices, endoscopy should be repeated every 2 years in the case of compensated cirrhosis and every year in the case of decompensated cirrhosis [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop:..., De Franchis [/bib_ref]. (C1) 7. Patients with low-risk varices should receive nonselective beta blockers (NSBBs). (C1) 8. In compensated patients with varices (EV or receiving NSBBs there is no indication for endoscopic monitoring of the varices [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop:..., De Franchis [/bib_ref]. (C1) 9. If HVPG is measured as ≥10 mm Hg, endoscopy should be repeated every year in order to screen for the presence of varices, since CSPH is predictive of the formation of esophagogastric varices [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop:..., De Franchis [/bib_ref]. (A1) 10. There is no indication for subsequent endoscopic surveillance once large EVs or gastric varices (≥5 mm) are detected, unless endoscopic treatment is performed for primary or secondary prophylaxis of variceal bleeding [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop:..., De Franchis [/bib_ref]. (B1) ## Iii. preprimary prophylaxis and prevention of decompensation The effectiveness of NSBBs in the setting of preprimary prophylaxis (prevention of the development of varices and variceal bleeding in patients with compensated cirrhosis; cACLD) has been addressed in a landmark study which randomly assigned patients with cirrhosis and portal hypertension (defined by HVPG ≥6 mm Hg; 63% had CSPH) to timolol or placebo [bib_ref] Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis, Groszmann [/bib_ref]. After a median follow-up of nearly 5 years, approximately 40% of patients in both groups met the composite primary endpoint of development of varices or variceal bleeding. Thus, in general, there is no indication for NSBBs treatment in patients who have not developed varices; however, NSBBs might be indicated for extrahepatic comorbidities (e. g. arterial hypertension, coronary heart disease, and heart failure). In the aforementioned study, patients who had a relative HVPG decrease of >10% after 1 year showed a lower incidence of the primary endpoint [bib_ref] Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis, Groszmann [/bib_ref] ; however, relevant HVPG decreases during NSBBs treatment are only observed in patients with CSPH [bib_ref] Development of hyperdynamic circulation and response to beta-blockers in compensated cirrhosis with..., Villanueva [/bib_ref]. In a recent randomized controlled trial (RCT) restricted to patients with CSPH, preprimary prophylaxis (44%) or small varices without red spot signs (56%), propranolol/carvedilol decreased the risk of S136 Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III) K original article hepatic decompensation, mostly by decreasing the incidence of ascites [bib_ref] A Randomized trial to assess whether portal pressure guided therapy to prevent..., Villanueva [/bib_ref]. Thus, future studies should address the potential benefits of early initiation of NSBBs (especially carvedilol) treatment in the subgroup of patients with CSPH. 1. Preprimary prophylaxis defines the prevention of the development of varices and variceal bleeding in patients with compensated cirrhosis (cACLD) who do not have varices. (A1) 2. In general, there is no indication for NSBBs treatment in patients with cACLD who have not yet developed varices. Nevertheless, NSBBs might be indicated for extrahepatic comorbidities (e. g. arterial hypertension, coronary heart disease, and heart failure). (A1) 3. Preprimary prophylaxis with NSBBs can be considered in patients with CSPH since it may reduce the risk of developing ascites. (B2) ## Iv. primary prophylaxis of variceal bleeding ## Indications for primary prophylaxis This chapter addresses primary prophylaxis in patients with esophageal varices (EV) and recommendations for the management of gastric varices is discussed in Chap. IX (gastric varices). Choice of treatment for primary prophylaxis 2. Patients with small EVs with risk factors (red spot signs and/or with decompensated cirrhosis Child-Pugh class B or C) should receive NSBBs since they reduce the risk of bleeding in this setting. (A1) 3. Patients with small EV without risk factors should also receive NSBBs prophylaxis, since NSBBs may reduce the incidence of variceal bleeding in this setting. (C1) 4. If monitoring of HVPG is available, treatment with NSBBs should be preferred, since achieving a hemodynamic response defines an excellent long-term prognosis [bib_ref] Hemodynamic response to Carvedilol is maintained for long periods and leads to..., Kirnake [/bib_ref]. (B1) 5. Hemodynamic response to NSBBs is defined as a reduction in HVPG ≤ 12 mm Hg or at least ≥10% from baseline. This is not only associated with a lower risk of first variceal bleeding but also with a lower incidence of ascites and death [bib_ref] Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary..., Villanueva [/bib_ref] [bib_ref] Development of ascites in compensated cirrhosis with severe portal hypertension treated with..., Hernandez-Gea [/bib_ref] [bib_ref] Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic..., Reiberger [/bib_ref]. (A1) 6. The lack of access to HVPG measurement should not prevent physicians from using NSBBs for primary prophylaxis, since bleeding rates in primary prophylaxis are low even in hemodynamic nonresponders to NSBBs. (B1) 7. Propranolol or carvedilol should be used for prophylactic pharmacological treatment of patients with varices. Carvedilol is more effective than propranolol in primary prophylaxis of variceal bleeding [bib_ref] Randomized comparison of long-term carvedilol and propranolol administration in the treatment of..., Banares [/bib_ref] [bib_ref] Carvedilol or propranolol in portal hypertension? A randomized comparison, Hobolth [/bib_ref]. (B1) 8. In patients with contraindications to NSBBs therapy, NSBBs intolerance, non-adherence to NSBBs or non-responders to NSBBs, EVL should be used. Endoscopic treatment [bib_ref] Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis, Groszmann [/bib_ref]. Use of EVL in primary prophylaxis should be performed in 2-6-week intervals until variceal eradication. A first follow-up endoscopy after variceal eradication should be performed after 6 months and then every 12 months. If EVL must be restarted the intervals are similar to first EVL [bib_ref] A randomized control trial of bi-monthly versusbi-weekly endoscopicvariceal ligation of esophageal varices, Yoshida [/bib_ref]. (B1) ## Pharmacological treatment with nsbbs 10. There is no need for follow-up endoscopy in patients on pharmacological therapy. (B1) 11. The initial dose of propranolol is 20-40 mg twice daily with a maximum dosage of 160 mg/day in patients without and 80 mg/day with ascites. The initial dose of carvedilol is 6.25 mg once daily with a maximum dosage of 12.5 mg/day [bib_ref] Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic..., Reiberger [/bib_ref]. (B1) 12. The dose of NSBBs should be increased to achieve a resting heart rate of 55-60 beats per minute (bpm). The systolic blood pressure should not decrease below 90 mm Hg. (B1) 13. There is no relationship between reduction in portal pressure or protection from variceal bleeding and the reduction in resting heart rate or in blood pressure. There is no consensus on whether NSBBs treatment should be continued in patients without a hemodynamic response to NSBBs treatment; however, the benefit of NSBBs treatment may go beyond the portal pressure reducing effect and may also reduce the incidence of ascites, infections, decompensation and death [bib_ref] Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary..., Villanueva [/bib_ref] [bib_ref] Development of ascites in compensated cirrhosis with severe portal hypertension treated with..., Hernandez-Gea [/bib_ref]. (B1) 14. In patients with severe or refractory ascites NSBBs should be discontinued during spontaneous bacterial peritonitis (SBP), a decline of systolic blood pressure <90 mm Hg or hyponatremia Na < 125 mmol/l or in the presence of acute kidney injury [bib_ref] Nonselective beta blockers increase risk for hepatorenal syndrome and death in patients..., Mandorfer [/bib_ref] [bib_ref] Beta adrenergic blockade and decompensated cirrhosis, Reiberger [/bib_ref]. (C2) 15. Isosorbide mononitrate (ISMN) (alone or combined with NSBBs) is not recommended for primary prophylaxis, since it is not more effective in preventing first bleeding but increases side effects [bib_ref] Isosorbide-5-mononitrate versus propranolol in the prevention of first bleeding in cirrhosis, Angelico [/bib_ref] [bib_ref] Isosorbide mononitrate in the prevention of first variceal bleed in patients who..., Garcia-Pagan [/bib_ref]. (B1) 16. The combination of endoscopic treatment and NSBBs treatment does not further decrease the incidence of bleeding or death but is associated K Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III) S137 with a higher number of side effects and cannot be recommended for primary prophylaxis [bib_ref] Endoscopic variceal ligation plus propranolol versus endoscopic variceal ligation alone in primary..., Sarin [/bib_ref]. (A1) 17. The presence of varices does not represent an indication for proton pump inhibitors (PPIs); however, a short course of PPI post-variceal ligation reduces ulcer size and early bleeding risk [bib_ref] Use of proton pump inhibitors in the management of gastroesophageal varices: A..., Lo [/bib_ref] [bib_ref] Proton pump inhibitor therapy is associated with reduction of early bleeding riskafter..., Kang [/bib_ref]. (C1) 18. Transjugular intrahepatic portosystemic shunt (TIPS) placement is not recommended for prevention of first variceal hemorrhage [bib_ref] The treatment of portal hypertension: A meta-analytic review, D'amico [/bib_ref]. (C1) ## V. acute variceal bleeding The Billroth-III algorithm for treatment of acute variceal bleeding is summarized in Definition 1. Acute variceal bleeding (AVB) is diagnosed in cases of: (a) active bleeding at endoscopy or (b) signs of upper GI bleeding (hematemesis, blood or coagulated blood, melena) in patients with varices in the absence of any other source of bleeding. ## Blood products 2. Blood volume restitution should be done conservatively using packed red cells to maintain a Hb level of 7-8 g/dl (unless comorbidities/active bleeding necessitate more aggressive substitution), and substitution of fluids to maintain hemodynamic stability [bib_ref] Transfusion strategies for acute upper gastrointestinal bleeding, Villanueva [/bib_ref] Antibiotic prophylaxis [bib_ref] Liver stiffness plus platelet count can be used to exclude high-risk oesophageal..., Ding [/bib_ref]. Antibiotic prophylaxis is an integral part of the therapy of variceal bleeding and should be started at admission with i. v. broad spectrum antibiotics which can be de-escalated according to culture results. In the absence of overt infections and successful control of AVB, antibiotic prophylaxis can be stopped after 5-7 days [bib_ref] Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with..., Bernard [/bib_ref]. Prognosis [bib_ref] Isosorbide mononitrate in the prevention of first variceal bleed in patients who..., Garcia-Pagan [/bib_ref]. Active bleeding at endoscopy (under vasoactive therapy) is a poor prognostic sign regarding successful control of bleeding for the short-term period after variceal bleeding [bib_ref] A predictive model for failure to control bleeding during acute variceal haemorrhage, Ben-Ari [/bib_ref]. (B1) 25. An HVPG of ≥20 mm Hg, active bleeding at endoscopy and a Child-Pugh class C are associated with an increased failure to control bleeding and early mortality [bib_ref] Prognostic value of early measurements of portal pressure in acute variceal bleeding, Moitinho [/bib_ref]. (B1) Failure to control bleeding [bib_ref] Use of proton pump inhibitors in the management of gastroesophageal varices: A..., Lo [/bib_ref] (C1) 11. EVL to prevent rebleeding in secondary prophylaxis should be continued at 2-4-week intervals until eradication of varices (small residual varices can be tolerated) and should then be repeated after 6 months and 12 months. If EVL must be restarted the intervals are similar to the first EVL. 12. Patients with advanced stage liver disease should be evaluated for liver transplantation. In these patients, endoscopic and/or medicinal therapy should be continued until liver transplantation. (C2) 13. EVL is the therapy of choice for variceal rebleeding (or insufficient decrease in HVPG on NSBBs), although EVL may have only moderate beneficial effects especially in these patients (B2). 14. TIPS is indicated in patients with failure of secondary prophylaxis and should be preferred over surgical shunts. (B1) 15. BRTO and surgical devasculariziation are a rescue therapy in patients with failure of secondary prophylaxis with NSBBs and EVL combination therapy if neither a TIPS nor shunt surgery is feasible. 16. TIPS should be considered for secondary prophylaxis in patients with severe/refractory concomitant ascites and/or in patients with NSBBs intolerance or non-response. (C1) 17. In patients with severe or refractory ascites NSBBs should be discontinued during SBP, a decline of systolic blood pressure <90 mm Hg or hyponatremia Na < 125 mmol/L or in cases of acute kidney injury (AKI). ## Vii. measurement of hepatic venous pressure gradient (hvpg) 1. Portal pressure, assessed by the hepatic venous pressure gradient (HVPG) drives the development of liver-related complications and mortality in patients with (compensated) advanced chronic liver disease (cACLD) [bib_ref] Measurement of portal pressure, Abraldes [/bib_ref] [bib_ref] Cirrhosis and portal hypertension: The importance of risk stratification, the role of..., Mura [/bib_ref]. (A1) 2. HVPG measurements are indicated for assessing the prognosis and monitoring the response to etiologic and HVPG-lowering treatment [bib_ref] Measurement of portal pressure, Abraldes [/bib_ref] [bib_ref] Cirrhosis and portal hypertension: The importance of risk stratification, the role of..., Mura [/bib_ref]. (A2) 3. The number needed to treat (NNT) for NSBBs for preventing variceal bleeding ranges from 5 (secondary prophylaxis) to 10 (primary prophylaxis) [bib_ref] Pharmacological treatment of portal hypertension: An evidence-based approach, D'amico [/bib_ref] , underlining the need for methods to assess the expected benefits of NSBBs treatment in the individual patient. (B2) 4. HVPG response is the only established surrogate for the effectiveness of NSBBs in preventing (recurrent) variceal bleeding. If HVPG decreases to a value of <12 mm Hg or is reduced by ≥20% during NSBBs treatment, patients are protected from variceal bleeding and survival is increased [bib_ref] Hemodynamic events in a prospective randomized trial of propranolol versus placebo in..., Groszmann [/bib_ref] [bib_ref] Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal..., Feu [/bib_ref]. (A1) 5. The assessment of acute HVPG response to intravenous propranolol (0.15 mg/kg given as 15 min infusion) provides a valuable alternative to chronic response assessment (separate measurements). An HVPG reduction by >10% or to <12 mm Hg (measured after the 15 min infusion) is sufficient in the acute setting [bib_ref] Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary..., Villanueva [/bib_ref] [bib_ref] Prognostic value of acute hemodynamic response to i. v. propranolol in patients..., Mura [/bib_ref]. (A1) 6. Several studies support the use of HVPG-guided therapy. Thus, in centers with sufficient experience, HVPG response should be assessed to guide treatment decisions [bib_ref] A Randomized trial to assess whether portal pressure guided therapy to prevent..., Villanueva [/bib_ref] [bib_ref] Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic..., Reiberger [/bib_ref] [bib_ref] Hemodynamic response-guided therapy for prevention of variceal rebleeding: an uncontrolled pilot study, Gonzalez [/bib_ref] [bib_ref] Clinical trial: A randomized controlled study on prevention of variceal rebleeding comparing..., Villanueva [/bib_ref] [bib_ref] Early identification of haemodynamic response to pharmacotherapy is essential for primary prophylaxis..., Sharma [/bib_ref] [bib_ref] Prevention of Rebleeding from esophageal Varices in patients with cirrhosis receiving small-diameter..., Sauerbruch [/bib_ref]. (A2) 7. HVPG measurements should be performed in fasting conditions. Since the procedure is generally well tolerated [bib_ref] A prospective observational study on tolerance and satisfaction to hepatic haemodynamic procedures, Casu [/bib_ref] , ideally no sedation, or if necessary only low doses of midazolam (maximum 0.02 mg/kg) should be used [bib_ref] Low-dose midazolam sedation: An option for patients undergoing serial hepatic venous pressure..., Steinlauf [/bib_ref] [bib_ref] Impact of deep sedation on the accuracy of hepatic and portal venous..., Reverter [/bib_ref]. (A1) 8. HVPG measurements should be performed using a balloon catheter ensuring a sufficient wedge position and in order to maximize the assessed amount of liver parenchyma [bib_ref] Comparison of balloon vs. straight catheter for the measurement of portal hypertension, Zipprich [/bib_ref] [bib_ref] Prospective study comparing different indirect methods to measure portal pressure, Maleux [/bib_ref] [bib_ref] Evaluation of a new balloon occlusion catheter specifically designed for measurement of..., Ferlitsch [/bib_ref]. (A1) 9. Free hepatic venous pressure (FHVP) should be measured in a liver vein 2 cm from the inferior vena cava (stable values are usually obtained after 15 s) [bib_ref] The prognostic value of hepatic venous pressure gradient in patients with cirrhosis..., Silva-Junior [/bib_ref]. A difference between the inferior vena S140 Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III) ## Viii. portal hypertensive gastropathy 1. Portal hypertensive gastropathy (PHG) is defined as a macroscopically visible mosaic-like pattern of the gastric mucosa (usually fundus or corpus) and can be found in 35-80% of cirrhotic patients, correlates with the Child-Pugh score and the degree of portal hypertension (PHT) [bib_ref] Portal hypertensive gastropathy: A systematic review of the pathophysiology, clinical presentation, natural..., Gjeorgjievski [/bib_ref]. A summary for the management of PHT is shown in . (A1) 2. PHG should be differentiated into mild PHG (without signs of bleeding) and severe PHG (red marks or active bleeding). (A1) 3. Gastric antral vascular ectasia (GAVE) is a distinct entity that is endoscopically characterized by tortuous columns of erythematous (mild) or hemorrhagic (severe) lesions in a "watermelon" or diffuse pattern (in the latter case histology may help to confirm diagnosis). GAVE may be present without cirrhosis and is associated with PHT in only 30% of cases [bib_ref] Review article: The management of portal hypertensive gastropathy and gastric antral vascular..., Patwardhan [/bib_ref]. (A1) 4. The incidence of acute PHG bleeding is 2-20% (mostly in severe PHG) [bib_ref] Non-variceal gastrointestinal bleeding inpatientswithliver cirrhosis: A review, Kalafateli [/bib_ref]. (B2) 5. The incidence of chronic PHG bleeding is around 3-26% and is defined by a >2 g/dl decrease in Hb or by the presence of anemia together with positive faecal occult blood tests [bib_ref] Non-variceal gastrointestinal bleeding inpatientswithliver cirrhosis: A review, Kalafateli [/bib_ref]. (B2) 6. If PHG is associated with iron deficiency anemia, iron substitution and in severe cases (Hb < 7 g/dL) transfusion should be considered. (B1) 7. There is no evidence for PHG screening or primary bleeding prophylaxis, yet the use of NSBBs for other indications is not discouraged. (C2) 8. Acute bleeding should be pharmacologically treated as AVB. Emergency gastroscopy should rule out other causes for GI bleeding and help to manage endoscopically treatable bleeding [bib_ref] Portal hypertensive gastropathy with a focus on management, Snyder [/bib_ref] [bib_ref] Portal hypertensive gastropathy and colopathy, Urrunaga [/bib_ref]. (A1) 9. PHG with chronic bleeding should be treated with NSBBs [bib_ref] Portal hypertensive gastropathy: A systematic review of the pathophysiology, clinical presentation, natural..., Gjeorgjievski [/bib_ref] [bib_ref] Non-variceal gastrointestinal bleeding inpatientswithliver cirrhosis: A review, Kalafateli [/bib_ref]. (B1) 10. In cases of refractory PHG bleeding TIPS, shunt surgery, argon-plasma coagulation (APC) or even liver transplantation represent rescue therapies. (B2) 11. GAVE bleeding should be treated by APC or Nd:YAG laser coagulation but multiple treatment sessions might be necessary [bib_ref] Diagnosis and management of gastric antral vascular ectasia, Fuccio [/bib_ref]. (A1) 12. In severe or treatment resistant GAVE, band ligation, cryotherapy, radiofrequency ablation or surgical antrectomy represent potential salvage therapies [bib_ref] Diagnosis and management of gastric antral vascular ectasia, Fuccio [/bib_ref]. Acute variceal bleeding from gastric varices [bib_ref] Prevalence, classification and natural history of gastric varices: A long-term follow-up study..., Sarin [/bib_ref]. Initial management of patients with acute variceal bleeding from gastric varices is similar to bleeding from EVs, including vasoactive drugs, restrictive transfusion policy and antibiotic prophylaxis. (B1) 9. Cyanoacrylate glue injection is the treatment of choice for acute variceal bleeding from cardiofundal varices (GOV2, IGV1) and may be also used for GOV1 and IGV2 [bib_ref] Management of gastric varices, Garcia-Pagan [/bib_ref]. (A1) 10. A single injection should consist of maximum 1.0 ml of a cyanoacrylate/lipiodol mixture (1:1) ## X. management of ascites 30% of patients with compensated cirrhosis develop ascites within 5 years of follow-up [bib_ref] Compensated cirrhosis: natural history and prognostic factors, Gines [/bib_ref]. Occurrence of ascites significantly impairs prognosis of liver cirrhosis, with a mortality of 15-20% within 1 year and 44% within 5 years [bib_ref] Natural history and prognostic indicators of survival in cirrhosis: A systematic review..., D'amico [/bib_ref] [bib_ref] Natural history of patients hospitalized for management of cirrhotic ascites, Planas [/bib_ref]. Treatment of ascites has not yet resulted in significant improvements in survival; however, treating ascites is important because it improves the quality of life of cirrhotic patients and the occurrence of SBP is unlikely in patients without ascites. Important definitions, grading and treatment are summarized in [fig_ref] Table 2: Diagnosis and therapy of ascitesNSAIDs, angiotensin converting enzyme inhibitors, angiotensin receptor blockers,... [/fig_ref]. ## Diagnostic approach in patients with ascites 1. Ascites should be graded according to the International Ascites Club guidelines into uncomplicated (grade 1: only visible on ultrasound, grade 2: moderate ascites, grade 3: massive ascites), and refractory ascites (not responsive or intolerant to diuretic therapy even after paracentesis). (A1) 2. Diagnostic paracentesis is indicated in (i) all cirrhotic patients presenting with ascites for the first time, (ii) cirrhotic patients with ascites with unscheduled admission to hospital regardless of the reason, and (iii) cirrhotic patients with ascites with signs of clinical deterioration (such as fever, hepatic encephalopathy, leucocytosis, abdominal pain, upper gastrointestinal bleeding or deterioration in renal function). Substitution of coagulation factors or platelets is not indicated even in patients with severe coagulopathy, because paracentesis rarely leads to serious bleeding complications [bib_ref] Paracentesis of ascitic fluid. A safe procedure, Runyon [/bib_ref]. (B1) 3. Investigation of ascites should include at least determination of ascitic neutrophil count, protein concentration, and the serum-ascites albumin gradient (SAAG). Uncomplicated ascites due to portal hypertension is expected to show a neutrophil count <250/µl, a SAAG >1.1 g/dl [bib_ref] The serum-ascites albumin gradient is superior to the exudate-transudate concept in the..., Runyon [/bib_ref] and a protein level <2.5 g/dl. The SAAG is calculated by subtracting the ascitic fluid albumin level from the serum albumin level (both determined on the same day). (B1) 4. Additionally, aerobic and anaerobic blood culture bottles should be inoculated with ascitic fluid for bacteriological diagnosis of SBP or bacterascites (neutrophil count <250/µl but positive ascites fluid culture). (B1) Therapy of uncomplicated ascites [bib_ref] Noninvasive tools and risk of clinically significant portal hypertension and varices in..., Abraldes [/bib_ref]. Initial therapy of patients with cirrhosis and ascites consists of moderate sodium restriction (90 mmol NaCl/day, corresponding to 5.2 g NaCl/day), and diuretic therapy. Sodium restriction to less than 5 g NaCl/day is not recommended due to the risk of aggravating malnutrition that is usually present in these patients [bib_ref] Protein-calorie malnutrition in liver cirrhosis, Lautz [/bib_ref]. (B1) 6. Diuretic therapy should be started with spironolactone 100 mg and furosemide 40 mg [bib_ref] Diuresis in the ascitic patient: A randomized controlled trial of three regimens, Fogel [/bib_ref] [bib_ref] Combined versus sequential diuretic treatment of ascites in non-azotaemic patients with cirrhosis:..., Angeli [/bib_ref]. In the case of insufficient ascites control or lack of effectiveness, doses of spironolactone and furosemide can be increased by 100 mg and 40 mg every 3-5 days. The daily dose of 400 mg spironolactone and 160 mg furosemide should not be exceeded. (A1) 7. Furosemide should not be administered intravenously as a bolus in cirrhotic patients because of risk of deterioration in the glomerular filtration rate (GFR) [bib_ref] Immediate effects of furosemide on renal hemodynamics in chronic liver disease with..., Daskalopoulos [/bib_ref]. (B1) 8. The use of spironolactone or amiloride as single agents or combined with thiazides may have a role for outpatients or previously untreated patients due to a lesser need for dose adjustments [bib_ref] Spironolactone alone or in combination with furosemide in the treatment of moderate..., Santos [/bib_ref] [bib_ref] Optimum use of diuretics in managing ascites in patients with cirrhosis, Bernardi [/bib_ref] (B1) 9. Eplerenone is an alternative for men with gynecomastia, but has not been compared to spironolactone or furosemide in the setting of portal hypertensive ascites [bib_ref] Eplerenone reversesspironolactone-inducedpainful gynaecomastiain cirrhotics, Dimitriadis [/bib_ref]. 100 mg of spironolactone is considered equivalent to 50 mg of eplerenone. Furthermore, amiloride as single agent or combined with thiazides may have a role in patients who are intolerant or develop side effects to spironolactone or furosemide [bib_ref] Randomized clinical study of the efficacy of amiloride and potassium canrenoate in..., Angeli [/bib_ref]. (B2) 10. Vaptans are not beneficial for the long-term management of portal hypertensive ascites [bib_ref] Satavaptan for the management of ascites in cirrhosis: Efficacy and safety across..., Wong [/bib_ref]. (A1) 11. Rapid weight loss during diuretic therapy might increase the risk of hypovolemia, AKI and hepatic encephalopathy and thus, weight loss during diuretic therapy should not exceed 1 kg/day or 4 kg/ week. (B2) 12. In patients with tense ascites (grade 3), paracentesis is the treatment of choice and should be followed by diuretic therapy. Total paracentesis should be carried out as a single procedure, even when a large volume of ascites is present, as long as it is hemodynamically tolerated by the patient. (B1) 13. Plasma volume expansion using albumin is recommended in all patients undergoing paracentesis if more than 5 l of ascites have been removed, for prevention of hypovolemia and circulatory dysfunction [bib_ref] Albumin infusion in patients undergoing large-volume paracentesis: A meta-analysis of randomized trials, Bernardi [/bib_ref]. Albumin at a dose of 8 g/l of ascites removed should be administered (i. e. 100ml 20% albumin per 2.5 l ascites removed). Removal of less than 5 l does not appear to have hemodynamic consequences. (A1) K Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III) S143 original article [bib_ref] Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary..., Villanueva [/bib_ref]. Patients responsive to diuretics should primarily be treated with sodium restriction and diuretics and should not undergo serial paracentesis. (B1) 15. In cirrhotic patients with severe hyponatremia (plasma sodium levels <125 mmol/l) fluid restriction is recommended since the underlying pathophysiology is usually dilutional/hypervolemic hyponatremia. (A1) [bib_ref] Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic..., Reiberger [/bib_ref]. In severe hyponatremia diuretics should be stopped, since at these levels diuretics are ineffective and worsen hyponatremia. Substitution with concentrated NaCl solutions should be avoided [bib_ref] Severe symptomatic hyponatremia: treatment and outcome. A study of 64 cases, Sterns [/bib_ref]. (C2) 17. If hyponatremia occurs together with hepatic encephalopathy or with AKI, plasma volume expansion with saline and/or albumin should be considered. (C2) 18. Patients with moderate to severe ascites should be evaluated for liver transplantation. (B1) 19. The administration of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with decompensated cirrhosis and ascites can lead to renal failure and therefore should be avoided [bib_ref] Effect of indomethacin and prostaglandin A1 on renal function and plasma renin..., Boyer [/bib_ref]. The same is true for angiotensin receptor blockers and angiotensin converting enzyme inhibitors [bib_ref] Acute effects of captopril on systemic and renal hemodynamics and on renal..., Pariente [/bib_ref] [bib_ref] Effects of low-dose captopril on renal hemodynamics and function in patients with..., Gentilini [/bib_ref]. Aminoglycosides should only be used in cases where infections cannot be otherwise treated [bib_ref] Aminoglycoside nephrotoxicity in cirrhosis. Value of urinary beta 2-microglobulin to discriminate functional..., Cabrera [/bib_ref] [bib_ref] Risk factors forthedevelopmentofrenaldysfunctioninhospitalizedpatients with cirrhosis, Hampel [/bib_ref]. (A1) 20. In the absence of strong indications, proton pump inhibitors (PPIs) should not be used in patients with ascites since PPIs might be associated with a higher risk of infections [bib_ref] Long-term use of antibiotics and proton pump inhibitors predict development of infections..., O'leary [/bib_ref]. (A2) 21. Ascites per se is not a contraindication for NSBBs, but they should be used with caution. Carvedilol should not be used in patients with severe or refractory ascites due to induction of hypotension [bib_ref] Beta-blockersinpatients with cirrhosis and ascites: Type of beta-blocker matters, Njeib [/bib_ref]. In patients with severe or refractory ascites, high doses of propranolol (>80 mg/day) should be avoided [bib_ref] Betaadrenergicblockadeanddecompensated cirrhosis, Reibergert [/bib_ref]. (C2) ## Refractory ascites Only less than 10% of patients with cirrhosis and ascites are refractory to treatment regimens consisting of sodium restriction and oral diuretics [bib_ref] Peritoneovenous shunting as compared with medical treatment in patients with alcoholic cirrhosis..., Stanley [/bib_ref]. ## Refractory ascites is defined by the international ascites club [70] (a1): -as ascites that cannot be mobilized by intensive diuretic therapy (up to a maximum of 400 mg spironolactone and 160 mg furosemide per day) and confirmed dietary sodium restriction (diuretic-resistant ascites), -or as ascites that rapidly reaccumulates after therapeutic paracentesis (within 4 weeks), -or as the situation, where the maximum dose of diuretics cannot be administered due to side effects, such as electrolyte imbalance, renal fail-ure, and encephalopathy (diuretic-intolerant ascites). 23. Refractory ascites can develop secondary to hepatocellular carcinoma or portal vein thrombosis; therefore, ultrasound examination should be performed to exclude these complications of cirrhosis. (B1) 24. A characteristic feature of refractory ascites is impaired urinary sodium excretion despite maximum tolerated doses of diuretics [bib_ref] Management of cirrhosis and ascites, Gines [/bib_ref]. Since urine collection for 24 h is cumbersome, a spot urinary sodium/potassium ratio <2.5 is a reasonable surrogate for diuretic-resistant ascites [bib_ref] Spot urinary sodium for assessing dietary sodium restriction in cirrhotic ascites, El-Bokl [/bib_ref]. Diuretic treatment should be continued only when urinary sodium excretion under diuretic therapy is greater than 30 mmol/day. (B2) 25. Due to the poor prognosis of patients with refractory ascites liver transplantation must be considered. (A1) [bib_ref] Use of proton pump inhibitors in the management of gastroesophageal varices: A..., Lo [/bib_ref]. Patients with refractory ascites should be evaluated for TIPS, since TIPS is associated with improved survival [bib_ref] Transjugular intrahepatic portosystemic shunt for refractory ascites: A meta-analysis of individual patient..., Salerno [/bib_ref] [bib_ref] Survival benefit of TIPS versus serial paracentesis in patients with refractory ascites:..., Gaba [/bib_ref] [bib_ref] Association between Transjugular Intrahepatic Portosystemic shunt and survival in patients with cirrhosis, Berry [/bib_ref]. (A1) 27. If TIPS is contraindicated or refused by the patient, repetitive large volume paracentesis in combination with albumin substitution, sodium restriction and diuretic therapy should be performed. (B1) 28. The efficacy and safety of low-flow pump systems to remove ascites from the peritoneal cavity into the bladder in patients with refractory ascites remains to be established [bib_ref] Automated low flow pump system for the treatment of refractory ascites: A..., Bellotp [/bib_ref] [bib_ref] Automated low-flow ascites pump for the treatment of cirrhotic patients with refractory..., Stirnimann [/bib_ref]. (C2) 29. In patients with severe/refractory ascites NSBBs should be discontinued during SBP [bib_ref] Nonselective beta blockers increase risk for hepatorenal syndrome and death in patients..., Mandorfer [/bib_ref] , a decline of systolic blood pressure <90 mmHg, hyponatremia <125 mmol/L or in the presence of AKI. Hepatic hydrothorax [bib_ref] Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with..., Bernard [/bib_ref]. Hepatic hydrothorax represents a (usually a rightsided) pleural effusion in patients with cirrhosis and ascites in the absence of any other pleural or pulmonary disease [bib_ref] Hepatic hydrothorax: Clinical features,management,andoutcomesin77patientsandreview of the literature, Badillo [/bib_ref]. (A1) 31. Diagnostic pleuracentesis of hepatic hydrothorax should be performed at first diagnosis and include similar testing as for ascitic fluid. (B1) 32. The absolute neutrophil count is usually higher than in the ascitic fluid and thus, the diagnosis of bacterial infection of the pleural effusion should mainly be based on culture results [bib_ref] Spontaneous bacterial empyema in cirrhotic patients: Analysis of eleven cases, Xiol [/bib_ref]. (C2) 33. Hepatic hydrothorax should be primarily treated with salt restriction and diuretics [bib_ref] Evidence-based review of the management of hepatic hydrothorax, Singh [/bib_ref]. (B1) 34. TIPS should be considered for recurrent hepatic hydrothorax not responsive to diuretic therapy [bib_ref] Treatment of refractory hepatic hydrothorax with transjugular intrahepatic portosystemic shunt: Longterm results..., Siegerstetter [/bib_ref] [bib_ref] Safety and efficacy of transjugular intrahepatic portosystemic shunt creation for the treatment..., Spencer [/bib_ref]. (B1) 35. Other treatment modalities including pleurodesis [bib_ref] Effectiveness and safety of Pleurodesis for hepatic Hydrothorax: A systematic review and..., Hou [/bib_ref] or permanent drainage systems [bib_ref] Outcome analysis of cirrhotic patients undergoing chest tube placement, Liu [/bib_ref] cannot be recommended for treatment of hepatic S144 Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III) K original article hydrothorax. The role of novel indwelling pleural catheters is not yet clear [bib_ref] Indwelling tunneled pleural catheters for the management of hepatic Hydrothorax. A pilot..., Chen [/bib_ref]. (B2) 36. Patients with recurrent hepatic hydrothorax should be evaluated for liver transplantation [bib_ref] Liver transplantation in patients with hepatic hydrothorax, Xiol [/bib_ref]. (A1) ## Xi. spontaneous bacterial peritonitis (sbp) 1. All patients presenting with ascites for the first time, with recurrence of ascites, or deterioration of ascites, evidence of systemic infection, GI bleeding, worsening liver or renal function, or hepatic encephalopathy should undergo paracentesis to screen for SBP. (A1) 2. Ascitic fluid and blood cultures should be performed using blood culture bottles. Even in culture-negative SBP, positive blood cultures might hint at the responsible organism. (A1) 3. In patients with an ascitic fluid absolute neutrophil count >250/µl or a positive ascitic fluid culture, antibiotic therapy with gram-negative coverage (e. g. aminopenicillin/beta-lactamase inhibitor, third generation cephalosporin, or quinolone) should be started immediately. (A1) 4. Chinolones should not be used to treat SBP in patients who were on norfloxacin prophylaxis. (B1) 5. In selected high-risk patients (e. g. nosocomial SBP as defined by onset of signs and symptoms of infection after 72 h from hospitalization and/or patients with sepsis), the use of combination regimens as initial therapy might be warranted [bib_ref] The empirical antibiotic treatment of nosocomial spontaneous bacterial peritonitis: Results of a..., Piano [/bib_ref]. (A2) 6. To prevent the development of hepatorenal syndrome (HRS) type of AKI, 1.5 g/kg bodyweight albumin should be administered in patients with SBP at the time of diagnosis, plus 1 g/kg body weight on day three [bib_ref] Effect of intravenous albumin on renal impairment and mortality in patients with..., Sort [/bib_ref]. (A1) 7. Blood pressure should be carefully monitored in patients with SBP and NSBBs should be discontinued in the case of systolic blood pressure <90 mm Hg, hyponatremia Na < 125 mmol/L, or AKI [bib_ref] Beta adrenergic blockade and decompensated cirrhosis, Reiberger [/bib_ref]. (C2) 8. In the case of an ascitic fluid neutrophil count <250/µL but clinical evidence of infection, similar antibiotic therapy should be initiated and continued until culture results are available. (B1) 9. A second paracentesis should be performed 48 h after initiation of the antibiotic therapy to demonstrate a decrease of the ascitic absolute neutrophil count by 25% of the initial value [bib_ref] Polymorphonuclear cell count response and duration of antibiotic therapy in spontaneous bacterial..., Fong [/bib_ref]. (A1) 10. A smaller drop is highly suggestive of failure of the antibiotic regimen. In these patients, antibiotic therapy should be adopted based on culture results and susceptibility testing. (A1) 11. If culture-negative, antibiotic therapy should be changed to cover gaps in the antibacterial spectrum of the initial therapy, as well as relevant multidrug-resistant gram-negative and gram-positive bacteria (e. g. meropenem plus daptomycin) [bib_ref] The empirical antibiotic treatment of nosocomial spontaneous bacterial peritonitis: Results of a..., Piano [/bib_ref]. (B1) 12. Due to the poor prognosis of patients who recovered from SBP, liver transplantation should be considered in these patients. (A1) 13. All patients with a history of SPB should be treated continuously with secondary prophylaxis using norfloxacin 400 mg/day or alternatively co-trimoxazole (800 mg/160 mg/day). (A1) 14. Given the inevitable risk of antibiotic resistance, the use of prophylactic antibiotics in patients without a history of SBP should be restricted to patients at high risk for SBP: low ascites protein (<15 g/l) with advanced liver failure (Child-Pugh score ≥9 points with serum bilirubin ≥3 mg/dL) or impaired renal function (serum creatinine sCr ≥ 1.2 mg/dL, blood urea nitrogen ≥25 mg/dl, or serum sodium ≤130 mmol/L) [bib_ref] Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival..., Fernandez [/bib_ref] [bib_ref] Antibiotic prophylaxis in cirrhosis: Good and bad, Fernandez [/bib_ref]. (C1) 15. In patients with Child-Pugh C10-15 norfloxacin prophylaxis seems to decrease 6-months mortality. (B1)16. Based on the currently available evidence, rifaximin cannot be used as a substitute for norfloxacin/co-trimoxazole [bib_ref] The role of rifaximin in the primary prophylaxis of spontaneous bacterial peritonitis..., Hanouneh [/bib_ref] [bib_ref] Long-term administration of rifaximin improves the prognosis of patients with decompensated alcoholic..., Vlachogiannakos [/bib_ref] [bib_ref] Impact of rifaximin on the frequency and characteristics of spontaneous bacterial peritonitis..., Lutz [/bib_ref] [bib_ref] Efficacy and safety of alternating norfloxacin and rifaximin as primary prophylaxis for..., Assem [/bib_ref] [bib_ref] Randomized-controlled trial of rifaximin versus norfloxacin for secondary prophylaxis of spontaneous bacterial..., Elfert [/bib_ref] [bib_ref] Rifaximin has no effect on hemodynamics in decompensated cirrhosis: A randomized, double-blind,..., Kimer [/bib_ref]. ## Xii. management of acute kidney injury and hepatorenal syndrome (hrs-aki) Acute kidney injury (AKI) is a common complication of cirrhosis with a significant prognostic impact [bib_ref] Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis, Arroyo [/bib_ref] [bib_ref] New consensus definition of acute kidney injury accurately predicts 30-day mortality in..., Wong [/bib_ref]. As a consequence of systemic and splanchnic arterial vasodilatation, renal perfusion is critical in patients with advanced cirrhosis and CSPH [bib_ref] Recent advances in our understanding of hepatorenal syndrome, Wong [/bib_ref]. AKI is commonly triggered by precipitating events leading to further circulatory compromise including overdose of diuretics, large volume paracentesis without albumin replacement, GI blood loss, and infections (e. g. SBP) [bib_ref] Liver cirrhosis and kidney, Gerbes [/bib_ref]. ## Diagnosis and definitions The traditional diagnostic criteria of renal failure in cirrhosis (percentage increase in sCr, ≥50% to a final value ≥1.5 mg/dl) [bib_ref] Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis, Salerno [/bib_ref] were replaced by the Kidney Disease Improving Global Outcome (KDIGO) criteria to diagnose AKIand adapted for patients with cirrhosis by the International Club of Ascites (ICA) in 2015 [bib_ref] Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised..., Angeli [/bib_ref]. One of the main modifications of the ICA-AKI criteria is the abandonment of a threshold of sCr ≥ K Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III) S145 - Continuous infusion (initial dose 0.5 mg/h; max. studied in RCTs 3 mg/hour) - Complete response is defined by a decrease in sCr to a value within 0.3 mg/dL of the baseline value. - Partial response is defined by a regression of at least one AKI stage - The vasoconstrictor dose should be increased if there is no response after 3 days of treatment - In non-responders, treatment should be discontinued after 14 days ## Other considerations for hrs-aki - RRT should be restricted to patients eligible for liver transplantation - TIPS should be considered in patients with severe/refractory ascites - Patients with HRS-AKI associated with SBP should receive secondary antibiotic prophylaxis - Patients should be evaluated for liver transplantation Normal renal 1.5 mg/dl to diagnose AKI in cirrhosis, since smaller rises in sCr have also been shown to have a negative prognostic impact in these patients [bib_ref] New consensus definition of acute kidney injury accurately predicts 30-day mortality in..., Wong [/bib_ref] [bib_ref] New diagnostic criteria and management of acute kidney injury, Wong [/bib_ref]. A detailed algorithm for diagnosis and treatment of AKI in patients with cirrhosis is shown in . ## Diagnosis and definitions 1. AKI in cirrhosis should be diagnosed according to the ICA-AKI criteria [bib_ref] Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised..., Angeli [/bib_ref]. (B1): -Increase in sCr ≥ 0.3 mg/dl within 48 h or -Increase in sCr ≥ 50% from a baseline value that is known or presumed to have occurred in the past 7 days. -A baseline sCr value obtained in the previous 3 months should be used. If no previous sCr value is available, the sCr on admission should be used. In cases of impairment of renal function (sCr ≥ 1.5 mg/dl) at time of admission and a clearly identifiable precipitating event, it is reasonable to assume AKI based on clinical judgement. -The use of a reduction in urine output as part of the diagnostic criteria was eliminated in the new ICA criteria for the diagnosis of AKI because many patients with cirrhosis and ascites are oliguric as part of the sodium and water retention syndrome and yet maintain a nearly normal GFR [bib_ref] Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised..., Angeli [/bib_ref] [bib_ref] Tubular site of renal sodium retention in ascitic liver cirrhosis evaluated by..., Angeli [/bib_ref]. Based on that only the changes in sCr should be S146 Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III) K original article used to diagnose AKI in patients with cirrhosis (B1). 2. AKI in cirrhosis should be staged according to the ICA-AKI criteria [bib_ref] Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised..., Angeli [/bib_ref] : (B1) -ICA-AKI stage 1: increase in sCr ≥ 0.3 mg/dl or ≥1.5 to 2-fold from baseline -ICA-AKI stage 2: increase in sCr > 2 to 3-fold from baseline -ICA-AKI stage 3: increase in sCr > 3-fold from baseline or ≥4 mg/dl with an acute increase ≥0.3 mg/dl or need for renal replacement therapy (RRT) 3. The hepatorenal syndrome type of AKI (HRS-AKI, formerly known as HRS type 1) is defined as ≥ stage 2 ICA-AKI fulfilling all other diagnostic criteria of HRS-AKI [bib_ref] Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised..., Angeli [/bib_ref] : (A1) -Presence of ascites -No improvement in sCr after 2 consecutive days of withdrawal of diuretics and plasma volume expansion with albumin (1 g/kg, max.100 g/day) -Absence of shock -Exclusion of nephrotoxic agents (e. g. NSAIDs, aminoglycosides, contrast media) -Exclusion of parenchymal kidney disease (proteinuria <500 mg/day, <50 red blood cells per high power field, normal renal ultrasound) 4. Hepatorenal syndrome type 2 is defined as slowly progressive impairment of renal function (sCr > 1.5 mg/dl) [bib_ref] Working Party proposal for a revised classification system of renal dysfunction in..., Wong [/bib_ref] [bib_ref] The evolving concept of acute kidney injury in patients with cirrhosis, Wong [/bib_ref] fulfilling the abovementioned diagnostic criteria of HRS-AKI and is usually associated with refractory ascites [bib_ref] Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis, Arroyo [/bib_ref] [bib_ref] New consensus definition of acute kidney injury accurately predicts 30-day mortality in..., Wong [/bib_ref] (A1). ## Management of aki and hrs-aki in cirrhosis The initial management of AKI should focus on identification and correction of precipitating factors that further exaggerate the already disturbed hemodynamics in advanced cirrhosis [bib_ref] Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised..., Angeli [/bib_ref] [bib_ref] Acutekidneyinjuryinlivercirrhosis: Newdefinition andapplication, Wongf [/bib_ref] [bib_ref] Diagnosing and treating renal disease in cirrhotic patients, Wong [/bib_ref]. 5. The following measures should be taken in cirrhotic patients with initial ICA-AKI stage 1. (A1) -Review of all medications (including over the counter drugs) -Reduction or withdrawal of diuretic therapy and/ or lactulose for patients who are volume-depleted from diuretics or excess lactulose use -Withdrawal of all potentially nephrotoxic agents (e. g. NSAIDs) -Careful assessment of ongoing use of drugs potentially inducing/aggravating hypotension (e. g. NSBBs) [bib_ref] Betaadrenergicblockadeanddecompensated cirrhosis, Reibergert [/bib_ref] [bib_ref] Interferon-free regimens improve portal hypertension and histological necroinflammation in HIV/HCV patients with..., Schwabl [/bib_ref] -Plasma volume expansion with crystalloids or albumin in patients with clinically suspected hypovolemia -Blood transfusion in patients with AKI after GI blood loss -Screening for bacterial infections (e. g. SBP) and early or empiric antibiotic treatment if an infection is diagnosed or strongly suspected [bib_ref] Antimicrobial therapeutic determinants of outcomes from septic shock among patients with cirrhosis, Arabi [/bib_ref] 6. In the case of response (return of sCr to a value within 0.3 mg/dl of the baseline value), patients should be followed closely for early identification of potential new episodes of AKI [bib_ref] Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised..., Angeli [/bib_ref] [bib_ref] Acute kidney injury in decompensated cirrhosis, Tsien [/bib_ref]. (B2) -Assessment of sCr every 2-4 days during hospitalization -Assessment of sCr every 2-4 weeks during the first 6 months after discharge 7. In the case of stage 2 or 3 ICA-AKI or progression of stage 1 ICA-AKI to a higher stage, patients need to be assessed for the presence of HRS-AKI in addition to the following measures [bib_ref] Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised..., Angeli [/bib_ref]. (B1): -Administration of the same general measures as described for patients with ICA-AKI stage 1, -Withdrawal of diuretics if not withdrawn already, -Plasma volume expansion with albumin for two consecutive days (1 g/kg body weight, maximum 100 g/day). ## Treatment of hrs-aki 8. Patients with HRS-AKI should be treated with vasoconstrictors (terlipressin or norepinephrine) in combination with albumin (40 g/day) [bib_ref] Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised..., Angeli [/bib_ref]. (A1). 9. Patients with ICA-AKI stage 1 and sCr < 1.5 mg/dl fulfilling the diagnostic criteria of HRS-AKI can be treated the same way on a case-by-case basis [bib_ref] Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised..., Angeli [/bib_ref]. (C2). 10. Patients with HRS type 2 can be treated similarly [bib_ref] Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome:..., Martin-Llahi [/bib_ref] [bib_ref] Renal failure in cirrhotic patients: Role of terlipressin in clinical approach to..., Alessandria [/bib_ref] [bib_ref] Treatment of type 2 hepatorenal syndrome in patients awaiting transplantation: Effects on..., Rodriguez [/bib_ref]. (A1). original article [bib_ref] Randomized comparison of long-term carvedilol and propranolol administration in the treatment of..., Banares [/bib_ref]. Patients should be monitored for hyponatremia, which more commonly occurs in patients with less advanced liver disease and (near) normal baseline serum sodium levels [bib_ref] Hyponatremia in patients treated with terlipressin for severe gastrointestinal bleeding due to..., Sola [/bib_ref]. (A1). 18. Continuous infusion (initial dose of 2 mg/day; maximum 12 mg/day) decreases the rate of adverse events, the mean effective terlipressin dose and, thus, might also decrease costs as compared to bolus administration (initial dose of 0.5 mg every 4 h; maximum 2 mg every 4 h). Continuous infusion might be preferred over bolus administration [bib_ref] Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment..., Cavallin [/bib_ref]. (A1) 19. Although terlipressin has been consistently shown to improve renal function, its impact on survival is less clear. (A1) 20. Terlipressin is particularly beneficial in patients with systemic inflammatory response or sepsis and might also prevent variceal bleeding during the period of discontinuation of NSBBs [bib_ref] Arandomizedtrialcomparingterlipressin and noradrenaline in patients with cirrhosis and septic shock, Choudhury [/bib_ref]. (B2) Norepinephrine 21. Norepinephrine (initial dose of 0.5 mg/h; maximum dose studied in RCTs: 3 mg/h) is an equally effective and inexpensive alternative to terlipressin [bib_ref] Terlipressin versus noradrenaline in the treatment of hepatorenal syndrome: Systematic review with..., Mattos [/bib_ref]. ## (a1) Response to treatment and considerations for follow-up [bib_ref] Beta adrenergic blockade and decompensated cirrhosis, Reiberger [/bib_ref]. Complete response to treatment is defined by a decrease in sCr to a value within 0.3 mg/dl of the baseline value, while a regression of at least one AKI stage is considered as partial response. (B1) [bib_ref] Isosorbide-5-mononitrate versus propranolol in the prevention of first bleeding in cirrhosis, Angelico [/bib_ref] [bib_ref] Natural history and prognostic indicators of survival in cirrhosis: A systematic review..., D'amico [/bib_ref]. Patients with acute PVT should receive anticoagulation for at least 6 months to prevent extension to mesenteric veins and intestinal ischemia and in order to achieve recanalization [bib_ref] Acuteportal vein thrombosis unrelated to cirrhosis: A prospective multicenter followup study, Plessier [/bib_ref] [bib_ref] Portal vein thrombosis, Chawla [/bib_ref]. (A1) 5. For acute PVT, LMWH should be initiated and shifted to oral anticoagulation after stabilization of the patient. (A1) 6. In symptomatic patients with acute, non-cirrhotic PVT (i. e. ascites and/or risk of intestinal infarction) a TIPS combined with local clot fragmentation/aspiration should be considered [bib_ref] Ascites in patients with noncirrhotic nonmalignant extrahepatic portal vein thrombosis, Spaander [/bib_ref]. (B1) 7. Lifelong anticoagulation should be given to PVT patients with a permanent prothrombotic condition. (A1) 8. Long-term anticoagulation is also recommended in patients without identifcation of (prothrombotic) risk factor or thrombus extension into the mesenteric/splenic vein. Malignant PVT (regardless of cirrhotic/non-cirrhotic PVT) [bib_ref] A randomized control trial of bi-monthly versusbi-weekly endoscopicvariceal ligation of esophageal varices, Yoshida [/bib_ref]. In general, anticoagulation is not indicated for malignant PVT. (C2) 20. Anticoagulation may be considered for symptomatic and progressive malignant PVT. (C1) 21. TIPS should not be used for treatment of malignant PVT. (C1) Acute cirrhotic, non-malignant PVT [bib_ref] Beta adrenergic blockade and decompensated cirrhosis, Reiberger [/bib_ref]. Anticoagulation is indicated in cirrhotic patients with acute PVT with progression to mesenteric/ splenic vein or signs of intestinal ischemia. (A1) 23. Anticoagulation should be considered in all candidates for liver transplantation with PVT [bib_ref] Splanchnic vein thrombosis in candidates for liver transplantation: Usefulness of screening and..., Francoz [/bib_ref]. (B1) 24. Anticoagulation may also be used in non-candidates for liver transplantation with progressive PVT or with persisting prothrombotic conditions [bib_ref] Prospective evaluation of anticoagulation and transjugular intrahepatic portosystemic shunt for the management..., Senzolo [/bib_ref] [bib_ref] Splanchnic vein thrombosis in candidates for liver transplantation: Usefulness of screening and..., Francoz [/bib_ref] [bib_ref] Natural course of extrahepatic nonmalignant partial portal veinthrombosisinpatientswithcirrhosis, Luca [/bib_ref] [bib_ref] Systemic thrombolysis of portal vein thrombosis in cirrhotic patients: A pilot study, Santis [/bib_ref] [bib_ref] Portal vein thrombosis after variceal endoscopic sclerotherapy in cirrhotic patients: Role of..., Amitrano [/bib_ref] [bib_ref] Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis:..., Nery [/bib_ref] [bib_ref] Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein..., Delgadomg [/bib_ref]. (C1) 25. No recommendations regarding type of anticoagulation treatment can be made for cirrhotic PVT; however, LMWH and VKA appear to be equally effective for cirrhotic, non-malignant PVT [bib_ref] Prospective evaluation of anticoagulation and transjugular intrahepatic portosystemic shunt for the management..., Senzolo [/bib_ref] [bib_ref] Systemic thrombolysis of portal vein thrombosis in cirrhotic patients: A pilot study, Santis [/bib_ref] [bib_ref] Portal vein thrombosis after variceal endoscopic sclerotherapy in cirrhotic patients: Role of..., Amitrano [/bib_ref] [bib_ref] Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis:..., Nery [/bib_ref] [bib_ref] Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein..., Delgadomg [/bib_ref]. (B1) 26. LMWH should be used as a fixed or weight-adjusted dose. Anti-Xa monitoring of LMWH is not representative in patients with cirrhosis [bib_ref] Increased anticoagulant response to low-molecular-weight heparin in plasma from patients with advanced..., Senzolo [/bib_ref]. (C2) 27. VKA should be monitored in patients with cirrhosis with an INR aimed at 2-3. (C1) 28. Before starting anticoagulation in patients with cirrhotic PVT bleeding prophylaxis should be implemented. (C1) 29. Patients with low platelet count (<50 G/L) are at higher risk of bleeding complications under anticoagulation [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop:..., De Franchis [/bib_ref] [bib_ref] Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein..., Delgadomg [/bib_ref]. (B2) 30. Recent data suggest that DOACs can be safely used in patients with compensated cirrhosis [bib_ref] Direct oral anticoagulants in cirrhosis patients pose similar risks of bleeding when..., Intagliata [/bib_ref]. [fig] Figure 1: Flow chart for screening of varices in cirrhotic patients. TE transient elastography, PLT platelet count, GOV gastroesophageal varices II. Diagnosis and screening of portal hypertension [/fig] [fig] Vasoconstrictor treatment 11: Patients receiving vasoconstrictors should be preferably treated in an intermediate care (IMCU) or intensive care unit (ICU). (B1) 12. Vasoconstrictors should be preferably administered via a central venous line under continuous blood pressure and electrocardiography (ECG) monitoring. (B1) 13. Non-availability of an IMCU/ICU should, however, not defer the use of vasoconstrictors in patients with HRS-AKI. (B1) Terlipressin 14. Terlipressin is the most intensively studied vasoconstrictor for the treatment of HRS-AKI. (A1) 15. A bolus of terlipressin induces a statistically significant reduction in portal pressure over 3-4 h and also increases mean arterial pressure [145]. (A1). 16. Terlipressin should be used with caution in patients with cardiovascular disease, since it may induce ischemia. (A1)K Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III) S147 [/fig] [table] Table 2: Diagnosis and therapy of ascitesNSAIDs, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, aminoglycosides, carvedilol, propranolol with caution (not more than 80 mg/day) NSAIDs non-steroidal anti-inflammatory drugs, TIPS transjugular intrahepatic portosystemic shunt, OLT orthotopic liver transplantation in order to minimize the risk of embolization; however, more than one single injection is usually needed to obtain sufficient obliteration[65]. (B2) 11. Endoscopic variceal sclerotherapy is not recommended for treatment of acute or prophylactic treatment of gastric varices. (B1) 12. EVL is not an established therapy for bleeding GOV2, IGV1 + IGV2 due to a higher rebleeding rate compared to cyanoacrylate, EVL may only be per-Linton-Nachlas balloon tamponade can be used as a bridge to hemostatic therapy in cases of failure to control bleeding from cardiofundal varices; however, risk of rebleeding after deflation is high. (B2) 15. BRTO represents an additional treatment option for bleeding cardiofundal varices. (B2) 16. Rarely surgical shunts, surgical devascularization (plus splenectomy), or splenic embolization are needed as rescue therapy for bleeding gastric varices not responding to vasoactive and endoscopic therapy if a TIPS cannot be performed. (C2) [/table]	None	https://link.springer.com/content/pdf/10.1007/s00508-017-1262-3.pdf	None
b8fda63bef716fda8137bc32fe0885cd6bc9864b	pubmed	Management of patients on antithrombotic agents undergoing emergency and elective endoscopy: joint Asian Pacific Association of Gastroenterology (APAGE) and Asian Pacific Society for Digestive Endoscopy (APSDE) practice guidelines	Management of patients on antithrombotic agents undergoing emergency and elective endoscopy: joint Asian Pacific Association of Gastroenterology (APAGE) and Asian Pacific Society for Digestive Endoscopy (APSDE) practice guidelines # Background Antithrombotic agents, which include antiplatelet agents and anticoagulants, are increasingly used in Asia. Management of patients on antithrombotics undergoing emergency or elective gastrointestinal (GI) endoscopy has become a common and important clinical challenge. While practice guidelines have been developed by GI and endoscopy societies in the USA, 1 Europe 2 and the UK,it was uncertain whether they should be fully adopted in the Asian Pacific region. In September 2015 the Asian Pacific Association of Gastroenterology (APAGE) and the Asian Pacific Society for Digestive Endoscopy (APSDE) appointed KS and FKLC to form an ad hoc working group to evaluate current practice guidelines on the management of patients on antithrombotics undergoing GI endoscopy. In collaboration with the Institute of Digestive Disease of The Chinese University of Hong Kong (CUHK), we systematically reviewed the evidence supporting published guidelines. We concluded that the available practice guidelines in Western countries could not completely meet the specific needs of the Asian Pacific region. For example, many Asian countries have a high case load of non-variceal upper GI bleeding. Current guidelines do not provide comprehensive guidance on the management of GI bleeding in patients with high thromboembolic risks. Another example is that invasive endoscopic procedures such as endoscopic submucosal dissection (ESD) are more commonly performed in Asia than in Western countries due to the high prevalence of certain GI cancers. Furthermore, we noticed inconsistencies between different guidelines and raised doubts about certain recommendations (box 1). In June 2016 a steering committee representing the APAGE and the APSDE (FKLC and KS) and a member nominated by the Japanese Circulation Society (SH) was established to develop practice guideline statements. The steering committee invited members to form a Joint Task Force to participate in the process of finalising guideline development for the Asian Pacific region. Task Force members included gastroenterologists, endoscopists, cardiologists, neurologists and public health specialists. This joint APAGE-APSDE Practice Guideline is intended to be an educational tool that assists clinicians in improving care for patients on antithrombotics who require emergency or elective GI endoscopy in the Asian Pacific region. The Task Force is aware of the fact that clinical decisions for individual patients may lead to deviations of practice from these guidelines. Therefore, this set of guidelines should not be construed as establishing a legal standard of care or as encouraging, advocating, requiring or discouraging any particular treatment. # Method We performed a systematic literature search to review the management of oral antithrombotic agents in patients undergoing GI endoscopy. Searches of the OVID MEDLINE database were performed using keywords related to antithrombotic Guidelines agents, gastrointestinal and endoscopy. The search duration was from 1 January 1990 to 31 July 2016. Publications were identified by title; their relevance was then determined by reviewing the abstract of all records. Studies were excluded if the content was considered irrelevant. The initial guideline statements were drafted based on published systematic reviews, meta-analyses, randomised controlled trials and prospective and retrospective observational studies. A collection of selected literature was made available to all panel members. A two-stage modified Delphi process was used to develop consensus. The first vote was conducted anonymously with an internet-based voting platform. Each member was asked to rank each statement on a 6-point Likert scale, where A+ indicated agree strongly and D+ indicated disagree strongly. Feedback was solicited on the statements and the results were collated (vote 1). Agreement with a statement (A+ or A) by at least 80% of the Task Fforce was defined a priori as consensus. A faceto-face meeting of the Task Force was held on 2-3 September 2016 in Tokyo, Japan. During the meeting the results of vote 1 were shown, and suggested modifications to the statements were discussed. Members discussed statements with divergent opinions. A second vote was cast on all statements by using electronic keypads to ensure anonymity (vote 2). Focused discussion was carried out on those statements that failed to reach consensus, followed by a third vote, again by using electronic keypads (final vote). The consensus method did not force agreement. The level box 1 Major differences between Joint APAGe-APsde Practice Guidelines and other guidelines APAGE-APSDE: no need to omit DOACs before low-risk procedures; resume DOACs when adequate haemostasis is achieved after high-risk procedures; no heparin bridging of agreement in the final vote was given for each statement, which was expressed as the percentage vote at each point on the Likert scale. The recommendations were graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.The APAGE and APSDE endorsed the consensus meeting. # Funding source The funding of this Joint Task Force was derived from an educational grant from the Institute of Digestive Disease of CUHK and sponsorship from Takeda Pharmaceuticals Company Limited. The sponsor was not involved in panel member selection, development of practice guidelines or manuscript preparation. Panel members received no honoraria. Our guidelines are categorised according to the urgency of the endoscopy (ie, emergency and elective). We arbitrarily define bleeding that causes a high likelihood of death as life-threatening. Under each category, the recommendations are divided into the type of antithrombotics used (ie, single antiplatelet agent, dual antiplatelet therapy and anticoagulants). Anticoagulants are subdivided into warfarin and direct anticoagulants (DOACs). For elective procedures, we classified them as low-risk, high-risk and ultra-high risk. We attempted to provide recommendations on the management of antithrombotic therapy according to the thrombotic risk of patients. ## Summary of recommendations: emergency endoscopy for non-variceal upper gi bleeding The Joint Task Force has established the following guideline statements and recommendations according to the type of antithrombotic therapy received by patients. single antiplatelet agent 1. We recommend withholding aspirin before endoscopy in aspirin users presenting with serious or life-threatening ## Single antiplatelet agent In the Asian Pacific region, aspirin is most commonly used for established cardiovascular diseases whereas primary prophylaxis with aspirin is still uncommon. Primary prevention trials conducted in Japan failed to show any benefits of aspirin for cardiovascular events. Other new non-aspirin antiplatelet agents, including P2Y12 receptor inhibitors (prasugrel and ticagrelor) and protease-activated receptor (PAR-1) antagonist (vorapaxar), are mostly used together with aspirin and will be discussed below under 'Dual antiplatelet therapy (DAPT)'. Most major hospitals in Asia are able to provide an after office hours emergency endoscopy service for patients with life-threatening bleeding. Patients with unstable haemodynamics often undergo endoscopy within 12 hours. However, the Task Force considers that withholding aspirin before endoscopy is relevant in places where emergency endoscopy is not readily available. That being said, emergency endoscopy should not be delayed in aspirin users because the antiplatelet effect of aspirin will last for 5-7 days after the last dose taken. Currently available guidelines do not give a consistent recommendation. The American Society of Gastrointestinal Endoscopy (ASGE) Practice Guidelines recommend all patients on antiplatelet agents with life-threatening or serious GI bleeding should have these agents held only after discussion with their cardiologist.In contrast, the European Society of Gastrointestinal Endoscopy (ESGE) Guidelines recommend withholding aspirin until day 3 after endoscopic treatment of high-risk stigmata.While ASGE Practice Guidelines mention platelet transfusion as an option for patients on antiplatelet agents with life-threatening or serious bleeding,to support this practice. In a retrospective cohort study of 204 patients receiving antiplatelet agents with GI bleeding, platelet transfusion did not reduce rebleeding but was associated with higher mortality.Although the increase in mortality could be due in part to residual bias associated with more severe bleeding in cases than controls, the lack of benefit of platelet transfusion does not support its use in patients with GI bleeding who are receiving antiplatelet agents. The timing of resuming aspirin after non-variceal upper GI bleeding is critical in terms of the risks of early rebleeding and serious cardiovascular outcomes. In a double-blind randomised trial conducted in Hong Kong, 156 aspirin users with established cardiovascular diseases who had actively bleeding peptic ulcers were randomised to resume aspirin or placebo immediately after endoscopic haemostasis.At 8 weeks, all-cause mortality was 10 times lower in the aspirin group than in the placebo group (1.3% vs 12.9%; 95% CI 3.7% to 19.5%), although the 30-day rebleeding rate was numerically two times higher in the aspirin group. In another retrospective study of 118 aspirin users who had peptic ulcer bleeding, 40% of patients discontinued aspirin. In a median follow-up of 2 years, patients with cardiovascular comorbidities who discontinued low-dose aspirin therapy had an almost sevenfold increase in risk for death or acute cardiovascular events (HR 6.9; 95% CI 1.4 to 34.8) compared with patients who continued this therapy during the first 6 months of the follow-up period. 9 ## Dual antiplatelet therapy (dapt) The Task Force recommends discussion with the cardiologist before discontinuation of antiplatelet therapy, particularly in patients with acute coronary syndrome within 6 months, because these patients have a higher risk of stent thrombosis than patients with stable coronary artery disease.As a general principle, we do not recommend withholding both antiplatelet agents simultaneously because the median time to coronary stent thrombosis can be as short as 7 days with both drugs withheld compared with 122 days with only clopidogrel withheld.Whether one should temporarily discontinue aspirin or clopidogrel in acute non-variceal upper GI bleeding remains controversial. The ESGE Guidelines recommend continuation of aspirin without interruption and consultation with a cardiologist for resumption of second antiplatelet agent after GI bleeding. 2 However, no justification was provided for this recommendation. In patients on DAPT with aspirin and clopidogrel, we recommend continuing aspirin and withholding clopidogrel in acute non-variceal upper GI bleeding for two reasons. First, there is evidence that continuation of aspirin alone delays the onset of coronary events in patients on DAPT.Second, high-dose proton-pump inhibitors (PPIs) will be used in the management of acute bleeding. The prevalence of slow metabolisers of CY2C19 is as high as 25% in certain Asian populations compared with less than 5% in Western populations. Whether there is any clinically important interaction between PPIs and clopidogrel remains controversial. 14 The Food and Drug Administration has issued a warning label against the concomitant use of clopidogrel and PPIs that are extensively metabolised by CYP2C19.In a subgroup analysis of a French registry of acute myocardial infarction there was a threefold increased risk of serious cardiovascular outcomes (12%) in the cohort of PPI users with two loss-of-function alleles compared with the cohort with wild type CY2C19 (4%).Our Task Force cannot exclude the possibility that use of high-dose PPI in slow metabolisers of CYP2C19 may reduce the efficacy of clopidogrel. We therefore recommend discontinuing clopidogrel while continuing aspirin in Asian patients receiving DAPT for coronary stents complicated by acute non-variceal upper GI bleeding. Other new P2Y12 receptor inhibitors include prasugrel and ticagrelor. They are more potent and reported to have a higher risk of major spontaneous bleeding compared with clopidogrel. Similar to clopidogrel, prasugrel irreversibly inhibits platelet function. In contrast, ticagrelor is a reversible P2Y12 receptor inhibitor with platelet function returning in 3-5 days after discontinuation (compared with about 5 days for clopidogrel and 7 days for prasugrel). It follows that, in acute non-variceal upper GI bleeding, patients with drug-eluting coronary stents should resume ticagrelor preferably within 2-3 days whereas re-initiation of clopidogrel and prasugrel can be delayed up to 5 days after endoscopic haemostasis. However, there are no clinical data on the optimal timing of re-initiation of P2Y12 receptor inhibitors in GI bleeding. Another new antiplatelet agent is vorapaxar, a protease-activated receptor (PAR-1) antagonist that inhibits thrombin receptor. It is indicated in patients with a history of myocardial infarction or peripheral arterial disease, and is usually prescribed in addition to DAPT.Due to its increased risk of intracranial haemorrhage, vorapaxar is contraindicated in patients with a history of stroke, transient ischaemic attack or intracranial haemorrhage. Currently, vorapaxar is not yet approved in some Asian countries including Japan. To date, there are no data on the GI procedural risk associated with vorapaxar. ## Warfarin Current guidelines recommend reversal of anticoagulation in patients with serious life-threatening bleeding irrespective of whether the INR is at therapeutic or supra-therapeutic levels. However, available evidence does not show any correlation between INR at presentation and outcomes of GI bleeding. A number of retrospective studies reported a very high initial success rate of endoscopic haemostasis (>95%) in anticoagulated patients with baseline INR between 1.5 and 2.5 A systematic review of over 1800 patients found that INR at presentation did not predict recurrent non-variceal upper GI bleeding.We therefore do not recommend normalising INR in all patients as it may delay endoscopy for life-threatening bleeding. Although no randomised clinical trials have been performed to compare prothrombin complex concentrate (PCC) with fresh frozen plasma (FFP) for warfarin reversal in acute GI bleeding, we recommend a combination of 4-factor PCC and low-dose vitamin K (<5 mg) if urgent reversal of anticoagulation is deemed necessary. PCC, which contains clotting factors from pooled human plasma, has a number of advantages over fresh frozen plasma, including no need for ABO matching, faster onset of action and minimal risk of fluid overload and transmitting infection.Factor VII, which is present in 4-factor PCC and fresh frozen plasma, has a short half-life of about 4 hours. We recommend concomitant replacement with vitamin K, either orally or intravenously, to restore endogenous factor VII. Both ESGE 2 and American College of Chest Physicians' (ACCP) practice guidelines recommend 5-10 mg vitamin K for life-threatening bleeding.In contrast, we recommend low-dose vitamin K (<5 mg) especially in patients for whom early re-anticoagulation is necessary to reduce the risk of hypercoagulopathy. Our recommendation is based on evidence from four randomised trials that the optimal doses of vitamin K for normalisation of INR are between 1 and 2.5 mg.Guidelines There is evidence from retrospective data that early resumption of warfarin is associated with a lower risk of thromboembolism and death.The optimal timing of resuming warfarin depends on the thrombotic risk of individual patients (box 2). A number of retrospective studies have shown that resumption of warfarin between 7 and 30 days significantly reduced the risk of thromboembolism and death without increasing the risk of rebleeding, whereas resuming warfarin within 7 days of the bleeding episode was associated with a twofold increased risk of rebleeding. However, a note of caution is that the available data were derived from a heterogeneous group of patients with different thrombotic risks. Since the risk of early rebleeding decreases considerably after the first 3 days and the time required for full re-anticoagulation may be prolonged, especially after warfarin reversal, we recommend early resumption of warfarin after day 3, especially in patients with high thromboembolic risk. According to the ESGE guidelines, 2 the timing for resumption of anticoagulation should be assessed on a patient-by-patient basis. They recommend that resuming warfarin between 7 and 15 days following the bleeding event appears safe and effective in preventing thromboembolic complications for most patients.The joint British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) Guidelines (abbreviated as BSG-ESGE guidelines) recommend bridging therapy using low molecular weight heparin (LMWH) for patients at high thrombotic risk undergoing elective endoscopy.While we agree with the above guideline for uncomplicated elective procedures, we recommend using unfractionated heparin as bridging therapy after emergency endoscopy for bleeding in patients with high thrombotic risk. This is because unfractionated heparin has a much shorter half-life (1-2 hours after intravenous injection) that allows rapid reversal in case rebleeding occurs. 36 ## Direct oral anticoagulants (doacs) To date, four DOACs including dabigatran, apixaban, rivaroxaban and edoxaban have been approved by the FDA and are available in many countries in the Asia Pacific region. Unlike vitamin K antagonists, DOACs are direct inhibitors of factor thrombin (dabigatran) and factor Xa (apixaban, rivaroxaban, edoxaban). This new class of anticoagulants has a rapid onset (1-4 hours) and offset of action (about 24 hours). However, drug elimination is prolonged in patients with reduced renal clearance. Dabigatran is mostly eliminated by the kidneys (∼80%),edoxaban has 50% of the dose undergoing renal elimination,whereas rivaroxaban (∼33%)and apixaban (∼25%)are less affected by renal impairment. However, the use of DOACs should be cautious in patients with severe renal insufficiency (ie, creatinine clearance (CrCl) 15-29 mL/min). No DOAC should be used in patients with CrCl <15 mL/min.Hepatic impairment also increases the risk of bleeding. Child-Pugh B cirrhosis affects the pharmacokinetics of rivaroxaban and apixaban (but not dabigatran) to a clinically relevant degree. Rivaroxaban is contraindicated in patients with Child-Pugh B and C cirrhosis. Apixaban should be used with caution in patients with Child-Pugh A or B cirrhosis. Dabigatran and apixaban are contraindicated in patients with advanced liver disease associated with coagulopathy, whereas in Japan edoxaban can be used with caution in patients with severe hepatic impairment.Unlike vitamin K antagonists, DOACs have a lower potential for drug-drug interactions. However, concomitant drugs that share the elimination pathways may increase the risk of bleeding. Apixaban and rivaroxaban are metabolised mainly via cytochrome P450 (CYP) 3A4-dependent and P-glycoprotein (P-gp)-dependent pathways. Strong inhibitors of both CYP3A4 and P-gp, such as ketoconazole and HIV protease inhibitors (eg, ritonavir), should not be co-administered with apixaban and rivaroxaban.Other concomitant drugs that may increase the risk of bleeding include antiplatelet agents and non-steroidal anti-inflammatory drugs (NSAIDs). Neither the ASGE 1 nor the ESGE 2 Guidelines provide specific recommendations on acute bleeding with DOACs. Contrary to the BSG-ESGE Guidelines,we do not recommend the use of platelet transfusion or desmopressin in severe acute bleeding with DOACs because there is no clinical or laboratory evidence to support such practice. As mentioned in the section on acute bleeding with antiplatelet therapy, new data suggest that platelet transfusion is associated with increased mortality.Since prothrombin time (PT) and activated partial thromboplastin time (APTT) do not necessarily indicate whether anticoagulation is supratherapeutic, therapeutic or subtherapeutic in patients receiving DOACs, the BSG-ESGE Guidelines 3 recommend using specific assays to measure the anticoagulant activity of DOACs in acute bleeding. However, we do not make this recommendation because assessment of the anticoagulant activity of DOACs requires specific assays that are not routinely available. Furthermore, withholding DOACs will lead to rapid loss of anticoagulation due to their short half-lives unless the patient has impaired renal clearance. Management of acute bleeding in patients receiving DOACs depends on the severity of bleeding, timing of the last dose of DOAC, creatinine clearance and the pharmacokinetic properties of individual DOACs. Since DOACs are not vitamin K antagonists, vitamin K is not useful as an antidote to overdose of DOACs. For bleeding that is not life-threatening, standard haemodynamic support measures and temporary cessation of DOACs is probably sufficient due to their short half-lives. For severe bleeding with haemodynamic instability, we recommend the use of activated charcoal if the last dose of DOAC is taken within less than 3 hours. Our panel recommends a time window of 3 hours because most DOACs reach their peak plasma concentration within 3 hours of oral ingestion, although one healthy volunteer study suggested that activated charcoal can substantially reduce the terminal half-life of apixaban 6 hours postdose.However, the efficacy of activated charcoal has not been evaluated in clinical practice. On the other hand, we do not recommend dialysis as a treatment option, with the exception of dabigatran, because the other three DOACs have high protein binding and therefore are not dialyzable.Both the ASGE Guidelines 1 and the BSG-ESGE Guidelines 3 are cautious about the use of FFP and PCC in life-threatening bleeding with DOACs. We reviewed the literature and found that there is no human study on FFP for the reversal of the anticoagulant effect of DOACs. In fact, FFP is unlikely to be effective because it will be required to overcome the direct inhibitory effect of DOACs rather than replenishing depleted factors as in the case of reversal of warfarin. One randomised trial of healthy volunteers showed that a non-activated 4-factor PCC reversed the prolonged PT with rivaroxaban but did not normalise the APTT or thrombin time with dabigatran.To date, there have not been any human studies on the efficacy of PCC either on laboratory bleeding time or clinical bleeding associated with DOACs. In October 2015 the Food and Drug Administration in the USA granted accelerated approval to idarucizumab, a potent monoclonal antibody directed against dabigatran, for use in patients during emergency situations. In a multicentre open-label study of 503 patients who had uncontrolled bleeding or were about to undergo an urgent procedure, 5 g of idarucizumab reversed the anticoagulant effect of dabigatran within 4 hours in almost all patients.While current evidence demonstrates the capacity of idarucizumab to reverse laboratory abnormalities of dabigatran-associated coagulopathy, its clinical benefit is still unclear because of the scarcity of available data. Specific recommendations on the timing of re-initiation of DOACs after endoscopic haemostasis for acute bleeding are not available in the ASGE, ESGE or BSG-ESGE Guidelines. 1-3 After haemostasis has been achieved, we recommend early resumption of DOACs without bridging therapy with heparin. Our recommendation is based on the fact that DOACs have short terminal half-lives (about 12 hours) in patients without impaired renal clearance. It follows that the residual antiacoagulant effect will be minimal after the first 3 days and early resumption of DOACs is needed for patients with high thrombotic risk. Bridging therapy is not necessary since these drugs have a rapid onset of action (between 1 and 4 hours). We do not consider re-initiation of DOACs should be deferred because of concerns about early rebleeding in the absence of specific antidotes. Our local experience suggests that management of rebleeding after resumption of DOACs in a controlled environment is predictable compared with patients with severe bleeding due to toxic ingestion of DOACs. ## Triple and double antithrombotic therapies In patients with both non-valvular atrial fibrillation and acute coronary syndrome or coronary stenting, a short period of triple antithrombotic therapy (ie, DAPT and an oral anticoagulant) followed by double therapy (ie, single antiplatelet agent and an oral anticoagulant) for up to 1 year is often required. The optimal management of antithrombotic therapy after bleeding remains uncertain because large-scale clinical outcome data are not available. The European Society of Cardiology (ESC) Working Group on Thrombosis 49 recommends stopping either aspirin or clopidogrel in patients who develop bleeding during triple therapy. In addition, they recommend discontinuation of antiplatelet agent when a patient develops bleeding on double therapy. In patients with non-valvular atrial fibrillation and low risk of stroke who develop bleeding during triple or double therapy, however, they recommend DAPT alone without oral anticoagulant for 1 year after acute coronary syndrome or coronary stenting. Given the complexity of these cases, our Task Force believes that communication with a cardiologist to make individualised decisions is essential. ## Low-risk procedures Both the ASGE 1 and ESGE-BSG Guidelines 3 have stratified endoscopic procedures into low risk and high risk for bleeding. The stratification was largely based on retrospective observational studies where the majority of the patients undergoing endoscopy did not receive antithrombotics. Furthermore, there is no international consensus on the definition a high-risk procedure. For example, enteral stenting is classified as low risk in the ASGE Guidelines 1 and high risk in the ESGE-BSG Guidelines.Our Task Force classifies those procedures with bleeding risk less than 1% as low risk. Low-risk procedures include diagnostic procedures with mucosal biopsies and therapeutic procedures without cutting open the mucosa or breaching the deep layers. We do not recommend interruption of antiplatelet agents or anticoagulants for patients undergoing these procedures. Mucosal biopsy while continuing antithrombotics is thought to be safe. Apart from a retrospective observational study, 50 one randomised trial of aspirin versus clopidogrel in healthy volunteers found no bleeding events in the aspirin group and one minor endoscopic bleeding event in the clopidogrel group.Only one retrospective study, which was conducted in Japan, reported the safety of performing biopsy in patients on more than one antithrombotic drug. Among 112 patients, where 30 patients were on multiple antithrombotic agents, no patients experienced bleeding symptoms in the 2-week observation period after biopsy. However, the bleeding time was up to 9 min in four patients who had multiple biopsies.There are no studies on the safety of biopsies in patients receiving the newer antiplatelet drugs (prasugrel, ticagrelor, vorapaxar) or DOACs. The risk of bleeding with double balloon enteroscopy in patients not on antithrombotic drugs has been reported at 0.2%,but there are no studies on enteroscopy in patients receiving antiplatelet drugs or anticoagulants. ## Ultra-high risk procedures Both ASGE 1 and BSG-ESGE 3 Guidelines are comparable in their classification of high-risk procedures. In general, there is consensus between professional societies that aspirin can be safely continued in patients undergoing procedures with a high bleeding risk. The BSG-ESGE Guidelines 3 recommend continuing aspirin in all high-risk procedures with the exception of ESD, large colonic endoscopic mucosal resection (EMR) (>2 cm), upper gastrointestinal EMR and ampullectomy. Our Task Force has further stratified high-risk procedures into highrisk and ultra-high risk. The latter includes ESD and EMR of large (>2 cm) polyps. Unlike the BSG-ESGE Guidelines,we do not classify ampullectomy as an ultra-high risk procedure as our regional data suggest that aspirin can be continued for patients with high thrombotic risk.We recommend interruption of all antithrombotic agents for ultra-high risk procedures provided that the perceived benefits of the procedure outweigh the patient's thrombotic risk. However, decisions have to be individualised after liaison with cardiologists or neurologists. We believe it is important to add this category of ultra-high procedures in the Asian Pacific region because: (1) these procedures (eg, ESD) are frequently performed in this part of the world;many studies in the literature were conducted in Asia; and (3) the conflicting outcomes reflect different standards of care and levels of expertise. Two observational studies have assessed the risk of delayed post-polypectomy bleeding after EMR of polyps >2 cm while continuing antithrombotic drugs, but the results are conflicting. Burgess et al studied 101 patients (68 patients continuing aspirin, 14 patients on warfarin interrupted without bridging therapy, and 19 patients on warfarin interrupted with bridging therapy) and the use of antithrombotics was not associated with delayed post-polypectomy bleeding.In contrast, Mertz et al reported that aspirin use was an independent risk factor for delayed bleeding with large colonic EMR after multivariate analysis. The incidence of bleeding with aspirin was reported at 29.4% (5/17 patients).Duodenal EMR carries a high risk of bleeding, reportedly at 12.3% (14/113) 57 and 6.3% (7/11) 58 from two observational studies. There are no studies reporting the incidence of bleeding after duodenal EMR in patients receiving antithrombotics. ESD carries a higher risk of bleeding than EMR, irrespective of location of lesion in the GI tract (OR 2.20 95% CI 1.58 to 3.07).The rate of bleeding with gastric ESD ranges from 3.6% to 6.9%.The risk of bleeding with continuation of aspirin in gastric ESD has yielded conflicting results. These retrospective observational studies reported either no increased riskor increased risk of bleeding. However, most of these studies do not have a control group of non-aspirin users and do not differentiate between antiplatelet drugs and anticoagulants. No studies have reported the rate of bleeding with ESD in patients receiving non-aspirin antiplatelet drugs. ## High-risk procedures colonoscopy and polypectomy Observational data on patients receiving aspirin and undergoing polypectomy suggest that continuation of aspirin as monotherapy does not increase the risk of bleeding.A meta-analysis of five observational studies (two published in abstract form only) of 574 subjects continuing clopidogrel and 6179 controls reported an increased risk of delayed post-polypectomy bleeding with continued clopidogrel therapy (pooled relative risk 4.66, 96% CI 2.37 to 9.17).There are no data on the incidence of post-polypectomy bleeding in patients receiving new antiplatelet drugs. Current guidelines on the management of anticoagulation for polypectomy are largely based on expert opinion. Two retrospective observational studies reported the incidence of delayed bleeding with uninterrupted warfarin at 0% (0/21) 73 and 0.8% (1/123).All the patients had prophylactic clipping after polypectomy. One prospective study compared cold snaring versus hot snaring of small colonic polyps (<1 cm) in patients with uninterrupted warfarin. The rate of delayed bleeding was 0% with cold snaring and 14% (5/35) with hot snaring.There are no direct reports on the bleeding risk in patients treated with DOACs undergoing colonoscopy. According to the safety data of the RE-LY trial, which compared dabigatran and warfarin for prevention of thromboembolism in 4591 patients, about 10% of the patients underwent colonoscopy. There was no significant difference in peri-procedural bleeding risk between the two groups. ## Endoscopic retrograde cholangiopancreatography (ercp) and sphincterotomy Only a few studies have reported the risk of bleeding with continuation of antiplatelet drugs in patients undergoing ERCP and sphincterotomy. Using a nationwide database in Japan, Hamada et al reported that both sphincterotomy and balloon dilatation can be performed safely in patients taking aspirin.A small observational study reported 95 patients with uninterrupted antithrombotic therapy undergoing ERCP with minimal sphincterotomy and balloon dilation (aspirin plus clopidogrel in 55 patients, aspirin plus an anticoagulant in 45 patients, and triple therapy with aspirin plus clopidogrel plus an anticoagulant in five patients). Among them, 14 received DOACs. The overall bleeding rate was 4%.Endoscopic ultrasound (EUS) with fine needle aspiration (FNA) The risk of bleeding from EUS-FNA is around 1%. For EUS-FNA of pancreas cystic lesions, the rate of bleeding is up to 6%.In a prospective observational study, the bleeding rates with EUS-FNA were 0% (0/26), 33.3% (2/6) and 3.7% (7/90) in patients receiving aspirin/NSAIDs, LMWH and no drugs.There are no studies investigating the safety of EUS-FNA with continuation of non-aspirin antiplatelet drugs, warfarin or DOACs. ## Percutaneous endoscopic gastrostomy (peg) In a retrospective analysis of 990 patients undergoing PEG, the rates of bleeding were 3.6% and 2.7% with aspirin and clopidogrel, respectively.In another retrospective study of 450 patients, no post-PEG bleeding was observed in patients using anticoagulants including heparin and vitamin K antagonists.No studies exists on the safety of PEG in users of DOACs. To date there is no convincing evidence that prophylactic endoscopic treatment can reduce the risk of bleeding in patients receiving antithrombotics. Pooled analyses from two separate meta-analyses have reported that prophylactic measures reduce the risk of post-polypectomy bleeding. However, it is uncertain whether the benefit can be extrapolated to patients receiving antithrombotics as all studies excluded patients receiving antiplatelet drugs or anticoagulants. ## Risk of cardiac events following endoscopy in patients with coronary stents There are no direct data on the risk of major adverse cardiac events (MACEs) following GI endoscopy in patients with coronary stents. According to the 2014 American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines,the risk of ACEs in patients undergoing non-cardiac surgery is high in those with drug-eluting coronary stents (DES) placed within 12 months or bare metal coronary stents (BMS) placed within 1 month. The American College of Chest Physicians recommends that surgery should be deferred for at least 6 weeks after placement of a BMS and for at least 6 months after placement of a DES.However, recent evidence derived from a US national retrospective cohort study of about 42 000 Veterans Affairs (VA) and non-VA operations in the 24 months after a coronary stent placement found that the risk of MACEs is actually comparable between DES and BMS. The risk is highest within the first 6 weeks, remains high from 6 weeks to 6 months and then becomes stable after 6 months. Importantly, DES is not a significant risk factor for MACEs. Three important risk factors for MACEs are emergency surgery, a history of myocardial infarction within 6 months prior to surgery, and a revised cardiac index greater than 2.The latter is available as an online preoperative surgical risk calculator that includes a history of myocardial infarction, a history of cerebrovascular accident, a history of congestive heart failure, diabetes mellitus requiring preoperative insulin and renal impairment (creatinine >176.8 µmol/L or 2 mg/dL). The European Society of Cardiology (ESC) Working Group on Thrombosis classified the risk of thrombosis into five categories according to the timing of acute coronary syndrome and percutaneous coronary intervention, type of coronary stents and presence of other cardiac risk factors.Our Task Force has simplified the thrombotic risk into three categories (very high, high, moderate to low) to guide the management of antithrombotic therapy for elective endoscopic procedures with high bleeding risk. ## Thrombotic risk with interruption of antithrombotics When to stop and resume antiplatelet drugs? If endoscopic procedures with high bleeding risks are deemed necessary, we recommend withholding P2Y12 receptor inhibitor for 5-7 days before the procedure while aspirin should be continued. In a large US registry, the median time to stent thrombosis can be as short as 7 days when both antiplatelet drugs are withheld whereas the median time is prolonged to 122 days when one antiplatelet drug is continued.Among patients without coronary stents the risk of myocardial infarction or stroke depends on the indication of antiplatelet therapy. The thrombotic risk without antiplatelet therapy is 10-fold higher in secondary prevention than in primary prevention (3.11% vs 0.34% yearly).Given the high bleeding risks associated with ultra-high risk procedures, our Task Force recommends withholding all antiplatelet agents provided that the perceived benefits of the procedure outweigh the patient's thrombotic risk. The total duration of interruption should not exceed 7 days due to a high risk of coronary stent thrombosis. Decisions have to be individualised after liaison with cardiologists or neurologists. We recommend discontinuing a P2Y12 receptor inhibitorwith the exception of ticagrelor which has a shorter duration of action-5 days before high-risk procedures while continuing aspirin based on the following expert opinion: (1) the effect of non-aspirin antiplatelet drugs will last for up to 5 days (about 3 days for ticagrelor) after taking the last dose; and (2) P2Y12 receptor inhibitor is more potent than aspirin, thereby carrying a high bleeding risk. In contrast, the ASGE guidelines recommend withholding P2Y12 receptor inhibitors for at least 5-7 days before high-risk procedures.We are concerned about the thrombotic risk of prolonged discontinuation of these antiplatelet drugs, especially in patients with DES. There are no data on the optimal timing of resuming antiplatelet drugs after elective endoscopic procedures. In patients who are at risk of coronary stent thrombosis, our Task Force recommends resumption of P2Y12 receptor inhibitor once adequate haemostasis has been achieved. ## Interruption of anticoagulants The BSG-ESGE Guidelines 3 stratify the risk of thromboembolism into two groups (low risk and high risk) whereas the ASGE Guidelines 1 stratify patients into three groups according to the Guidelines estimated annual risk of thromboembolism without anticoagulation (low risk (<5%), medium risk (5-10%) and high risk (>10%)). Our Task Force has made recommendations on the use of heparin bridging with interruption of warfarin (box 2). ## Atrial fibrillation For patients who have non-valvular atrial fibrillation, the risk of thromboembolism can be estimated using the CHA 2 DS 2 -VASc score. The total score ranges from 0 to 9: congestive cardiac failure (1 point), hypertension (1 point), age ≥75 (2 points), diabetes (1 point), stroke (2 points), vascular disease (prior myocardial infarction, peripheral artery disease, aortic plaque; 1 point), age 65-75 years (1 point), female sex (1 point). Patients with a score of ≥2 are prescribed anticoagulants (estimated annual risk of thromboembolism >2.2%). In the BSG-ESGE Guidelines, 3 low-risk patients include all patients with non-valvular atrial fibrillation but their CHA 2 DS 2 -VASc scores are not considered. Only those with atrial fibrillation associated with mitral stenosis or prosthetic heart valves are considered as high risk. ## Mechanical heart valves The risk of thromboembolism in patients with mechanical heart valves depends on the type, number and position of the valve and the presence of underlying heart failure or atrial fibrillation.Our Task Force recommends heparin bridging for patients with a metallic mitral valve alone or a metallic valve with atrial fibrillation (box 2). ## Venous thromboembolism (vte) The risk thromboembolism after VTE depends on the timing of VTE. Our Task Force recommends heparin bridging in patients with VTE within 3 months (box 2). However, no studies have assessed the risk of thromboembolism in high-risk patients without bridging therapy. ## Thrombophilia syndromes Some patients are predisposed to venous thrombosis. There is a wide spectrum of thrombophilia syndromes ranging from isolated laboratory abnormalities with a low thrombotic risk (eg, Factor V Leiden and the prothrombin mutation F2G20210A) to high-risk conditions such as antiphospholipid syndromes, deficiencies of antithrombin, protein C or protein S (box 2). ## When to stop and resume warfarin? There is very little evidence to guide when to stop warfarin prior to endoscopy. Recommendations are largely based on expert opinion. Our Task Force recommends stopping warfarin 5 days before endoscopy. We recommend resuming warfarin once adequate haemostasis has been achieved. ## Bridging therapy Bridging therapy is provided to those patients at high risk of thromboembolism (box 2). To date, only one large-scale randomised trial of patients with atrial fibrillation on warfarin undergoing an elective invasive procedure found that no heparin bridging was not inferior to bridging for prevention of thromboembolism. There was a significantly higher risk of bleeding in the bridging group compared with the no bridging group (1.3% vs 3.2%, P=0.005). However, the findings cannot be extrapolated to patients with a high thromboembolic risk as only a small proportion of patients had mitral stenosis or CHA2DS2-VASc score >5.Based on the above evidence, our Task Force recommends heparin bridging for non-valvular atrial fibrillation if the CHA 2 DS 2 -VASc score is >5. In contrast, the ASGE Guidelines recommend heparin bridging if the CHA 2 DS 2 -VASc score is >2.The choice of heparin formulations and the optimal timing of bridging therapy remain uncertain. A large prospective non-randomised study showed there was no difference in adverse events with bridging therapy using unfractionated heparin or LMWH in patients with mechanical heart valves.Observational studies on surgical patients showed no difference in risk of bleeding between the last dose of LMWH being given at 12 hours compared with that of 24 hours before surgery. Given the fact that heparin bridging is associated with a significantly higher risk of bleeding than no bridging, our Task Force recommends heparin bridging when INR falls <2 before high-risk procedures. There are no direct studies investigating the timing for re-starting heparin after endoscopy. A few observational studies support re-initiation of warfarin within 24 hours. It is commonly agreed among professional societies that heparin should be resumed once haemostasis is secured. There is no evidence to support the use of bridging therapy in patients receiving DOACs. Bridging therapy is indicated in patients with very high thrombotic risk such as mechanical heart valves but DOACs are not indicated for such patients. Furthermore, interruption of DOACs during the peri-endoscopic period is brief because DOACs have a short half-life and rapid onset of action. ## When to stop and resume doacs? No studies are available to guide the optimal time for discontinuation or resumption of DOACs for endoscopic procedures. Currently available guidelines are conflicting. The ASGE Guidelines recommend continuation of DOACs for low-risk procedures and discontinuing anticoagulation according to the pharmacokinetic properties of individual DOACs for high-risk procedures.The BSG-ESGE Guidelines suggest omitting the morning dose of DOACs on the day of low-risk procedures and recommend the last dose of DOACs be taken at least 48 hours before high-risk procedures.Given the minimal bleeding risk associated with diagnostic endoscopy and mucosal biopsy, our Task Force does not suggest omitting DOACs before low-risk procedures. For high-risk procedures, our recommendation depends on the choice of DOAC (dabigatran vs other DOACs) and the patient's creatinine clearance. For patients on dabigatran, the last dose should be taken 48 hours before the procedure if the renal function is normal (CrCl >80 mL/min). Lengthening the period of discontinuation is required in patients with renal impairment because 80% of dabigatran metabolite is excreted by the kidneys. For patients on other DOACs (apixaban, rivaroxaban and edoxaban), we recommend the last dose should be taken 48 hours before the procedure provided that CrCl is >15 mL/min.Since DOACs have short half-lives and rapid onset of action, heparin bridging is not recommended. We recommend early resumption of DOACs after haemostasis has been achieved.	None	https://gut.bmj.com/content/gutjnl/67/3/405.full.pdf	This Guideline is a joint official statement of the Asian Pacific Association of Gastroenterology (APAGE) and the Asian Pacific Society for Digestive Endoscopy (APSDE). It was developed in response to the increasing use of antithrombotic agents (antiplatelet agents and anticoagulants) in patients undergoing gastrointestinal (GI) endoscopy in Asia. After reviewing current practice guidelines in Europe and the USA, the joint committee identified unmet needs, noticed inconsistencies, raised doubts about certain recommendations and recognised significant discrepancies in clinical practice between different regions. We developed this joint official statement based on a systematic review of the literature, critical appraisal of existing guidelines and expert consensus using a two-stage modified Delphi process. This joint APAGE-APSDE Practice Guideline is intended to be an educational tool that assists clinicians in improving care for patients on antithrombotics who require emergency or elective GI endoscopy in the Asian Pacific region.
71e321c9afc7d55de5e094f70e6dd3838ec38932	pubmed	Evaluation of an evidence-based guidance on the reduction of physical restraints in nursing homes: a cluster-randomised controlled trial [ISRCTN34974819]	Evaluation of an evidence-based guidance on the reduction of physical restraints in nursing homes: a cluster-randomised controlled trial [ISRCTN34974819] Background: Physical restraints are regularly applied in German nursing homes. Their frequency varies substantially between centres. Beneficial effects of physical restraints have not been proven, however, observational studies and case reports suggest various adverse effects. We developed an evidence-based guidance on this topic. The present study evaluates the clinical efficacy and safety of an intervention programme based on this guidance aimed to reduce physical restraints and minimise centre variations.Methods/Design: Cluster-randomised controlled trial with nursing homes randomised either to the intervention group or to the control group with standard information. The intervention comprises a structured information programme for nursing staff, information materials for legal guardians and residents' relatives and a one-day training workshop for nominated nurses. A total of 36 nursing home clusters including approximately 3000 residents will be recruited. Each cluster has to fulfil the inclusion criteria of at least 20% prevalence of physical restraints at baseline. The primary endpoint is the number of residents with at least one physical restraint at six months. Secondary outcome measures are the number of falls and fall-related fractures. # Background The use of physical restraints with older people has been reported as common practice in numerous countries [bib_ref] Differences in period prevalence of the use of physical restraints in elderly..., Vries [/bib_ref]. International studies documented prevalence rates between 2% and 70% [bib_ref] Why do we use physical restraints in the elderly?, Hamers [/bib_ref]. Our epidemiological study in 30 German nursing homes with approximately 2400 resi-dents confirms that physical restraints are applied as routine care measure as indicated by a prevalence of 26% (95% confidence interval 21 to 31). Centre differences were pronounced with a range of 4% to 59% [bib_ref] Restraint use among nursing home residents: cross-sectional study and prospective cohort study, Meyer [/bib_ref]. A recent study comparing prevalences between five different countries confirms our findings [bib_ref] Use of physical restraints and antipsychotic medications in nursing homes: a cross-national..., Feng [/bib_ref]. The use of physical restraints is widely justified by nurses as safety measure, primarily for the prevention of falls [bib_ref] Use of physical restraints with cognitively impaired nursing home residents, Hamers [/bib_ref] [bib_ref] Minimizing the use of restrictive devices in dementia patients at risk of..., Capezuti [/bib_ref] [bib_ref] Perceptions regarding the use of physical restraints with elderly persons: comparison of..., Werner [/bib_ref]. Control of disruptive behaviour, safe use of medical devices and other reasons are also frequently reported [bib_ref] Why do we use physical restraints in the elderly?, Hamers [/bib_ref]. According to international evidence it is questionable, whether physical restraints are effective and safe devices [bib_ref] The effect of bedrails on falls and injury: a systematic review of..., Healey [/bib_ref]. Observational studies rather suggest an association with adverse effects like physical harm, for example serious injuries and increased mortality. Also, social and psychosocial adverse events like reduced psychological wellbeing or decreased mobility have been reported to be associated with physical restraints [bib_ref] Physical restraint initiation in nursing homes and subsequent resident health, Engberg [/bib_ref]. In the past decades different efforts have been undertaken to reduce the use of physical restraints with older people, starting in the US in the 1980s [bib_ref] Physical restraint in nursing homes: a review of the literature since the..., Castle [/bib_ref]. Recently, several trials have been conducted mainly evaluating multi-faceted interventions for the reduction of physical restraints, consisting of different components like educational sessions for nurses or information about alternatives [bib_ref] Why is it so hard for nurses to take off the restraints?, Lai [/bib_ref] [bib_ref] The effect of staff training on the use of restraint in dementia:..., Testad [/bib_ref] [bib_ref] Consequences of an intervention to reduce restrictive side rail use in nursing..., Capezuti [/bib_ref] [bib_ref] Preventing the use of physical restraints on residents newly admitted to psychogeriatric..., Huizing [/bib_ref] [bib_ref] Short-term effects of an educational intervention on physical restraint use: a cluster..., Huizing [/bib_ref]. The studies did not consistently result in clinically meaningful minimisation of restraints. A Cochrane review on the efficacy of interventions to reduce physical restraints in longterm geriatric care is in preparation. In view of the substantial prevalences of physical restraints in German nursing homes an effective restraint minimisation approach is urgently required. The pronounced centre variations indicate that standard care does not necessarily imply physical restraints. An evidencebased guidance may be a powerful tool to deliver restraint-free care in German nursing homes and to overcome practice variations [bib_ref] Clinical guidelines: potential benefits, limitations, and harms of clinical guidelines, Woolf [/bib_ref]. A systematic search did not reveal publicly available evidence-based guidelines for the avoidance of physical restraints in nursing homes [bib_ref] Analysis of international guidelines and standards on physical restraint use in nursing..., Möhler [/bib_ref]. Thus, we developed a guidance and aim to investigate the efficacy of an intervention programme based on this guidance within a randomised controlled trial. # Methods ## Study design and setting The study is a cluster-randomised controlled trial over six months with nursing homes randomised either to the intervention group or to the control group receiving standard information. # Ethical considerations The protocol has been approved by the ethics committee of the Hamburg chamber of physicians and the regional data protection office as well as by the ethics committee of the University of Witten/Herdecke. Written informed consent will be obtained from the heads of the participating nursing homes. As requested by the ethics committees and the data protection office, investigators have no direct access to residents' data. All resident-related data will be pseudonymised before given to investigators. During direct observation to assess restraint prevalence, investigators will always be accompanied by a member of the nursing staff. Investigators will enter residents' rooms only after the staff member had asked the resident, if he or she agreed to be visited. ## Study intervention The methodological framework of the guidance development has been based on internationally suggested approaches like a multidisciplinary guideline development group, methodological training of group members, methodologically sound development of recommendations, an inclusion of resident representatives and relevant stakeholders, an external review and critical appraisal [bib_ref] Development and validation of an international appraisal instrument for assessing the quality..., Cluzeau [/bib_ref]. The methodological framework has been published in advance. The guidance comprises 24 statements on relevant interventions to avoid physical restraints. Taking into account the poor evidence for most interventions, the group mostly made weak recommendations or felt unable to provide any recommendation. A single strong recommendation was made for "educational programmes". Based on the guidance, an intervention programme has been developed targeting the avoidance of physical restraints. The programme consists of structured information for nursing staff, provision of written information material, and an intensive one-day training workshop for nominated nurses who will be responsible for all issues concerning physical restraints within the centres. The development of the intervention followed the theory of planned behaviour [bib_ref] Adopting health behavior change theory throughout the clinical practice guideline process, Ceccato [/bib_ref]. A structured single information session of approximately 90 minutes will be provided for each cluster of the intervention group, so that at best all nurses will be informed. The information programme intends to sensitise nurses about the matter of physical restraints and the message of the guidance by addressing their subjective attitudes and experiences. By means of interactive training sequences nurses are motivated to discuss and develop alternative approaches. As supporting materials they receive a short version of the guidance and reminders like posters, pens, mugs, and note pads. Information materials like brochures and flyers for relatives and legal guardians will be provided. The nominated nurses of each cluster will attend a one-day intensive training workshop concerning their role and tasks within the intervention's implementation process. In-depth information and education about the avoidance of physical restraints will be provided. A declaration will be signed by the representatives of the participating clusters which should be posted in the nursing homes' foyers. Nurses in charge will be announced in this context as contact persons for residents, relatives, physicians, and legal guardians. Representatives of the control group clusters will receive personal and written brief standard information on legal and scientific evidence on physical restraints and alternatives aimed to avoid measures. No further intervention will be carried out in the control group. ## Identification of clusters and participants Recruitment of nursing homes takes place in the city of Hamburg, Northern Germany, and in surrounding cities of Witten/Herdecke, West Germany. Each nursing home has to fulfil the inclusion criteria of at least 20% selfreported prevalence of physical restraints. A cluster is defined as a nursing home by itself or an independently working unit of a large nursing home, including all residents. Descriptive data on the cluster, participating residents and prevalence data on physical restraint and psychotropic medication will be collected by a nurse supported by an external investigator. [fig_ref] Figure 1: Summary of trial design [/fig_ref] shows the summary of the trial design. ## Randomisation Computer generated randomisation lists will be used for allocation of clusters in blocks of four, six and eight nursing homes. Randomisation will be stratified by region (Hamburg and Witten/Herdecke). Clusters will be allocated after collection of baseline and prevalence data by an external researcher, not involved in the study. The external researcher informs each cluster about its group assignment. Statistical analysis will be conducted after six months at the end of the study to avoid an influence of the investigators by interim results. ## Clinical outcome measures The primary outcome is the number of residents with at least one physical restraint after six months of follow-up. Physical restraints are defined as any device, material or equipment attached to or near a person's body, which cannot be controlled easily or removed by the person and which deliberately prevents or is deliberately intended to prevent a person's free body movement to a position of choice [bib_ref] Patient injury and physical restraint devices: a systematic review, Evans [/bib_ref]. At first, characteristics of nursing homes and residents, the prevalence of physical restraints and psychotropic medication will be collected. Data collection instruments used in a previous epidemiological study will be adapted to this study's requirements [bib_ref] Restraint use among nursing home residents: cross-sectional study and prospective cohort study, Meyer [/bib_ref]. Each participating resident will get a code number. Prevalence data of physical restraints will be obtained by direct observation on three occasions on one day (morning, noon, evening) by trained external investigators. Data will be collected before randomisation, after three and after six months. The external investigators collecting the data will be blinded to allocation of nursing homes. The populations assessed at the three data collection time points will slightly vary, since some residents will have terminated the study period ahead of time and other residents will have been admitted between two data collections. For residents admitted to the nursing home between two data collection dates, an abbreviated baseline description will be performed. Reasons for early study termination will be assessed. Secondary outcome measures are the number of falls and fall-related fractures. Nursing staff will document fall events within their inhouse documentation system. If no documentation sheet for fall events exists, it will be provided by the researchers. Cost parameters on the expenses spent for the implementation of the intervention will be collected alongside the trial. ## Process evaluation Since we aim to implement a complex intervention programme intervening in a complex system, more insight into nurses' comprehension of the restraint reduction approach, the dissemination and delivery of the intervention is needed. Collection of process data will allow us to draw conclusions about potential barriers and facilitators of the intervention [bib_ref] Process evaluation in randomised controlled trials of complex interventions, Oakley [/bib_ref]. Nurses' knowledge and self-efficacy will be determined at the end of the structured single information session to assess proceeding of the new message. During follow-up, the nominated nurses will be contacted monthly during the first three months by telephone in order to explore barriers and facilitators of the intervention's implementation. Between the three and six month data collection visits, in all intervention group clusters one randomly selected staff nurse will be personally interviewed, whether the restraint reduction approach has been recognised and how it has been perceived. ## Sample size calculation We expect a significant reduction of the prevalence of physical restraints from 33% to 21%. Assuming comparable conditions as in the epidemiological study [bib_ref] Restraint use among nursing home residents: cross-sectional study and prospective cohort study, Meyer [/bib_ref] , a sample size of 2.824 residents in 34 nursing homes with a mean cluster size of 83 residents is required. Presuming a drop-out rate of 5% nursing homes and 2% residents, 36 nursing homes with a mean cluster size of 85 residents need to be recruited. It is planned to recruit 30 nursing homes in Hamburg and six in Witten/Herdecke. The assumed prevalence of 33% in the control group is consistent with the cluster-adjusted estimation of the subpopulation of all nursing homes of the epidemiological study with a prevalence of at least 20% [bib_ref] Restraint use among nursing home residents: cross-sectional study and prospective cohort study, Meyer [/bib_ref]. An intra-class correlation coefficient of ICCC = 0.034 and a design factor of DF = 5.0 were estimated for the primary outcome of physical restraint. Statistical significance is defined as α = 0.05, power is defined as 90%. # Statistical analysis The analysis population consists of participants seen at least once during the prevalence data collection at six months. The main outcome is the number of residents with at least one physical restraint after six months and will be analysed by using a two-sided cluster-adjusted chisquare test at a level of significance of α = 0.05 [bib_ref] Process evaluation in randomised controlled trials of complex interventions, Oakley [/bib_ref]. Baseline data of the three measuring points will be described for the control and intervention group. Secondary outcome measures i.e. incidences of falls and fall-related fractures will be analysed by using cluster-adjusted Poissonregression models, assuming Poisson-distributions. For the data interpretation the partial data dependency is to be taken into account. The incidence analysis refers to residents of two observation periods: those entering the study at the beginning and after three months of followup. ## Summary of trial design ## Time plan The information programme has been piloted in four nursing homes, who will not participate in the trial. The complete intervention will be piloted in the first two nursing homes allocated to the intervention group. If possible, these will further participate in the trial. Recruitment of clusters started in March 2009 and is expected to be completed in May 2009. # Discussion In case the intervention will not succeed, the randomised controlled trial will be followed by a three-month prepost-study investigating an optimised intervention programme delivered within the control group. Statistical analysis will be planned before starting this study. Results will only be interpreted as explorative. [fig] Figure 1: Summary of trial design. [/fig]	None	https://bmcgeriatr.biomedcentral.com/track/pdf/10.1186/1471-2318-9-42	None
04544dca5579292f0c20c1c517f8245036db23c1	pubmed	Suspected Anaphylactic Reactions Associated with Anaesthesia	Suspected Anaphylactic Reactions Associated with Anaesthesia ## Summary (1) The AAGBI has published guidance on management of anaphylaxis during anaesthesia in . This 2008 update was necessary to disseminate new information. (2) Death or permanent disability from anaphylaxis in anaesthesia may be avoidable if the reaction is recognised early and managed optimally. (3) Recognition of anaphylaxis during anaesthesia is usually delayed because key features such as hypotension and bronchospasm more commonly have a different cause. (4) Initial management of anaphylaxis should follow the ABC approach. Adrenaline (epinephrine) is the most effective drug in anaphylaxis and should be given as early as possible. (5) If anaphylaxis is suspected during anaesthesia, it is the anaesthetist's responsibility to ensure the patient is referred for investigation. (6) Serum mast cell tryptase levels may help the retrospective diagnosis of anaphylaxis: appropriate blood samples should be sent for analysis. (7) Specialist (allergist) knowledge is needed to interpret investigations for anaesthetic anaphylaxis, including sensitivity and specificity of each test used. Specialist (anaesthetist) knowledge is needed to recognise possible non-allergic causes for the 'reaction'. Optimal investigation of suspected reactions is therefore more likely with the collaboration of both specialties. (8) Details of specialist centres for the investigation of suspected anaphylaxis during anaesthesia may be found on the AAGBI website http://www.aagbi. org. (9) Cases of anaphylaxis occurring during anaesthesia should be reported to the Medicines Control Agency and the AAGBI National Anaesthetic Anaphylaxis Database. Reports are more valuable if the diagnosis is recorded following specialist investigation of the reaction. These guidelines apply only to suspected anaphylactic reactions associated with anaesthesia and it is presupposed that the patient is in the care of a trained anaesthetist. ## Objectives (1) To clarify the definitions used in allergy and anaphylaxis. (2) To review the epidemiology of anaesthesia-related anaphylaxis. (3) To provide advice on the recognition of anaesthetic anaphylaxis. (4) To make recommendations on the immediate management and initial investigation of suspected anaesthetic anaphylaxis. (5) To make recommendations concerning the further investigation of suspected anaesthetic anaphylaxis. [bib_ref] Increased risk for anaphylactoid reaction from contrast media in patients on beta-adrenergic..., Lang [/bib_ref] To assist anaesthetists in obtaining access to a specialist centre for comprehensive investigation of suspected anaesthetic anaphylaxis. [bib_ref] Rocuronium and anaphylaxisa statistical challenge, Laake [/bib_ref] To assist anaesthetists to provide appropriate information to the specialist centre. [bib_ref] Prevalence of IgE antibodies to morphine. Relation to the high and low..., Florvaag [/bib_ref] To make recommendations about the reporting and collection of data on anaesthetic anaphylaxis in Great Britain and Ireland. ## Definitions The term 'anaphylaxis' has been used for all types of acute life-threatening illness triggered by abnormal sensitivity (hypersensitivity) to a trigger agent, and for apparently spontaneous attacks with similar features (idiopathic anaphylaxis). This has made it difficult to define. The EAACI Nomenclature Committee proposed the following broad definition [1]: Anaphylaxis is a severe, life-threatening, generalized or systemic hypersensitivity reaction. Minor, localised or non-systemic reactions are outside the definition of anaphylaxis. Anaphylaxis may be divided into 'allergic anaphylaxis' and 'non-allergic anaphylaxis'. The clinical features of allergic anaphylaxis and nonallergic anaphylaxis may be identical. The EAACI committee proposed the term 'allergic anaphylaxis' should be used only when the reaction is mediated by an immunological mechanism (such as IgE, IgG, or complement activation by immune complexes). An anaphylactic reaction mediated by IgE antibodies, such as to amoxicillin, is referred to as 'IgE-mediated allergic anaphylaxis'. The term 'anaphylactoid' reaction had been introduced for non-IgE-mediated anaphylactic reactions but the EAACI committee has recommended this term should no longer be used. This proposal has not been universally accepted. An authoritative recent American practice parameter [2] states: 'Anaphylaxis is defined … as a condition caused by an IgE-mediated reaction . Anaphylactoid reactions are defined as those reactions that produce the same clinical picture as anaphylaxis but are not IgE mediated.' In these guidelines we will follow the European (EAACI) nomenclature. Anaphylaxis is not a homogeneous process: the pathways, mediators, time course and response to treatment depend on the trigger agent, its route and rate of administration, the nature of the patient's hypersensitivity and the state of health of the patient, including incidental pathology such as respiratory or cardiovascular disease and the effects of concomitant medication such as b-blockers and ACE inhibitors. Although anaphylaxis commonly involves respiratory, cutaneous and circulatory changes, variations such as shock with gastrointestinal disturbance or shock alone are possible. Alternatively, reactions may be fatal without significant shock except as the terminal event following respiratory arrest. Angioedema and urticaria may be features of anaphylaxis but commonly result from mechanisms other than anaphylaxis. Intravascular volume redistribution is an important component of anaphylactic shock. Cardiac output may be decreased as a result of reduced coronary artery perfusion pressure as well as impaired venous return. Local release of mediators may cause coronary artery spasm and there may be features of acute left or right ventricular failure. Myocardial ischaemia with ECG changes is expected within minutes of anaphylactic shock becoming severe. Asphyxia may be due to upper airway occlusion caused by angioedema, or bronchospasm with mucus plugging of the lower airways; the latter most commonly occurs in patients taking daily treatment for asthma. Both these processes may occur simultaneously in patients reacting to foods, latex, b-lactam antibiotics or aspirin. Anaphylaxis usually resolves in 2-8 h but secondary pathology arising from the reaction or its treatment may prolong this. Resolution is complete except when cerebral hypoxia at the peak of the reaction has caused significant brain damage, or when disordered clotting leads to bleeding. ## Epidemiology ## Geographical variation Most reports on anaesthesia-related anaphylaxis originate from France, Australia, New Zealand and the United Kingdom. Other case series have been described from Scandinavia and the USA. The true incidence and their associated morbidity and mortality remain poorly defined. Both the accuracy and completeness of reporting is not optimal. 10% of anaesthesia-related reactions reported to the UK Medicines Control Agency (MCA) were fatal. These data should be interpreted with caution because it is likely that many less-severe reactions are not reported . Reactions that are accepted as side-effects of certain drugs, for instance, histaminergic reactions due to atracurium and mivacurium, may be under-reported. During a time period of over 6 years only 361 reactions were reported to the MCA. In a 2-year period 789 reactions were reported in France in a comparable population where there is a well-established culture of reporting anaesthesiarelated reactions . Based on studies in Australia and France, the incidence of anaphylaxis during anaesthesia has been estimated at between 1 in 10 000 and 20 000The true incidence of anaphylaxis during anaesthesia in the UK is not known. By extrapolating the French and Australian data to the UK, it is estimated that there are approximately 500 severe reactions in the UK each year. Anaphylactic reactions are more common when drugs are given intravenously. In one large study an immune basis was demonstrated in two-thirds of patients investigated for anaphylaxis [2]: the remainder comprised non-allergic anaphylaxis and mechanisms other than anaphylaxis. The tests currently available for the diagnosis of anaesthetic anaphylaxis are imperfect. Skin tests and blood tests have limited sensitivity and specificity and their positive and negative predictive value varies between drugs. Patient characteristics (age, sex, ethnicity, smoking etc) Neuromuscular blocking drugs and latex appear to cause anaphylaxis more commonly in female patients. There appears to be a connection between smoking and antibiotic anaphylaxis, possibly because smokers may become sensitised by exposure to repeated courses of antibiotics for respiratory tract infections. Individuals with a history of atopy, asthma or allergy to some foods appear to be at increased risk of latex allergy but not anaphylaxis to neuromuscular blocking drugs or antibiotics [bib_ref] Anaphylaxis during anaesthesia. Results of a two-year survey in France, Laxenaire [/bib_ref]. Anaphylaxis associated with radiographic contrast media appears to be associated with atopy [bib_ref] Increased risk for anaphylactoid reaction from contrast media in patients on beta-adrenergic..., Lang [/bib_ref]. Patients with asthma or taking b-blocking drugs may suffer a more severe reaction. Some of these reactions may be refractory to conventional therapy. ## Possible environmental sensitising agents The prevalence of anaphylactic reactions to neuromuscular blocking agents (NMBAs) is reported to be at least six times more frequent in some countries [bib_ref] Rocuronium and anaphylaxisa statistical challenge, Laake [/bib_ref] [bib_ref] Prevalence of IgE antibodies to morphine. Relation to the high and low..., Florvaag [/bib_ref] : it is considerably more common in Norway than in Sweden. Quaternary ammonium ions (QAI) are proposed to be the allergenic epitopes in NMBAs. Common environmental chemicals such as toothpastes, washing detergents, shampoos, and cough medicines share these allergenic epitopes with the NMBAs [bib_ref] Prevalence of IgE antibodies to morphine. Relation to the high and low..., Florvaag [/bib_ref]. Numerous possibilities exist for a predisposed individual to become sensitised to QAIs and thus be at risk of developing anaphylaxis to NMBAs during anaesthesia. In a recent Scandinavian survey, use of certain cough medicines was found to be the only significant difference in environmental chemical exposure [bib_ref] Prevalence of IgE antibodies to morphine. Relation to the high and low..., Florvaag [/bib_ref]. In Norway, but not Sweden, cough syrups containing pholcodine are available without prescription. IgE-antibodies to pholcodine were seen in 6% of a general population (blood donors) in Norway but not in Sweden (0%). ## Muscle relaxants Approximately 60% of cases of anaesthesia-related anaphylaxis are thought on the basis of skin tests to be due to Suspected anaphylactic reactions associated with anaesthesia . neuromuscular blocking agents. Mivacurium and atracurium are associated with non-allergic anaphylaxis in which release of mediators (notably histamine) from mast cells exactly imitates allergic anaphylaxis. Cisatracurium, although sharing a benzylisoquinolinium structure, is not associated with non-allergic anaphylaxis, although several cases of allergic anaphylaxis have been reported. It is generally accepted that succinylcholine is the NMBA most likely to be associated with allergic anaphylaxis, although rocuronium has been implicated in a similar number of cases in France. The prevalence of sensitisation to NMBAs in the community is higher than the incidence of reactions would suggest. In one study, approaching 10% of the general population exhibited skin reactivity to NMBAs, an incidence that far exceeds the incidence of anaphylaxis on administration of these drugs during anaesthesia [bib_ref] Prevalence of muscle relaxant sensitivity in a general population: implications for a..., Porri [/bib_ref]. A previous history of specific drug exposure is not necessary, particularly for neuromuscular blocking drugs. A history of previous exposure is found in fewer than 50% of patients who are allergic to neuromuscular blocking drugs. Conversely, an uneventful exposure may sensitise an individual to subsequent administration of the drug. Cross-sensitivity between different NMBAs is relatively common, probably because they share a quaternary ammonium epitope. If anaphylaxis to an NMBA is suspected, the patient should undergo skin prick testing with all the NMBAs in current use. If a patient demonstrates a positive skin prick test (SPT) to an NMBA, the patient should be warned against future exposure to all NMBAs if possible. If it is mandatory to use an NMBA during anaesthesia in the future, it would seem appropriate to permit the use of an NMBA which has a negative skin test, accepting that a negative skin test does not guarantee that anaphylaxis will not occur. The apparent excess of cases of anaphylaxis to rocuronium in some countries should be interpreted with caution until much more data have been collected. Large sample sizes are needed to estimate the true incidence: if the true incidence is 1 in 5000, a sample size of 7 million would be needed to have a 95% chance of being within 5% of the true value [bib_ref] Anaphylaxis during anaesthesia: current aspects of diagnosis and prevention, Fisher [/bib_ref]. There is a need for further epidemiological studies. ## Latex Latex hypersensitivity is the second most common cause of anaesthesia-related anaphylaxis in many studies (up to 20% of cases). However, the incidence of anaphylaxis to latex is considerably less than would be suggested by the prevalence of positive skin tests or positive IgE tests. It appears that the incidence may be waning, at least in some countries; possibly as a result of a change or decline in the use of latex gloves. Certain patient groups are more susceptible to latex anaphylaxis (see Appendix II). ## Antibiotics Approximately 15% of anaesthesia-related anaphylactic episodes are due to antibiotics. This proportion has increased in recent years and may merely mirror increased exposure to antibiotics in the community [bib_ref] Allergy to anesthetics, Moss [/bib_ref]. The pre-operative history is important. Although only a minority of patients who report allergy to antibiotics have a true allergy, the consequence of anaphylaxis to intravenous antibiotics may be catastrophic, and selfreporting should be taken seriously. Skin testing is only approximately 60% predictive of clinical hypersensitivity. Penicillins and cephalosporins which share the b-lactam ring are responsible for approximately 70% of antibioticinduced anaphylaxis. Many antibiotics possess a b-lactam ring: [formula] - Benzylpenicillin, phenoxymethylpenicillin - Flucloxacillin, temocillin - Amoxicillin, ampicillin, co-amoxiclav - Co-fluampicil - Piperacillin, ticarcillin, - Pivmecillinam HCl - Cephalosporins - Aztreonam - Ertapenem, imipenem with cilastatin, meropenem [/formula] The structure of the side chains attached to the b-lactam ring is also important in determining the response of the immune system. First generation cephalosporins and cefamandole share a similar side chain with penicillin and amoxicillin. A recent meta-analysis suggested that patients who are allergic to penicillin or amoxicillin have a higher incidence of allergic reactions to first generation cephalosporins and cefamandole, but not other cephalosporins [bib_ref] Safe use of selected cephalosporins in penicillin-allergic patients: a meta-analysis, Pichichero [/bib_ref]. The issue is complicated because the classification of cephalosporins relates to their antimicrobial activity rather than their chemical structure. Third generation cephalosporins ## First generation cephalosporins [formula] - Cefalexin (cephalexin)* - Cephaloridine - Cephalothin - Cefazolin - Cefradine (cephradine)* - Cefadroxil * Second generation cephalosporins - Cefaclor* - Cefamandole - Cefuroxime- Cefixime - Cefotaxime* - Cefpodoxime* - Ceftazidime* - Ceftriaxone* Fourth generation cephalosporins - Cefepime - Cefpirome *Listed in the British National Formulary. [/formula] Local anaesthetics Anaphylactic reactions to local anaesthetic drugs are very uncommon. Local anaesthetic esters are more likely than amides to provoke a Type lV allergic reaction. Preservatives such as methyl-paraben or metabisulphites may be responsible in some cases. It has been suggested that inadvertent intravascular injection of a local anaesthetic or the systemic absorption of adrenaline may be responsible for many of the reported reactions. Reactions occurring in the dental chair may also be associated with idiopathic angioedema or latex allergy. ## Opioids Opioids are an uncommon cause of anaesthesia-related anaphylaxis. Diagnosis is difficult and the true incidence is unknown. Morphine, pethidine and codeine are wellknown to cause non-specific histamine release which precludes diagnostic skin testing. The diagnosis of opioid anaphylaxis often rests on a careful history and the exclusion of other possibilities. Challenge testing may be appropriate in some cases but may be performed only in specialist centres. ## Anaesthetic induction agents Anaphylaxis to propofol is very uncommon. The antigenic determinant may be the isopropyl groups. It has been stated that patients with egg allergy or soy allergy should avoid propofol but there is no strongly-supportive evidence. It has been suggested that propofol anaphylaxis is more likely if lignocaine is added to reduce pain on injection: there is no evidence to support this suggestion. Anaphylaxis to thiopental has become extremely uncommon, probably reflecting the decline in its use. A small number of cases of midazolam anaphylaxis have been reported. Non-steroidal anti-inflammatory drugs (NSAIDs) Several mechanisms may be responsible for reactions to NSAIDs. Inhibition of the PGE 2 pathway leads to excessive leukotriene synthesis and subsequent mediator release, causing urticaria or bronchospasm. IgE-mediated reactions may also occur in relation to some NSAIDs. Fatal anaphylaxis has been described after oral administration of NSAIDs. ## Halogenated volatile anaesthetics There are no published reports of anaphylaxis to halogenated volatile anaesthetics. The rare fulminant form of hepatitis associated with halothane has an immune basis which is unrelated to anaphylaxis. ## Colloids Intravenous colloids are responsible for approximately 4% of all peri-operative anaphylactic reactions. In one study, gelatin solutions were responsible for 95% of the intravenous colloid reactions. It has been stated that the incidence may be greater with the urea-linked gelatins compared with the modified fluid gelatins. Intravenous gelatin solutions should be avoided in patients with a history of allergy to gelatin-containing vaccines. Anaphylaxis to intravenous dextrans has been reported, with an incidence similar to the modified fluid gelatins. Anaphylaxis to hydroxyethyl-starch is rare. ## Antiseptics and disinfectants Reactions to chlorhexidine have come into greater prominence in recent years. There appears to be a significant difference in incidence between countries. Reactions range from contact dermatitis to life-threatening anaphylaxis. Anaphylaxis has occurred when chlorhexidine was used as an antiseptic for urological and gynaecological procedures as well as insertion of central venous and epidural catheters. The chlorhexidine coating of certain central venous catheters has been implicated in such reactions. It is prudent to allow skin disinfectant to completely dry before beginning an invasive procedure. Anaphylaxis to polyvinylpyrrholidine as povidone-iodine or as an excipient for oral medicines occurs but is rare. ## Miscellaneous agents Many agents to which patients may be exposed during anaesthesia may be associated with anaphylaxis, including aprotinin, protamine, heparins, radiological contrast material, dyes and oxytocin. Anaphylaxis to glycopyrronium and neostigmine may occur very rarely. In a closely monitored patient such as during anaesthesia, when a fall in blood pressure, change in heart rate or difficulty with ventilation are noticed, anaphylaxis is so rarely the cause that inevitably treatment is given for another diagnosis before anaphylaxis is recognised; the response to this treatment has commonly delayed or even prevented recognition of the true cause. It is therefore probable that many grade I and II acute allergic reactions to anaesthetic drugs are missed. Conversely, a cause other than allergic anaphylaxis seems more likely in around one-third of the patients referred to specialist centres for investigation of suspected anaphylaxis during anaesthesia. ## Previous history Any clue that appropriately raises anticipation of anaphylaxis will be helpful. A previous history of reaction to anaesthetic drugs, antibiotics, other drugs, chlorhexidine or latex should obviously lead to appropriate avoidance. Because it is always possible the wrong trigger factor was identified, the exact details of exposure leading to any previous reaction should be sought during the pre-operative assessment. Cross-reactivity between nonanaesthetic drugs such as pholcodine or environmental chemicals containing quaternary ammonium groups such as cosmetics and detergents has been proposed as the source of sensitivity to opioids and muscle relaxants: a history of cutaneous sensitivity to cosmetics or rashes from cough medicines should raise caution. Anaphylaxis to amoxicillin and cephalosporins is commonest in asthmatic smokers who have had multiple courses of these antibiotics without reacting: the symptoms of anaphylaxis in such a patient are likely to be initially misinterpreted (quite reasonably) as those expected from anaesthesia in an asthmatic smoker. ## Clinical features Although anaesthesia-related anaphylaxis usually results from intravenous drug administration, administration by other routes, for example cutaneous, mucosal ⁄ vesical peritoneal, intra-articular or intramuscular may be responsible. Clinical features include hypotension, tachycardia or bradycardia; cutaneous flushing, rash or urticaria; bronchospasm; hypoxia; angioedema and cardiac arrest. If an adverse event such as hypotension or bronchospasm occurs during anaesthesia it is appropriate to suspect anaphylaxis unless there exists a significantly more likely cause. Tachycardia is not invariable: bradycardia is seen in approximately 10% of patients with allergic anaphylaxis during anaesthesia. Hypotension is the sole clinical feature in approximately 10% of patients and is likely to be exaggerated in patients undergoing anaesthesia with neuraxial blockade. Widespread flushing or urticaria is seen in the majority of patients but the absence of cutaneous signs does not exclude anaphylaxis. Bronchospasm may be more common in patients with pre-existing asthma. The clinical features usually occur within a few minutes but may be delayed by up to an hour. Substances to which the clinical reaction may be delayed include latex, antibiotics, intravenous colloids and Cidex OPA (used to disinfect surgical instruments). However, an immediate response does not exonerate these substances. The clinical features of anaphylaxis to neuromuscular blocking agents usually develop rapidly. Deflation of a surgical tourniquet may induce anaphylaxis if the allergen has been sequestered in the limb. ## Immediate management These management guidelines presuppose that the patient is in the care of an appropriately-trained anaesthetist and full resuscitation facilities and appropriate vital signs monitors are available. There is a wide spectrum of severity and combinations of clinical features. Although management should be tailored to the individual patient, there is consensus that adrenaline should be given as early as possible. In addition to having alpha-agonist activity, adrenaline is a valuable beta-agonist which is inotropic and a bronchodilator, and reduces further mediator release. Other causes of hypotension or difficulty in ventilation should be excluded, for example a misplaced tracheal tube or equipment failure. a Initial sample as soon as feasible after resuscitation has started -do not delay resuscitation to take the sample. b Second sample at 1-2 h after the start of symptoms. c Third sample either at 24 h or in convalescence (for example in a follow-up allergy clinic). This is a measure of baseline tryptase levels as some individuals have a higher baseline level. ## Intravenous Intravenous adrenaline may be used in children in acute areas such as operating theatres or intensive care units by those familiar with its use and if IV access is already available. Great care should be taken to avoid dose errors when preparing drug dilutions. Prepare a syringe containing 1 ml of 1 : 10 000 adrenaline for each 10 kg body weight (0.1 ml.kg )1 of 1 : 10 000 adrenaline solution = 10 lg.kg )1 . Titrate to response, starting with a dose of one-tenth of the contents of the syringe, i.e. 1 lg.kg )1 . Often a child will respond to as little as 1 lg.kg )1 . In smaller children, further dilution may be needed to allow dose titration (check carefully for decimal point and Suspected anaphylactic reactions associated with anaesthesia . Any patient who has a suspected anaphylactic reaction associated with anaesthesia should be investigated fully, but investigations should not interfere with the immediate treatment of the patient. The anaesthetist who administered the anaesthetic or the consultant anaesthetist in charge of the patient is responsible for ensuring that the reaction is investigated. The patient should be referred to a specialist Allergy or Immunology centre that has appropriate experience of investigating this type of problem. Anaesthetic departments should identify a lead anaesthetist for anaesthetic anaphylaxis. Referral pathways should be agreed prospectively with the appropriate specialist centre. Criteria for referral to a specialist centre for investigation Patients in whom allergic or non-allergic anaphylaxis is suspected should be referred to a specialist clinic for investigation. A patient should be referred if there is any of the following: 1 Unexplained cardiac arrest during anaesthesia. 2 Unexplained, unexpected hypotension (for example a decrease of mean arterial pressure of more than 30 mmHg) which requires active treatment. 3 Unexplained, unexpected bronchospasm, particularly if the bronchospasm is severe, causes a significant decrease in oxygen saturation and is relatively resistant to treatment. 4 Widespread rash, flushing or urticaria. 5 Angioedema. A detailed analysis of events surrounding the suspected anaphylactic reaction must be undertaken. The time of onset of the reaction in relation to induction and other events is the most important information. All drugs and other agents to which the patient was exposed before and during the anaesthetic as well as their timing in relation to the reaction must be recorded. Details sent to the specialist centre along with a letter of referral must include: - A legible photocopy of the anaesthetic record - A legible photocopy of the recovery room chart - Legible photocopies of drug charts - A description of the reaction and time of onset in relation to induction - Details of blood tests sent and their timing in relation to the reaction - Contact details of the surgeon and the general practitioner A standard referral proforma is useful (see Appendix S1 in Supporting Information). ## Tests performed at the specialist centre ## Skin tests Patients should be referred for skin testing as soon as possible after the clinical event. Skin testing can be performed as soon as the patient has made a full clinical recovery and the effects of any antihistamine given to treat the reaction have fully worn off. Skin tests can provide confirmation of sensitisation to a specific drug but must be interpreted within the clinical context. There are a variety of techniques and several different criteria are used for positivity [1-4] so skin testing must be performed by suitably trained and experienced personnel. A histamine solution and physiological saline are used as positive and negative controls respectively. Drugs with anti-histamine activity must be discontinued a few days before testing. There is no need to discontinue oral or inhaled steroids. Skin prick tests are usually done on the volar surface of the forearm. A drop of the drug is placed on the skin and the skin pricked through the drop with a lancet. The results are read after 15-20 min. Intradermal tests may be performed where skin prick tests are negative. Although they are more sensitive, they are less specific, more difficult to interpret and more likely to precipitate a systemic reaction. Intradermal tests are usually performed on the forearm or back. 0.02 to 0.05 ml of a dilute solution is injected intradermally and the results read after 20-30 min. Both skin prick tests and intradermal tests are widely used in the diagnosis of IgE mediated allergic reactions though the diagnostic value of a positive test for most drugs is limited due to lack of subsequent challenge data. If the mechanism is unknown a negative test is unreliable. All drugs used during anaesthesia may be tested and lists of non-irritant dilutions have been compiled for both skin prick tests and intradermal tests [bib_ref] Anaphylaxis during anaesthesia. Results of a two-year survey in France, Laxenaire [/bib_ref]. Skin tests are most useful for latex, beta lactam antibiotics and NMBAs. They are also useful for induction agents, protamine [bib_ref] Increased risk for anaphylactoid reaction from contrast media in patients on beta-adrenergic..., Lang [/bib_ref] and chlorhexidine. Intradermal testing may be more reliable for propofol . Skin tests are not usually performed for opioids because false positive results are common. However, skin prick testing appears to be informative for the synthetic opioids fentanyl and remifentanil. Skin tests are not useful for NSAIDs, dextrans or iodinated radiological contrast media [bib_ref] Increased risk for anaphylactoid reaction from contrast media in patients on beta-adrenergic..., Lang [/bib_ref] because anaphylaxis to these agents is not usually IgE-mediated. Patch tests are the mainstay of diagnosis for contact allergic reactions and may be useful for diagnosing exanthematous drug rashes but are not helpful in eliciting the cause of suspected anaphylactic reactions occurring during anaesthesia. ## Blood tests Appropriate further blood investigations depend on the drug in question, and the experience of the specialised laboratory service. Blood samples for specific IgE tests may be taken at the time of the reaction, or soon afterwards during that hospital admission. If the results are negative these tests should be repeated when the patient is seen at the specialist centre in case the initial results might be falsely negative due to possible consumption of relevant IgE antibodies during the reaction. The most commonly used test for allergen-specific IgE uses target allergen or drug bound onto a three-dimensional spongelike solid matrix or 'CAP' and a fluorescent detection system. The Radio-AllergoSorbent Test (RAST) uses a radioactive detection system: it is now rarely used but the name has persisted in common use. Specific IgE antibodies against succinylcholine (thiocholine ester) can be assayed in serum but the sensitivity is relatively poor (30-60%). Tests for serum IgE antibodies against other neuromuscular blocking drugs are not available in the UK. Specific IgE antibodies against several antibiotics can be assayed. These include amoxicilloyl, ampicilloyl, penicilloyl G, penicilloyl V and cefaclor, however the diagnostic value of these tests is less well defined. Tests for specific antibodies against latex, chlorhexidine and bovine gelatin are available. The presence of drug-specific IgE in serum is evidence of allergic sensitisation in that individual and provides a possible explanation of the mechanism and specific drug responsible for the reaction. It is not in itself proof that the drug is responsible for the reaction. It is important to emphasise that attribution of cause and effect is a judgement made after considering all the clinical and laboratory information relevant to the reaction. ## Experimental tests There is much research into ways of improving the in vitro elucidation of anaphylaxis. In addition to tissuebound mast cells, circulating basophils are also involved in anaphylaxis. During anaphylaxis, proteins such as CD63 and CD203c become newly or increasingly expressed on the surface of basophils. These can be detected by flow cytometry which forms the basis of experimental druginduced basophil stimulation tests. # Appendix i Frequently asked questions Should I give a test dose of IV antibiotic? No. Predictive testing would require serial challenges with increasing doses, starting with a minuscule dose and allowing at least 30 min between each dose. This approach is impossible within the constraints of an operating list. Should I avoid cephalosporins in a patient who gives a history suggestive of penicillin allergy? Most patients who give a history of a penicillin-related rash are not allergic to cephalosporins. However, there are now many suitable alternatives to cephalosporins and, unless there are compelling bacteriological indications, it would be appropriate to consider avoiding first and second generation cephalosporins. If there is a convincing history of penicillin-related anaphylaxis, the case for avoiding first and second generation cephalosporins is stronger. ## Should i use crystalloid or colloid in the immediate management of anaphylaxis? There is no evidence that one is better than the other. If an IV colloid has already been given to the patient before the appearance of clinical signs of anaphylaxis, it should be discontinued and either replaced by crystalloid or replaced by a colloid of a different class; e.g. replace a gelatin-based colloid with a starch-based colloid. Should I give an H2-blocking drug as part of the immediate management of anaphylaxis? There is no evidence to support the use of H2-blocking drugs in this situation. What should I do if a patient with a convincing history of cardiorespiratory collapse during a previous anaesthetic presents for emergency surgery without having been investigated for anaphylaxis? 1 Covert cardiac or respiratory disease should be sought in accordance with normal pre-operative practice. 2 It may be possible to exclude latex allergy by taking a detailed history from the patient. If this is impossible, a latex-free environment should be provided. 3 Inhalational agents are likely to be safe unless the previous collapse was due to malignant hyperthermia. 4 If previous records are available: a It would be appropriate to avoid all drugs given during the previous anaesthetic before the onset of cardio-respiratory collapse, with the exception of inhalational agents. b If the patient received a neuromuscular blocking drug before the collapse, then all neuromuscular blocking drugs should be avoided if possible because cross-sensitivity is common. 5 If previous records are not available: a It would be appropriate to avoid all neuromuscular blocking drugs if possible (the anaesthetist will need to assess the balance of risks). b Drugs used in local and regional anaesthesia are likely to be safe; allergy to amide local anaesthetic drugs is extremely rare. c It would be appropriate to avoid chlorhexidine preparations if possible; allergy to povidone iodine is less common than allergy to chlorhexidine. d The previous reaction may have been the result of non-allergic anaphylaxis; it would be appropriate to avoid drugs that are known to release histamine, for example morphine. 6 There is no evidence that pre-treatment with hydrocortisone or histamine-blocking drugs will reduce the severity of anaphylaxis. What should I say to a patient who wishes to be screened for anaesthetic allergy pre-operatively? Unless there is a history suggestive of previous anaesthetic anaphylaxis, pre-operative screening is of no value. The sensitivity and specificity of skin tests and blood tests is relatively low. If the pretest probability is very low, i.e. there is no positive history, neither a negative test nor a positive test is likely to be predictive of outcome. Should I avoid propofol in patients who are allergic to eggs, soya or nuts? There is no published evidence indicating that propofol should be avoided in patients who are allergic to eggs, soya or nuts. Propofol contains purified egg phosphatide and soya-bean oil. It is likely that the manufacturing process removes or denatures the proteins responsible for egg allergy and soya allergy. However, a cautious approach would seem to be appropriate in patients with egg allergy or soya allergy. I don't have a specialist allergy centre nearby. Should I do my own skin-testing? The results of skin tests are very technique-dependent and their interpretation requires specialist training and experience. of sensitized individuals also react to certain fruits cross reacting with latex proteins. 2 Contact dermatitis: a delayed Type IV hypersensitivity reaction consisting of an eczematous reaction starting 24-48 h after repeated skin or mucosal contact with additives used during rubber production. This is a T cell-mediated, non-life-threatening reaction. It may, however, predispose the individual to a more severe systemic reaction. 3 Clinical non-immune-mediated reaction: irritant dermatitis resulting from a mild irritant effect of the powder in the gloves and that of disinfectants, sweating etc. This is the most frequent reaction, is limited to the contact area and is characterised by itching, irritation and blistering at the side of contact. ## High risk individuals Approximately 8% of the population is sensitized to latex but only 1.4% of the population exhibits latex allergy. The following groups are at increased risk: - Patients with atopy - Children undergoing multiple surgical procedures, such as spina bifida, or children undergoing surgery at a very young age - Patients with severe dermatitis of their hands - Healthcare professionals - Patients with allergy to fruits; most frequently banana, chestnut and avocado - Industrial workers using protective gear - Occupational exposure to latex Pre-operative assessment A history of pre-operative symptoms suggestive of latex allergy is present in approximately a quarter of patients who develop intra-operative NRL anaphylaxis. A thorough history, including an occupational history, should be part of the pre-operative assessment. It is useful to ask specifically whether contact with balloons, condoms or latex gloves provokes itching, rash or angioedema. ## Pre-operative testing If the clinical history is positive or equivocal, the patient should be referred for testing before the surgical procedure and surgery should proceed only in an emergency. In the preoperative situation, it is particularly important to exclude IgE-mediated sensitivity. The choice of test: either a blood test for latex-specific IgE, or skin testing may depend on local availability. Current tests have a sensitivity of approximately 75-90%; skin prick testing may be more sensitive than blood tests for specific IgE. It is important that skin prick tests are performed by trained staff. It may be appropriate to proceed to challenge testing in some patients. ## Peri-operative precautions - If NRL allergy is diagnosed pre-operatively, avoidance is mandatory. - Care should be taken to avoid introducing additional, unrelated hazards when latex precautions are implemented in the operating theatre. - Latex allergy should be recorded in the case-notes and on the patient's wrist bracelet. - The surgical team and the nursing and anaesthetic support teams should be alerted. - There is no evidence that premedication with an antihistamine or steroid is useful. - The operating theatre should be prepared the night before to avoid the release of latex particles and the patient should be scheduled first on the list. Evidence is limited regarding the need for this degree of caution in operating theatres where all latex gloves are of the nonpowdered type. - A 'Latex allergy' notice should be placed on the doors to the anaesthetic room and operating theatre. - Staff traffic should be limited. - Absolute use of synthetic gloves when preparing equipment and during anaesthesia, surgery and postoperative care. - Non-essential equipment should be removed from the vicinity of the patient. - The anaesthetic and surgical areas must contain only latex free products. - Only latex-free dressings and tapes should be applied. - Equipment in resuscitation boxes and trolleys must contain only latex free material. ## Postoperative investigation of possible latex anaphylaxis If skin testing and specific IgE testing is negative or equivocal in the presence of a suggestive history, it may be appropriate for the patient to proceed to a provocation test with the finger of a latex glove. This procedure must be performed by trained staff and resuscitation facilities must be available. Patch testing by an expert is useful in the diagnosis of delayed (Type lV) hypersensitivity to rubber. ## Hospital latex-allergy policy It is recommended that all hospitals have a latex-allergy policy which should address the following: [fig] 10: This guidance recommends that all Departments of Anaesthesia should identify a Consultant Anaesthetist who is Clinical Lead for anaesthetic anaphylaxis. Introduction The AAGBI published its first guidelines on suspected anaphylactic reactions in 1990. Subsequent revisions were published in 1995 and 2003. The current guidelines incorporate advice from a large number of clinical immunologists, allergists and anaesthetists throughout the UK. In common with the 1995 and the 2003 editions, this report is published jointly with the British Society for Allergy and Clinical Immunology (BSACI). This document is intended to be concordant with, and complementary to, the 2007 Scandinavian Clinical Practice Guidelines, the 2008 Resuscitation Council UK guidelines and the BSACI guidelines: Investigation of suspected anaphylaxis during anaesthesia. [/fig]	None	https://europepmc.org/articles/pmc3082210?pdf=render	Summary (1) The AAGBI has published guidance on management of anaphylaxis during anaesthesia in 1990, 1995 and 2003. This 2008 update was necessary to disseminate new information. (2) Death or permanent disability from anaphylaxis in anaesthesia may be avoidable if the reaction is recognised early and managed optimally. (3) Recognition of anaphylaxis during anaesthesia is usually delayed because key features such as hypotension and bronchospasm more commonly have a different cause. (4) Initial management of anaphylaxis should follow the ABC approach. Adrenaline (epinephrine) is the most effective drug in anaphylaxis and should be given as early as possible. (5) If anaphylaxis is suspected during anaesthesia, it is the anaesthetist’s responsibility to ensure the patient is referred for investigation. (6) Serum mast cell tryptase levels may help the retrospective diagnosis of anaphylaxis: appropriate blood samples should be sent for analysis. (7) Specialist (allergist) knowledge is needed to interpret investigations for anaesthetic anaphylaxis, including sensitivity and specificity of each test used. Specialist (anaesthetist) knowledge is needed to recognise possible non-allergic causes for the ‘reaction’. Optimal investigation of suspected reactions is therefore more likely with the collaboration of both specialties. (8) Details of specialist centres for the investigation of suspected anaphylaxis during anaesthesia may be found on the AAGBI website http://www.aagbi.org. (9) Cases of anaphylaxis occurring during anaesthesia should be reported to the Medicines Control Agency and the AAGBI National Anaesthetic Anaphylaxis Database. Reports are more valuable if the diagnosis is recorded following specialist investigation of the reaction. (10) This guidance recommends that all Departments of Anaesthesia should identify a Consultant Anaesthetist who is Clinical Lead for anaesthetic anaphylaxis.
ebb4d330e1e50e325025b3513a59e41942adf12f	pubmed	Palliative Renal Care and the Covid-19 Pandemic	Palliative Renal Care and the Covid-19 Pandemic Introdução: O cuidado paliativo é uma abordagem voltada para alívio do sofrimento, controle de sintomas e melhora da qualidade de vida. Deve ser oferecido em conjunto com o tratamento padrão de qualquer doença que ameace a continuidade da vida, como, por exemplo, a infecção pela Covid-19. Discussão: Os princípios bioéticos e as estratégias utilizadas pela medicina paliativa podem auxiliar os nefrologistas no cuidado dos pacientes com disfunção renal, que, além de serem do grupo de risco para evolução mais grave da infecção por coronavírus, enfrentam as dificuldades do isolamento no seguimento do tratamento dialítico e ambulatorial. Essas ferramentas são: I) tomada de decisão compartilhada, que proporciona a participação do paciente e dos familiares como facilitadores na sistematização do raciocínio da equipe, além de respeitar o princípio da autonomia; II) manejo de sintomas, que deve ser prioridade para a garantia do alívio do sofrimento mesmo em momento de isolamento social; III) habilidades em comunicação, sendo possível amenizar dificuldades em anunciar más notícias ou decisões complexas através de técnicas de comunicação; IV) assistência ao luto, em que, em situações agudas como a pandemia, de perdas inesperadas, a importância do acolhimento dos profissionais de saúde torna-se ainda maior. Conclusão: Os princípios dos cuidados paliativos são essenciais para enfrentar os desafios de uma crise humanitária, que causa sofrimento ao ser humano em todas as dimensões e exige a construção de estratégias que possam manter os pacientes assistidos, confortáveis e com medidas proporcionais à sua condição clínica e às suas preferências. Introdução: O cuidado paliativo é uma abordagem voltada para alívio do sofrimento, controle de sintomas e melhora da qualidade de vida. Deve ser oferecido em conjunto com o tratamento padrão de qualquer doença que ameace a continuidade da vida, como, por exemplo, a infecção pela Covid-19. Discussão: Os princípios bioéticos e as estratégias utilizadas pela medicina paliativa podem auxiliar os nefrologistas no cuidado dos pacientes com disfunção renal, que, além de serem do grupo de risco para evolução mais grave da infecção por coronavírus, enfrentam as dificuldades do isolamento no seguimento do tratamento dialítico e ambulatorial. Essas ferramentas são: I) tomada de decisão compartilhada, que proporciona a participação do paciente e dos familiares como facilitadores na sistematização do raciocínio da equipe, além de respeitar o princípio da autonomia; II) manejo de sintomas, que deve ser prioridade para a garantia do alívio do sofrimento mesmo em momento de isolamento social; III) habilidades em comunicação, sendo possível amenizar dificuldades em anunciar más notícias ou decisões complexas através de técnicas de comunicação; IV) assistência ao luto, em que, em situações agudas como a pandemia, de perdas inesperadas, a importância do acolhimento dos profissionais de saúde torna-se ainda maior. Conclusão: Os princípios dos cuidados paliativos são essenciais para enfrentar os desafios de uma crise humanitária, que causa sofrimento ao ser humano em todas as dimensões e exige a construção de estratégias que possam manter os pacientes assistidos, confortáveis e com medidas proporcionais à sua condição clínica e às suas preferências. ## Palavras # Abstract Introduction: Palliative care is an approach aimed at relieving suffering, controlling symptoms and seeking to improve quality of life. It must be offered in conjunction with standard treatment for any disease that threatens the continuation of life, such as a Covid-19 infection. Discussion: The bioethical principles and strategies used by palliative medicine can assist nephrologists in the care of patients with renal dysfunction, who face the difficulties of isolation at the beginning and follow-up of dialysis in outpatient treatment, and those who are at risk for a more serious disease progress. Some of them: -a Shared decision making, which enables the patient and family to participate as facilitators in the systematization of the team's reasoning, in addition to respecting the principle of autonomy; -Symptom Management: which should be a priority to ensure relief of suffering even in times of social isolation; -Communication skills: making it possible to alleviate suffering in announcing bad news or complex decisions through communication techniques;; -Bereavement assistance: which in acute situations such as the pandemic, causing unexpected losses, the importance of sympathy from healthcare professionals becomes even greater. Conclusion: The principles of palliative care are essential to face the challenges of a planet-wide crisis, which raises human suffering in all dimensions, and which requires the construction of strategies that can keep patients assisted, comfortable and with measures proportional to their clinical condition and preferences. According to the World Health Organization (WHO), the role of palliative care is fundamental in facing large human crises like this. These crises are defined by large-scale events that affect populations or societies, causing a variety of difficult and distressing consequences, which can include massive loss of life, disruption of livelihoods, society collapse, forced displacement and other political and economic factors, psychological and spiritual effects, such as, for example: pandemics, natural disasters and civil wars 1 . ## Keywords How to we explain the link between palliative care and a pandemic, a situation of acute and unexpected nature? Palliative care is an approach aimed at relieving suffering, controlling symptoms and improving quality of life. It should be offered in conjunction with standard treatment for any disease that threatens the continuity of life. In a time of Covid-19 pandemic, although the main goal of care is to save lives, it is not the only one. Not all lives can be saved, and even the saved ones will go through a process of great suffering, either in the physical sphere, with the appearance of symptoms that need to be controlled, or in the social sphere (family support, isolation, access to proper hygiene); and emotional, expressed by fear, anxiety and sadness, from patients, their family members and the care team 2 . In this context of public calamity, with different rules, the collapse of the healthcare system is a real risk; with healthcare professionals often physically and emotionally exhausted, and in which the very important presence of family members is not recommended, knowledge of palliative care can greatly contribute to assistance in the Covid-19 pandemic. Professionals on the front lines may face unprecedented situations, which will require skills and technical knowledge, common to palliative care professionals who routinely deal with human suffering. Some palliative care tools are also very relevant for nephrologists at this time of crisis: - Shared decision-making: Although decision-making is a technical issue and, therefore, related to the care team, it can be improved and even facilitated when we know the values, previous health information, social support and patient's wishes in a shared decision (team, patient and family). This is an example of good medical practice in complex situations, and one of the pillars of palliative care. The limitations of advanced life support, including the failure to perform renal replacement therapy, requires systematization of clinical reasoning, and must take into account a number of factors. In an attempt to follow the bioethical principle of not causing harm, nephrologists must careful assess the real benefits of offering dialysis to patients with other chronic diseases in progress that are not responding to the standard treatment already in place; to very old patients (but not as an isolated factor); fragile and totally dependent patients; to people with previous cognitive impairment and without social support. Thus, it is important to be aware of the fact that many patients infected by the coronavirus may already have such conditions, and therefore, regardless of an acute situation such as Covid-19, they would not benefit from intensive treatment involving more invasive measures, if their clinical condition requires it. Transfer to the intensive care unit, orotracheal intubation, dialysis, cardiopulmonary resuscitation, among others, can become procedures out of proportion to the health condition of some patients. - Symptom management: Patients who are already receiving renal palliative care should be reassessed periodically; especially those who have chosen not to undergo dialysis therapy and those who are rapidly progressing from an underlying disease. Uremic symptoms are expected to worsen over time, and with the progression of kidney disease, making the management of symptoms a priority to ensure suffering relief. Since they are a high-risk group, it is recommended to avoid travel and exposure in face-to-face consultations and opt for teleconsultation. The relief of human suffering involves the mastery of techniques and specific knowledge to control symptoms at any stage of the disease, especially in the case of patients who inevitably progress to the end of life. - Communication skills: Many conflicts related to death, clinical worsening or the feasibility of certain treatments, such as dialysis, could be mitigated by means of communication techniques that ensure clarity of information, listening, acceptance, respect for emotions and the cognitive ability of each one. It is necessary to be careful when communicating bad news and that is why we must prepare, with an appropriate environment, take time and plan the approach, always respecting the emotions of each one, including the desire to be informed or not of certain aspects of the disease. - Bereavement assistance: In acute situations such as a pandemic, the risk of unexpected loss is higher. A family member who takes his loved one to the hospital on one day, and never sees this person again, and on another day receives the news of the death, without having followed the illness process and without even being able to attend a funeral or a farewell event, has greater difficulty in accepting the loss. In these situations, the risk of complicated mourning is high, so the sympathy of health professionals becomes essential and must be maintained in the follow-up and care of the family members.To enable the best care during social isolation, the nephrologist can use telemedicine, which has been properly authorized by the Federal Board of Medicine, and not suspend family meetings to deal with the most diverse subjects, such as shared decision making, provide information about the progress of the patient, and assist in grieving. At this moment, a hug and the expression of a touch should be replaced by a phone call or a videoconference, and not by the silence of the lack of information, which can be misinterpreted by abandoning care. In nephrology, we also live an unprecedented scenario in the care of nephropathic patients. Despite the universal recommendation of social isolation, for dialysis patients (specifically, those on hemodialysis -93%) this is not a reality. They cannot stay at home, as they depend on treatment to stay alive, and the fear and risk of exposure increases, both for the team and the patient. Hemodialysis clinics need to adapt for this new reality, requiring greater allocation of financial resources, which are insufficient to date. All these new difficulties can generate physical and emotional stress on the healthcare team and on the dialysis patients, who need to be valued and cared for, in order to avoid the collapse of dialysis clinics. The principles of palliative care are essential to face the challenges of a huge crisis, which causes suffering to human beings in all dimensions. The humanitarian commitment focuses not only on the needs of the individual as an individual, but on the context in which he/she lives, gathering resources that ensure basic human rights, such as dignity. In a time of pandemic, we must understand that it is our role to fight to save lives, but not less important, it is also our role to alleviate the suffering of patients, family members and the healthcare team.	None	https://www.scielo.br/j/jbn/a/p3QsTX7LGxwYjnpSyMYCM7D/?lang=en&format=pdf	ABSTRACT Introduction Palliative care is an approach aimed at relieving suffering, controlling symptoms and seeking to improve quality of life. It must be offered in conjunction with standard treatment for any disease that threatens the continuation of life, such as a Covid-19 infection. Discussion The bioethical principles and strategies used by palliative medicine can assist nephrologists in the care of patients with renal dysfunction, who face the difficulties of isolation at the beginning and follow-up of dialysis in outpatient treatment, and those who are at risk for a more serious disease progress. Some of them: - a Shared decision making, which enables the patient and family to participate as facilitators in the systematization of the team’s reasoning, in addition to respecting the principle of autonomy; - Symptom Management: which should be a priority to ensure relief of suffering even in times of social isolation; - Communication skills: making it possible to alleviate suffering in announcing bad news or complex decisions through communication techniques;; - Bereavement assistance: which in acute situations such as the pandemic, causing unexpected losses, the importance of sympathy from healthcare professionals becomes even greater. Conclusion The principles of palliative care are essential to face the challenges of a planet-wide crisis, which raises human suffering in all dimensions, and which requires the construction of strategies that can keep patients assisted, comfortable and with measures proportional to their clinical condition and preferences.
84b2e1124c1fac83a3c358527f139ebe93147d7f	pubmed	Consensus on pre-operative total knee replacement education and prehabilitation recommendations: a UK-based modified Delphi study	Consensus on pre-operative total knee replacement education and prehabilitation recommendations: a UK-based modified Delphi study This document provides recommendations on pre-operative care for patients waiting for total knee replacement (TKR) surgery in the United Kingdom.The recommendations were developed using an approach known as a Delphi Consensus Technique. This involved a group of patients and professionals, known as 'panel members', completing three online questionnaires. All the items included in this list of recommendations were rated as 'Important' or 'Very important' by at least 70% of panel members in the final questionnaire.Further details about the study used to develop the recommendations are available at: https://doi. ## Pre-operative total knee replacement care recommendations This document provides recommendations on pre-operative care for patients waiting for total knee replacement (TKR) surgery in the United Kingdom. The recommendations were developed using an approach known as a Delphi Consensus Technique. This involved a group of patients and professionals, known as 'panel members', completing three online questionnaires. All the items included in this list of recommendations were rated as 'Important' or 'Very important' by at least 70% of panel members in the final questionnaire. Further details about the study used to develop the recommendations are available at: https://doi.org/10.1186/s12891-021-04160-5. A prioritised list of recommendations are available via the same link in Additional File 10. Other pre-operative treatments	None	https://bmcmusculoskeletdisord.biomedcentral.com/track/pdf/10.1186/s12891-021-04160-5	None
cc79a7b2d7e100470cae7076518fb8928e91fae2	pubmed	Practice guidelines for management of ovarian cancer in Korea: a Korean Society of Gynecologic Oncology Consensus Statement	Practice guidelines for management of ovarian cancer in Korea: a Korean Society of Gynecologic Oncology Consensus Statement Since after 2006 when the first edition of practice guidelines for gynecologic oncologic cancer treatment was released, the Korean Society of Gynecologic Oncology (KSGO) has published the following editions on a regular basis to suggest the best possible standard care considering updated scientific evidence as well as medical environment including insurance coverage. The Guidelines Revision Committee was summoned to revise the second edition of KSGO practice guidelines, which was published in July 2010, and develop the third edition. The current guidelines cover strategies for diagnosis and treatment of primary and recurrent ovarian cancer. In this edition, we introduced an advanced format based on evidence-based medicine, collecting up-to-date data mainly from MEDLINE, EMBASE, and Cochrane Library CENTRAL, and conducting a meta-analysis with systematic review. Eight key questions were raised by the committee members. For every key question, recommendations were developed by the consensus meetings and provided with evidence level and strength of the recommendation. # Introduction Ovarian cancer is the most lethal gynecologic cancer. Any screening test or early detection of symptom was not shown to effectively reduce mortality of the disease. In addition to epithelial ovarian cancer (EOC), which consists of more than 85% of ovarian cancer, there are less common histopathologies including germ cell tumor and sex cord-stromal tumors. EOC is classified into type I and II according to origin, moleculopathologic carcinogenesis, and clinical behavior. Compared with type II cancer, less common type I cancer mostly has precursor lesions and is likely to be detected earlier. However, type II cancer tends to be diagnosed at advanced stage and accounts for most of death from ovarian cancer. Thus, majority of studies for the treatment and prevention of ovarian cancer are focused on type II cancer. Recently, it is widely accepted that type II cancer might be originated from the epithelium of fallopian tube [bib_ref] Society of Gynecologic Oncology recommendations for the prevention of ovarian cancer, Walker [/bib_ref]. There is accumulating evidence supporting this hypothesis which showed that opportunistic bilateral salpingectomy in benign pelvic surgery could effectively prevent the development of ovarian cancer [bib_ref] Ovarian cancer risk after salpingectomy: a nationwide population-based study, Falconer [/bib_ref] [bib_ref] Prophylactic salpingectomy and delayed oophorectomy as an alternative for BRCA mutation carriers, Kwon [/bib_ref]. It is reported that pregnancy and delivery at the young ages before 25 years old, use of oral pill, and breast-feeding might reduce 30%-60% of the development of ovarian cancer. On the contrary, nulliparity and first delivery at ≥35 years old are known to increase the risk of the disease. Germline mutation of BRCA1 and BRCA2 or familial history including hereditary non-polyposis colon cancer (HNPCC) also increase the risk of ovarian cancer. Thus, hereditary cancer comprised approximately 10% of ovarian cancer. Risk-reducing salpingooophorectomy (RRSO) in high-risk patients with BRCA1 and BRCA2 mutation could reduce 80% of ovarian and fallopian tube cancer. Nevertheless, the risk of primary peritoneal cancer remains the same even after RRSO. Cancer statistics report from the Ministry of Health and Welfare which was updated in January 2015 said ovarian cancer has been slowly increasing. Annual incidence and crude incidence rate per 10 5 were 1,870 and 7.6 in 2008, 1,832 and 7.4 in 2009, 2,025 and 8.1 in 2011, and 2,167 and 8.6 in 2012. In 2012, ovarian cancer incidence ranked 10th in women cancer, which accounted for 1.9%. Regarding the age, most commonly occurs in the 50's (28.6%), followed by 40's (21.0%) and 60's (17.2%). The incidence is relatively stable. However, no significant improvement of survival outcomes in ovarian cancer between 1993-1995 and 2008-2012 (5-year survival rate, 58.7% vs. 61.9%, respectively), compared with those of breast cancer (78.0% vs. 91.3%), colon cancer (54.2% vs. 71.8%), stomach cancer (42.6% vs. 70.0%), and lung cancer (14.2% vs. 28.2%), makes the development of effective treatments for this obstinate disease urgent. # Materials and methods Methods are the same with those of practice guidelines for management of uterine corpus cancer [bib_ref] Practice guidelines for management of uterine corpus cancer in Korea: a Korean..., Lee [/bib_ref] and cervical cancer [bib_ref] Practice guidelines for management of cervical cancer in Korea: a Korean Society..., Lim [/bib_ref]. Since the last version (V2.0) of the KSGO practice guidelines for gynecologic cancer management in 2010, the Guidelines Revision Committee of KSGO convened again in 2015 to revise V2.0 and make V3.0. In the committee, a comprehensive method for systematic review of relevant literature between 2010 and 2015 was adopted in order to adhere to the principles of evidence-based medicine. The process was as followed: 1) selection of key questions; 2) searching for relevant literature published after 2010 for each key question; 3) determining the level of evidence and grade of recommendation; 4) deduction of the agreements; and 5) review and approval. Key questions were chosen and edited by ovarian cancer sub-committee members considering previous ones in V2.0, the need for further clarification, and new reports after V2.0 (Supplementary). Data and literature published between 2010 and 2015 were searched using 3 searching engines: Cochrane Library CENRAL, MEDLINE, and Embase. Then, a meta-analysis and systematic review were conducted for determining the level of evidence. Specifically, Cochrane methodology was used for randomized controlled trials, the Newcastle-Ottawa scale for non-random studies, and the quality assessment of studies of diagnostic accuracy included in systematic reviews (QUADAS-2) for diagnosis research. The level of evidence was decided as one of the 4 categories (high, moderate, low, and very low) using the methodology suggested by the grade group based on the research design, consistency among the research results, immediacy of the research subject and intervention, possibility of publishing bias, and accuracy of the research results [fig_ref] Table 3: Levels [/fig_ref]. The grade of recommendation was decided by the methodology suggested by the grade group based on the level of evidence, considering the application subject, hazard and benefit, social, and individual cost of the intervention, and patients' preference. The grade of recommendation was assigned as strong or weak recommendation [fig_ref] Table 3: Levels [/fig_ref]. The draft form and grades of recommendation were established through mutual consultation among all the members of the revision committee. ## Clinical considerations and recommendations ## Epithelial ovarian cancer ## 1) diagnosis (1) Pelvic mass suspicious of ovarian cancer Diagnostic tests for patients with pelvic mass (or ascites) or abdominal distension suspicious of cancer of ovary but not likely other sites include history, physical exam, and tumor markers. Serum cancer antigen (CA) 125 is firstly recommended. CA19-9 or carcinoembryonic antigen (CEA) may also be evaluated as clinically indicated. Serum alpha-fetoprotein (α-FP) and β-human chorionic gonadotropin (β-hCG) are the options for germ cell tumor. Risk of ovarian malignancy algorithm (ROMA), the combination of human epididymis protein 4 (HE4) and CA125 values, was reported to be more sensitive and specific than CA125 alone for diagnosis of ovarian cancer, for which the level of evidence, however, is low and can be used under the clinician's discretion (strength of recommendation and level of evidence 2D, evidence [fig_ref] Table 5: Definition of progression after first-line therapy in ovarian cancer proposed by gynecologic... [/fig_ref] in Supplementary). In addition to basic laboratory tests, including blood cell count, chemistry, and urinalysis, and electrocardiography, some imaging tests, such as chest X-ray, pelvic ultrasound, pelvis-abdomen-chest computed tomography (CT), magnetic resonance imaging (MRI), and positive emission tomography, are also among the options as clinically indicated. Genetic counseling is considered for the patients who have family history of ovarian and/or breast cancer. Endoscopic examinations for gastrointestinal tract are recommended in order to exclude metastasis from other sites. (2) Diagnosis of ovarian cancer after surgery For the patients who were diagnosed as ovarian cancer after surgery and did not undergo comprehensive surgical staging with maximal cytoreduction or such information is not available at the time of transfer, all diagnostic tests should be taken as noted above. Every pathology should also be reviewed. ## 2) primary treatment (1) Pelvic mass suspicious of ovarian cancer Primary treatment includes surgical staging with maximal cytoreduction followed by adjuvant chemotherapy. Open surgery with midline incision should be performed at surgeries for staging, primary debulking, interval cytoreduction after neoadjuvant chemotherapy (NAC), or secondary cytoreduction after recurrence. However, minimally invasive surgery (MIS) such as laparoscopic operation can be selectively considered for newly diagnosed cases confined to ovary and pelvic cavity only when experienced gynecologic oncologists are available (strength of recommendation and level of evidence 2D). Nonetheless, conversion to open surgery from MIS should be performed for the cases in which maximal cytoreduction is not likely achievable by MIS. MIS is also useful in confirming the feasibility of optimal cytoreduction with no residual tumor in newly diagnosed or recurrent ovarian cancer. Peritoneal lavage should be performed for cytologic examinations immediately after entering the abdomen even though there is no significant amount of ascites. Frozen biopsy during the operation can be of great help to decide treatment plan. All the peritoneal surfaces should be examined, and any peritoneal surface suspicious for harboring metastasis should be excised and biopsied. When there is no suspicious lesion, random peritoneal biopsies should be taken from the pelvis, paracolic gutters, and undersurfaces of the diaphragm. Diaphragm scraping for Papanicolaou smear is an acceptable alternative of excisional diaphragm biopsy. Procedures for comprehensive staging operation include hysterectomy, bilateral salpingooophorectomy (BSO), omentectomy, pelvic and paraaortic lymph node dissection (PLND and PALND), multiple peritoneal biopsy, and maximum cytoreduction as well as peritoneal cytologic examination. Every effort should be made during BSO and hysterectomy to keep an encapsulated mass intact during removal. For selected patients desiring to maintain fertility, unilateral salpingo-oophorectomy preserving the uterus and contralateral ovary may be considered for unilateral stage I tumors (stage IA and IC, but not stage IB) (strength of recommendation and level of evidence 2D, evidence in Supplementary). PALND should be performed by stripping the nodal tissue from the vena cava and the aorta bilaterally to at least the level of the inferior mesenteric artery and preferably to the level of the renal vessels. Preferred method of PLND is bilateral removal of lymph nodes overlying and anterolateral to the common iliac vessel, overlying and medial to the external iliac vessel, Practice guidelines for ovarian cancer in Korea Date PD: first date of the CA125 elevation to ≥2 × nadir value Patients group: A, patients with elevated CA125 pretreatment and normalization of CA125 (up to 60% of all new patients); B, patients with elevated CA125 pretreatment, which never normalizes (up to 30% of all new patients); C, patients with CA125 in normal range pretreatment (up to 10% of all new patients). CA125, cancer antigen 125; PD, progressive disease; RECIST, response evaluation criteria in solid tumors; UNL, upper normal limit. *Repeat CA125 anytime, but normally not less than 1 week after the first elevated level. CA125 level sampled within 4 weeks after surgery, paracentesis, or administration of mouse antibodies should not be taken into account. [formula] 6 [/formula] overlying and medial to the hypogastric vessels, and from the obturator fossa at a minimum anterior to the obturator nerve. PLND and/or PALND may be selectively performed for those patients with EOC apparently confined to an ovary under the physician's discretion despite the lack of evidence for survival improvement (strength of recommendation and level of evidence 2B, evidence [fig_ref] Table 1: Modified WHO classification of tumors of the ovary by the Gynecological Pathology... [/fig_ref] in Supplementary). In general, maximum cytoreduction is strongly recommended in stage II, III, and IV disease. Every effort should be made during a primary cytoreduction to removal all gross disease since this offers superior survival outcomes although residual disease <1 cm defines optimal cytoreduction [bib_ref] Improved progressionfree and overall survival in advanced ovarian cancer as a result..., Chi [/bib_ref]. However, NAC followed by interval debulking surgery may be considered for patients with extensive stage IIIC to IV disease who are not likely for optimal cytoreduction by upfront primary surgery (strength of recommendation and level of evidence 2A, evidence [fig_ref] Table 2: FIGO and TNM staging system for ovarian cancer International Federation of Gynecology... [/fig_ref] in . Tissue or cytologic diagnosis should be obtained by fine-needle aspiration, biopsy, or paracentesis before initiation of NAC. Overall survival was comparable between these patients, however, patients receiving NAC with interval debulking surgery had fewer complications [bib_ref] Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS):..., Kehoe [/bib_ref] [bib_ref] Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer, Vergote [/bib_ref]. Among patients with metastatic tumors <5 cm in diameter at randomization, overall survival was slightly longer in the primary surgery group than NAC group (hazard ratio [HR]=0.64; 95% confidence interval [CI]=0.45-0.93) [bib_ref] Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer, Vergote [/bib_ref]. Therefore, NAC could be considered for women who has peritoneal carcinomatosis including metastatic tumors ≥5 cm and are not likely to have optimal cytoreduction. For ovarian cancer involving pelvis and upper abdomen, omentum and lymph nodes suspicious of any tumor involvement should be completely removed along with performing washing cytology at pelvis and abdomen. In addition, multi-visceral resection including bowel resection, appendectomy (in case of mucinous carcinoma), diaphragm stripping and peritonectomy, splenectomy, partial cystectomy, ureteroneocystostomy, partial liver resection, partial gastrectomy, cholecystectomy, distal pancreatectomy and so on can be performed. Some of the patients who have residual tumor <1 cm after surgery could considered for postoperative intraperitoneal (IP) chemotherapy. Catheter for IP chemotherapy should be inserted during the primary surgery. Complete staging operation should be performed by gynecologic oncologists, and it is also recommended in this guideline. (2) Cancer diagnosis only after surgery For women with incomplete previous surgery and/or staging, treatment guidelines are as following. First, for patients who were thought to have stage IA or IB, grade 1 tumor, complete staging operation should be performed because no additional treatment is needed if stage IA or IB, grade 1 tumor is confirmed. Second, staging operation with cytoreduction is recommended for patients with suspected residual disease that is considered optimally resectable. Third, for patients who have more advanced cancer than stage IA or IB, grade 1 tumor but without residual tumor, chemotherapy or complete staging operation can be considered. Patients with stage IA or IB, grade 2 tumor might be followed up without chemotherapy. Fourth, for patients with stage II to IV disease who have residual disease that is considered unresectable, consider completion surgery after 3-6 cycles of chemotherapy based on the clinical judgment of the gynecologic oncologist. Postoperative chemotherapy may also be recommended depending on the surgical results. Patients with stage II-IV tumor but no residual tumor can receive 6-8 cycles of chemotherapy. [fig_ref] Table 3: Levels [/fig_ref] in Supplementary). Of the 3 randomized studies included in the meta-analysis for deciding level of evidence, the study of Katsumata et al. [bib_ref] Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks..., Katsumata [/bib_ref] was the only study that reported the significant survival improvement of dose-dense regimen. ## 3) postoperative adjuvant chemotherapy Although the meta-analysis failed to show the significant survival improvement of dosedense regimen compared with standard triweekly regimen, strength of recommendation and level of evidence 2B was decided considering expert opinion of gynecologic oncologists that weekly dose-dense regimen could improve survival outcomes based on the completeness of the study of Katsumata et al. [bib_ref] Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks..., Katsumata [/bib_ref]. After a public hearing where strength of recommendation and level of evidence was decided, evidence was updated with robust results from randomized trials of dose-dense regimen including ICON8 [bib_ref] Major clinical research advances in gynecologic cancer in 2017, Suh [/bib_ref] and GOG262 [bib_ref] Weekly vs. every-3-week paclitaxel and carboplatin for ovarian cancer, Chan [/bib_ref] , in both of which weekly paclitaxel, as compared with triweekly paclitaxel, did not prolong progression-free survival (PFS) among patients with EOC. However, ovarian cancer sub-committee members of the Guidelines Revision Committee of KSGO decided to maintain current recommendation level 2B. Regimens of primary adjuvant chemotherapy are listed up in . is associated with leukopenia, infection, fatigue, renal toxicity, and neurotoxicity. In the initial studies [bib_ref] Health-related quality of life during and after intraperitoneal versus intravenous chemotherapy for..., Wenzel [/bib_ref] [bib_ref] Utilization and toxicity of alternative delivery methods of adjuvant chemotherapy for ovarian..., Wright [/bib_ref] [bib_ref] Management of ovarian cancer. An impressive history of improvement in survival and..., Markman [/bib_ref] , only 42% of women were able to complete all 6 treatment cycles of the IP regimen because of toxicity. Patients with poor performance status, comorbidities, stage IV disease, or advanced age (>65 years) may not tolerate the IP regimen. In addition, high-dose chemotherapy using peripheral blood stem cell transplantation (PBST) is recommended to use only in the setting of clinical trial, because PBST did not show any survival improvement yet. ## 4) recommendations after primary treatment Patients without complete remission (i.e., progression, persistent disease, or stable disease) after initial treatment should be treated with second-line approaches. Observation with follow-up is recommended for patients who have complete remission. Maintenance therapy is an option based on the results from GOG178 of 3 vs. 12 months of further paclitaxel (135-175 mg/m 2 every 4 weeks for 12 cycles) after initial chemotherapy. The results of this trial suggested that patients receiving 12 months of therapy sustained a PFS advantage (28 vs. 21 months) (strength of recommendation and level of evidence 2C). In addition, use of 12-22 cycles of maintenance bevacizumab has been shown to modestly increase PFS when administered following initial chemotherapy with paclitaxel/carboplatin/bevacizumab (strength of recommendation and level of evidence 2A, evidence in Supplementary). Second-look operation can be selectively considered for the patients who were thought to achieve maximal debulking to resection of all visible disease, because there is no evidence that second-look operation lead to survival advantage (strength of recommendation and level of evidence E). Patients with residual disease in the second-look operation are thought to have a partial remission and recommended to have treatment for recurrent ovarian cancer. ## 5) follow-up recommendations After the completion of primary surgery and chemotherapy in patients with all stages of ovarian cancer, the standard recommendation is observation with follow-up to monitor for recurrent disease. Patients are recommended to visit for follow-up including history taking and physical examination every 2-4 months for the first 2 years, then 3-6 months for 3 years, then annually after 5 years. Blood test including CBC and chemistry profile and chest X-ray can be monitored as indicated. Chest/abdominal/pelvic CT, MRI, positron emission tomography (PET)/CT, or PET may also be ordered if clinically indicated. If the CA125 level was initially elevated, then measurement of a CA125 level or other tumor markers is recommended for every visit. Disease progression is typically defined using Gynecologic Cancer InterGroup (GCIG) criteria [fig_ref] Table 5: Definition of progression after first-line therapy in ovarian cancer proposed by gynecologic... [/fig_ref]. Indication of genetic counseling and clinical genetic testing on women with peritoneal, ovarian, and fallopian tubal cancers and their families were released at KSGO position statement in 2016 [bib_ref] Position statements on genetic test for peritoneal, ovarian, and fallopian tubal cancers:..., Choi [/bib_ref]. ## 6) treatment of recurrent disease Recurrent disease may be identified clinically, biochemically (i.e., elevated CA125 levels), with abnormal findings on imaging and/or biopsy. However, patients can be found to have an increasing CA125 level (during routine monitoring and follow-up) but no signs or symptoms of recurrent disease. After the documentation of an increased CA125 level (i.e., biochemical relapse), the median time for a clinical relapse is 2-6 months. Currently, there is no consensus on the time when the treatment for recurrence should be started. However, data suggest that immediate treatment for this biochemical relapse is not beneficial. After biochemical relapse, recommended options include enrollment in a clinical trial, delaying treatment (i.e., observation) until clinical symptoms arise (strength of recommendation and level of evidence 2D), or immediate treatment (strength of recommendation and level of evidence 2D). ## Practice guidelines for ovarian cancer in korea Treatment of recurrent disease is generally as follows depending on time interval between the completion of previous treatment and recurrence: 1) Enrollment in a clinical trial or treatment for recurrent disease can be considered for progressive/stable/persistent disease during or after primary adjuvant chemotherapy. 2) Options for patients with platinum-resistant disease with recurrence less than 6 months after the completion of chemotherapy or for those with stage II-IV disease who have a partial response (including confirmation of cancer at the second-look operation) after primary chemotherapy include clinical trial and recurrent therapy. For platinum-resistant disease, single non-platinum-based agents or regimens are preferred. Response rate of the following agents for recurrent cancer appears to be similar: topotecan, 20%; gemcitabine, 19% [bib_ref] Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in..., Mutch [/bib_ref] ; liposomal doxorubicin, 26% [bib_ref] Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive..., Ferrandina [/bib_ref] ; oral etoposide, 27% [bib_ref] Prolonged oral etoposide as second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma:..., Rose [/bib_ref] ; belotecan (CKD-602), 20% [bib_ref] Phase II evaluation of CKD-602, a camptothecin analog, administered on a 5-day..., Lee [/bib_ref] ; docetaxel, 22% [bib_ref] Ifosfamide and mesna in previously treated advanced epithelial ovarian cancer: activity in..., Markman [/bib_ref] ; irinotecan, 29% [bib_ref] The safety and efficacy of the weekly dosing of irinotecan for platinum-and..., Matsumoto [/bib_ref] ; and weekly paclitaxel, 21% [bib_ref] Phase II evaluation of pemetrexed in the treatment of recurrent or persistent..., Miller [/bib_ref]. Other potentially active agents include vinorelbine, cyclophosphamide, melphalan, etc. The response rate for single-agent bevacizumab is about 20% [bib_ref] Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer..., Burger [/bib_ref]. On the base of the study results (AURELIA trial) that combination targeted therapy regimens with bevacizumab and one of paclitaxel/topotecan/liposomal doxorubicin could significantly improve PFS, these combinations can be recommended even though bevacizumab may cause hypertension, proteinuria, or intestinal perforation (strength of recommendation 1). 3) For patients with platinum-sensitive disease (i.e., complete remission and relapse ≥6 months after completing prior chemotherapy), preferred combinations include carboplatin/ paclitaxel [bib_ref] Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed..., Parmar [/bib_ref] , carboplatin/liposomal doxorubicin (especially for partially platinumsensitive which recur between 6 months and 1 year after completing prior chemotherapy) [bib_ref] Efficacy of pegylated liposomal doxorubicin (PLD) plus carboplatin in ovarian cancer patients..., Power [/bib_ref] , carboplatin/gemcitabine/bevacizumab (strength of recommendation and level of evidence 2A, evidence in Supplementary) [bib_ref] OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or..., Aghajanian [/bib_ref] , carboplatin/weekly paclitaxel [bib_ref] Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks..., Katsumata [/bib_ref] , carboplatin/docetaxel [bib_ref] Phase II trial of docetaxel and carboplatin in recurrent platinum-sensitive ovarian, peritoneal..., Strauss [/bib_ref] , carboplatin/gemcitabine [bib_ref] Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian..., Pfisterer [/bib_ref] , or cisplatin/gemcitabine [bib_ref] Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian..., Pfisterer [/bib_ref]. Based on a recent phase 3 randomized trial (GOG213) [bib_ref] Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer..., Coleman [/bib_ref] , ovarian cancer sub-committee members of the Guidelines Revision Committee of KSGO decided to add carboplatin/ paclitaxel/bevacizumab as a potentially active regimen for patients with platinum-sensitive recurrent ovarian cancer (strength of recommendation and level of evidence 2A). Enrollment to a clinical trial is also strongly considered to this group of patients. For patients with platinum-sensitive disease who cannot tolerate combination therapy, the preferred single agent is carboplatin, cisplatin, or oxaliplatin [bib_ref] Multicentre phase II study of oxaliplatin as a single-agent in cisplatin/carboplatin +/−..., Dieras [/bib_ref]. Based on a recent phase 3 randomized trial (SOLO2/ENGOT-Ov21) [bib_ref] Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer..., Pujade-Lauraine [/bib_ref] , ovarian cancer sub-committee members of the Guidelines Revision Committee of KSGO decided to level up the recommendation for KQ8 from 1D to 2A: single-agent olaparib tablets for maintenance therapy can be considered if platinumsensitive disease with partial or complete response following 2 or more lines of platinumbased therapy (strength of recommendation and level of evidence 2A, evidence in . SOLO2/ENGOT-Ov21 showed that the median PFS was significantly longer in women receiving olaparib than in those receiving placebo (19.1 months, 95% CI=16.3-25.7] vs. 5.5 months, 95% CI=0.22-0.41; p<0.001). Serious adverse events including anemia (19% vs. 2%), fatigue or asthenia (4% vs. 2%), and neutropenia (5% vs. 4%) were more frequently observed in olaparib maintenance group than placebo group. For another 2018 update on olaparib, ovarian cancer sub-committee members added a footnote that olaparib single therapy can be considered for patients with deleterious germline BRCA-mutated advanced ovarian cancer (platinum-sensitive or resistant) who have been treated with ≥3 lines of chemotherapy (strength of recommendation and level of evidence 2D) [bib_ref] Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation, Kaufman [/bib_ref]. 4) Secondary cytoreductive surgery can be considered for patients who recur after a long disease-free interval ≥6 months and lesions are localized and small (strength of recommendation and level of evidence 2D, version 2.0) [bib_ref] The role of secondary cytoreductive surgery in the treatment of patients with..., Eisenkop [/bib_ref]. After secondary cytoreductive surgery, combination chemotherapy mentioned above including carboplatin/paclitaxel, carboplatin/gemcitabine, or carboplatin/liposomal doxorubicin or other recurrence therapy can be considered. 5) Patients who cannot tolerate or fail to chemotherapy can be considered for tamoxifen and other hormonally active agents, including letrozole, anastrozole, leuprolide acetate, or megestrol acetate (level of evidence D), localized radiation therapy (RT) can also provide effective palliation (evidence level E). Regardless of which regimen is selected initially, reevaluation should follow after 2-4 cycles of chemotherapy (depending on the agent) to determine if patients benefited from chemotherapy. Patients who primarily progress on 2 consecutive chemotherapy regimens without evidence of clinical benefit may not benefit from additional therapy. Decisions to offer supportive care, additional therapy, or clinical trials should be made on a highly individual basis. ## Borderline epithelial ovarian tumor (low malignant potential) ## 1) diagnosis and treatment A borderline epithelial tumor is a primary epithelial lesion with cytologic characteristics suggesting malignancy but without frank invasion and with a clinically indolent behavior and good prognosis with 5-year survival greater than 80%. In contrast to patients with frankly invasive ovarian carcinoma, women with borderline epithelial tumors tend to be younger and are often diagnosed with stage I disease. A borderline epithelial tumor may grossly resemble an invasive cancer. However, microscopic evaluation fails to reveal evidence of frank invasion by the tumor nodules, although rarely invasive implants can be identified microscopically by the pathologist. Some clinicians feel that the appearance of invasive implants on the peritoneal surfaces in patients with borderline epithelial tumors portends a less favorable prognosis; therefore, postoperative chemotherapy can be considered for these patients. However, the benefit of chemotherapy is controversial in patients with borderline epithelial tumors. Especially for the patients without microscopically demonstrable invasive implants, observation is recommended option because the benefit of postoperative chemotherapy has not demonstrated. Treatment of borderline epithelial tumors generally depends on the histologic and clinical characteristics, the age of the patients, stage, and whether invasive implants are present. (1) Patients with a borderline epithelial tumor who desire to maintain their fertility may undergo surgery limited to a unilateral salpingo-oophorectomy with resection of residual disease. However, if the patient does not desire fertility-sparing surgery, standard ovarian cancer staging operation (total abdominal hysterectomy, BSO, and debulking as needed) and resection of residual disease are recommended. There is not enough evidence of whether complete staging operation may lead to better survival compared with incomplete staging operation in serous borderline epithelial tumors (evidence level E, evidence in Supplementary). Observation without postoperative adjuvant therapy is recommended for patients without invasive implants or only with noninvasive implants after surgery [bib_ref] Ovarian papillary serous tumors of low malignant potential (serous borderline tumors). A..., Kennedy [/bib_ref]. For patients with invasive implants after surgery, observation or adjuvant chemotherapy with the same regimens used for EOC can be considered (strength of recommendation and level of evidence 2C). Practice guidelines for ovarian cancer in Korea (2) Pathologic reevaluation is recommended if borderline epithelial tumor is diagnosed at previously performed surgery. If complete staging operation was performed, adjuvant treatment is recommended as mentioned above. If patients with known borderline epithelial tumors were incompletely staged at the time of their initial surgery, recommendations depend on whether residual tumor is present. If residual tumor is suspected, patients who want to preserve their fertility should have fertility-sparing surgery and resection of residual disease (for patients with invasive implants) or observation without further treatment (for patients without invasive implants or unknown). If residual tumor is not suspected, patients can be followed up without any further treatment even after initial incomplete staging operation. ## 2) follow-up and recurrence treatment After the completion of primary treatment, patients should be monitored for recurrent disease. Recommended schedule for follow-up visit includes history taking and physical examination every 2-4 months for the first 2 years, then 3-6 months for 3 years, then annually after 5 years. Blood test including CBC and chemistry profile and chest X-ray can be monitored as indicated. Patients who chose fertility-sparing surgery should be monitored by ultrasound examinations if necessary. Chest/abdominal/pelvic CT, MRI, PET/CT or PET may also be ordered if clinically indicated. If the CA125 level was initially elevated, then measurement of a CA125 level or other tumor markers is recommended for every visit. At the time of clinical relapse, surgical evaluation and debulking are recommended if appropriate. Patients who have invasive implants or low-grade invasive carcinoma after surgery may be treated using the same recommendations as for low-grade serous EOC (strength of recommendation and level of evidence 2C); those with high-grade invasive implants may be treated using the same recommendations as for EOC. Observation is recommended for those with noninvasive disease. ## Less common ovarian histopathologies (lcoh) The LCOH include carcinosarcomas (malignant mixed Müllerian tumors [MMMTs]), malignant germ cell tumors, and malignant sex cord-stromal tumors. LCOH is rare and different from EOC in terms of biologic behavior and treatment strategy. Many of LCOH occur in girls, adolescents, and younger women who are often diagnosed with stage I disease. Therefore, fertility-sparing surgery is often considered for those desiring fertility preservation. MIS sometimes can be used [bib_ref] Diagnosis, treatment, and follow-up of borderline ovarian tumors, Fischerova [/bib_ref]. ## 1) recommended workup Diagnosis of LCOH is often not made until after surgery for s suspicious pelvic mass. Therefore, the workup for LCOH is the same as for other types of ovarian cancer (ultrasound, CT, MRI, and/or PET, etc.) except that tumor markers are measured and other testing is done to determine the specific histopathology. Tumor markers may include CA125, inhibin, β-hCG, α-FP, lactic dehydrogenase (LDH), and CEA. An intraoperative frozen section evaluation is recommended for women who would like to maintain their fertility. Fertility-sparing surgery may be performed if the intraoperative frozen section results are positive for apparent early-stage tumors and/or low-risk tumors (i.e., malignant germ cell tumors or clinical stage I sex cord-stromal tumors) [bib_ref] Survival and reproductive function after treatment of malignant germ cell ovarian tumors, Zanetta [/bib_ref]. Patients who do not desire fertility preservation; those who have a clinical stage II-IV EOC; those with a clinical stage II-IV sex cord-stromal tumor; or those with carcinosarcoma should undergo comprehensive surgical staging as per the ovarian cancer guidelines. The recommended initial surgical recommendation for patients who were pathologically diagnosed at the previous operation depends on the specific histologic diagnosis and the surgical completeness of the previous operation. 2) Diagnosis and treatment [bib_ref] Society of Gynecologic Oncology recommendations for the prevention of ovarian cancer, Walker [/bib_ref] (3) Carcinosarcoma After complete surgical staging, several postoperative chemotherapy regimens are recommended for patients with stage I-IV carcinosarcoma. Patients with stage I-IV carcinosarcoma or recurrence may be treated using the same primary chemotherapy regimens that are recommended for EOC. ## Summary of recommendation and conclusions The following recommendations and conclusions are based on 4 levels of evidence (A, high; B, moderate; C, low; D, very low) and 2 strengths of recommendation (1, strong; 2, weak). 1. Systemic PLND and/or PALND may be selectively performed for those patients with EOC apparently confined to an ovary under the physician's discretion despite the lack of evidence for survival improvement compared with selective or omitting PLND and/or PALND (2B). 2. NAC followed by interval debulking surgery may be considered for patients with extensive stage IIIC-IV EOC who are not likely for optimal cytoreduction by upfront primary surgery based on that overall survival was comparable between these patients (2A). 3. Weekly dose-dense paclitaxel is associated with increased hematologic toxicity compared with standard therapy given every 3 weeks. However, weekly regimen can be considered depending on clinical judgment of gynecologic oncologist because this regimen might improve survival (2B). 4. Bevacizumab maintenance following initial chemotherapy with paclitaxel/carboplatin/ bevacizumab in patients with EOC can be recommended based on this regimen has been shown to modestly increase PFS (2A). For recurrence therapy, bevacizumab-containing regimens can be recommended for platinum-sensitive recurrent EOC (2A) and platinumresistant recurrent EOC with priority (level 1) based on these regimens have been shown to increase PFS. 5. ROMA can be used for differential diagnosis of adnexal tumors under the clinician's discretion based on the results that ROMA might be more sensitive and specific than CA125 alone (2D). 6. Evidence level of whether complete staging operation may lead to better survival compared with incomplete staging operation in serous borderline epithelial tumors cannot be appropriately decided (E). 7. For young patients who desire to maintain their fertility, a unilateral salpingooophorectomy preserving the uterus and contralateral ovary and comprehensive surgical staging may be considered for select unilateral stage I tumors because fertility-sparing surgery does not seem to damage survival outcomes (2D). 8. Poly(ADP-ribose) polymerase (PARP) inhibitor (olaparib tablets) for maintenance therapy can be considered for patients with BRCA-associated EOC, particularly for platinum-sensitive recurrent EOC patients with germline BRCA mutation, because PARP inhibitor maintenance therapy can prolong PFS . [table] Table 1: Modified WHO classification of tumors of the ovary by the Gynecological Pathology Study Group of the KSP A. Epithelial tumors Korean Society of Pathologists; WHO, World Health Organization. [/table] [table] Table 2: FIGO and TNM staging system for ovarian cancer International Federation of Gynecology and Obstetrics; TNM, tumor, node, and metastasis. [/table] [table] Table 3: Levels [/table] [table] Table 5: Definition of progression after first-line therapy in ovarian cancer proposed by gynecologic cancer intergroup[15] [/table]	None	None	Since after 2006 when the first edition of practice guidelines for gynecologic oncologic cancer treatment was released, the Korean Society of Gynecologic Oncology (KSGO) has published the following editions on a regular basis to suggest the best possible standard care considering updated scientific evidence as well as medical environment including insurance coverage. The Guidelines Revision Committee was summoned to revise the second edition of KSGO practice guidelines, which was published in July 2010, and develop the third edition. The current guidelines cover strategies for diagnosis and treatment of primary and recurrent ovarian cancer. In this edition, we introduced an advanced format based on evidence-based medicine, collecting up-to-date data mainly from MEDLINE, EMBASE, and Cochrane Library CENTRAL, and conducting a meta-analysis with systematic review. Eight key questions were raised by the committee members. For every key question, recommendations were developed by the consensus meetings and provided with evidence level and strength of the recommendation.
cf0687d7936b11e0a7644235c69308d347569763	pubmed	Italian inter-society expert panel position on radiological exposure in Neonatal Intensive Care Units	Italian inter-society expert panel position on radiological exposure in Neonatal Intensive Care Units Background: In # Introduction In the last decades, the clinical progress, the better medical assistance for pregnant women even in very difficult gestations, together with the introduction of new complex technologies, allowed the improvement of preterm, and/or with serious disease infants, survival. Nevertheless, the survival increase in such high-risk infants frequently requires radiological surveys, mainly chest-and abdomen-x ray in incubator. In order to get better safety levels, it is a common opinion to share different specialist experiences in order to define best practice recommendation and guidelines. The aim of this document is to assist healthcare practitioners in taking choices involving radiation exposures of new-born infants and to give practical recommendation about justification and optimization in Neonatal Intensive Care Units. These expert panel was constituted by expert from four Italian main representative scientific societies: AIFM (Italian Association of Physics in Medicine), SIN (Italian Neonatology Society), SIP (Italian Paediatric Society), SIRM (Italian Medical Radiology Society) in order to guarantee good standard practices for every professional involved in Neonatal Intensive Care Units (NICU). The adherence to these practical recommendations could ensure a high quality and patient safety. More complex radiological practice, such as CT scan or fluoroscopy have been excluded. ## The expert panel The panel was constituted by experts from the main society on the field including paediatric radiologist, neonatologist, paediatricians, medical physics and radiologist with expertise in radiation protection. There are new evidence and regulation in radiation protection and a relative lack in radiation protection culture among clinicians. There is also a relative lack of consensus in the published literature as to the best approach to use to communicating risks to patients and relatives. The methodology used was: 1) recognized common clinical request for performing a radiological procedure; 2) good practice for the execution of the radiographic exams in NICU with a multidisciplinarity to facilitate diversity of views and expertise from paediatric radiologist, neonatologist, paediatricians, medical physics and radiation protection perspective; and 3) both a national and international recommendation (ICRP), European directive (EURATOM) context to facilitate a global representation and exchange of state-of-the-art knowledge, with the aim of implementing execution of the radiographic exams in NICU. ## Clinical indications The clinical indications for carrying out investigations that require the use of ionizing radiation in new-borns admitted to neonatal intensive care unit (NICU), and assisted in an incubator, are varied and mainly divided into prescriptions for the study of the thorax and abdomen. The most frequent thoracic indications areNeonatal respiratory distress syndrome (NRDS), which generally affects the preterm infant, and is secondary to a surfactant deficiency and to the immaturity of the respiratory system and alveolar capillary unit. Congenital abnormalities of surfactant synthesis. Transient tachypnoea of the new-born (or "wet lung disease") (TTN), a condition resulting from the abnormal retention of foetal lung fluid, generally found in births by elective caesarean delivery, or in "late preterm" new-borns, with 34-36 weeks gestational age. Meconium aspiration syndrome (MAS), which causes respiratory failure through various mechanisms, such as airway obstruction, infection, chemical irritation and surfactant inactivation. Bacterial, viral or fungal pneumonia can be considered, like the previous conditions, a real emergency, especially in preterm and low birth weight infants. Malformations (es, congenital diaphragmatic hernia (CDH), oesophageal atresia and tracheoesophageal fistula (TEF), congenital pulmonary airway malformation (CPAM), congenital heart diseases), before and after surgery. Bronchopulmonary dysplasia (BPD). Complications of mechanical ventilation or "air leak syndrome" (es, pneumothorax, pneumomediastinum, pulmonary interstitial emphysema (PIE)). Pleural or pericardial effusions in hydropic new-borns or following parenteral solutions extravasation. Suspected fractures or malformations of the thoracic skeleton. Prenatal ultrasound finding of suspected or confirmed anomaly. In these situations, only one radiogram in the anteriorposterior projection (AP) is generally sufficient; additional radiographic projections may be required whenever pneumothorax and/or pneumomediastinum are suspected. However, in the context of the aforementioned clinical indications the development of pulmonary ultrasound should be considered. There is no need to perform chest radiographs, without clear clinical indication, in case of or for: daily examination in new-borns with mechanical ventilation; pre-and post-intubation; each re-intubation to confirm the endotracheal tube position; any worsening of the value of SpO2 or any situation in which increasing the amount of O2 to be supplied to the new-born is needed; mild respiratory distress. ## Abdominal indications May occur in new-borns with prenatal ultrasound findings of suspected or confirmed anomaly, or with alterations of intestinal transit, which have gastric residual, vomiting, abdominal distension. In neonates with proximal occlusion and non bilious vomiting, a gastric atresia, congenital antral membrane, pyloric atresia or duodenal atresia should be suspected. If the vomit is bilious duodenal atresia or stenosis, malrotation or preduodenal portal vein can be the possible causes. In these cases radiograph in AP projection and ultrasound study are able to provide the correct diagnosis. In the suspicion of antral membrane or intestinal malrotation completing the investigation with oral administration of a lowosmolality contrast medium is opportune. In the case of new-borns with low occlusion and abdominal distension, in which a jejunoileal or colic pathology can be observed, the direct radiogram of the abdomen in anterior-posterior projection and a radiological study with endorectal low-osmolarity contrast medium shows the localization of upstream gas distension and a non-use microcolon pattern, respectively. In the anal atresia or imperforation, it is useful to request the invertogram with radio-opaque marker. A separate condition is necrotizing enterocolitis (NEC), which can develop in preterm and low birth weight newborns, and is characterized by pneumatosis intestinalis, necrosis and perforation. The radiogram in AP projection shows the signs of intestinal distension, intestinal and portal pneumatosis and, in the advanced stage, abdominal free air. If intestinal perforation is suspected, the lateral projection may be useful, in the supine position or in the left lateral decubitus. Radiograms of the abdomen do not need to be performed without clear clinical indicationin: gastroenteritis; hematemesis; hypertrophic pyloric stenosis (HPS). ## Other indications Are the verification of the correct positioning of endotracheal tubes, pleural or peritoneal drainages, venous or arterial lines (umbilical and central). In such cases, the AP projection of the thoracic or abdominal area to be examined is generally sufficient. However, the development of ultrasound in these areas must be taken into consideration. Good practice for the execution of the radiographic exams in NICU The implementation of the patient radioprotection principles, as reported in the national and international low, foresees that all the individual medical exposures must be preliminarily justified, keeping in mind the specific objectives of the exposure, the patient characteristics and the diagnostic path that the patient is completing. Following the choice of a considered appropriate exam, it is necessary to respect the optimization principle, that requires the implementation of all the shrewdness to maintain the doses as low as possible in accordance with a correct exam result. It means to use appropriate radiological devices subjected to a periodic Quality assurance program in line with the current law on patient protection. Moreover, some critical issues that can increase the patient doseshould be prevented: wrong patient positioning; optical field inaccurate or not present on the equipment; devices and execution protocols not well known because of the workers turnover; presence of devices or materials that could pollute the images; mechanical fragility and resulting in position instability; detectors impairment due to an accidental fall; artifacts due to poor detector cleaning. ## Appropriateness and quality of the equipment In a NICU, it is necessary to have a portable radiographic equipment that provides the best patient safety and adequate functionalities to produce radiographs with excellent diagnostic image quality in terms of acquisition and post-processing parameters, together with very short exposure times, suitable for new-borns. The image acquisition modality must be based on indirect digital detectors (CR, "computed-radiography") or direct (DR, "digitalradiography"). The latter method is preferable due to the increased sensitivity, dose reduction, speed and ease of use. It is also strongly recommended that the radiological equipment is equipped with a system that tracks and displays the delivered dose (P KA or DAP, dose-area product) at the time of exposure. It is advisable that the department has always access to the same equipment on which the radiographers have carried out a thorough training. It is also recommended that not only the current diagnostic reference levels (LDR) are respected, but also that a comparison is carried out considering the most recent recommendations found in international guidelines, which are constantly updated, and the specialist literature. ## Patient, examination and diagnostic images identification Generally, medical structures have internal procedures meant to correctly identify patients, based on national and/ or international guidelines. Below in this document, some good practice recommendations are provided. Operators shall verify the new-born's identity and the correspondence between the patient and the requested examination before every radiologic practice. Nowadays, these operations are simplified because the NICU (Neonatal Intensive Care Unit) issues identification bracelets that facilitate the patient's identification and the correspondence between personal details related to the examination request and the patient itself. Such data and position indicators (left and right) shall be clearly visible in the diagnostic image. ## Patient positioning and immobilization The correct patient positioning is essential for a successful radiographic examination and is one of the crucial factors to avoid repeated and undue exposures for the patient. Immobilization can be obtained through the use of some instruments, such as synthetic materials "nests" or paediatric sandbags. The radiographer provides nurses with all the indications about the aforementioned instruments positioning to avoid new-born incorrect position as well as interposition of medical devices within the field of investigation. In order to reduce risks related to the onset of infections or other problem for the new-born and to assure the diagnostic examination reproducibility, a good practice recommendation is to use, for the radiologic examination, a cassette (where available). Should the cassette be unavailable or in case of specific examination requirements, it is possible to perform the xray examination through the detector physically contacting the new-born. In such cases the detector must be wrapped in a polyethylene bag or similar, preferably sterile, in order to ensure the maximum safety and to limit infection risks. Exceptionally, new-borns may be immobilized by the operator, that shall be equipped with protection device from diffuse radiation and shall remain outside the primary beam. This task is strictly forbidden for women whose pregnancy Is ascertained. ## Size of the field of view and collimation Correct beam limitation to the field of interest is paramount. X-ray field size must never be larger than necessary, at the same time including the anatomy of interest in order not to compromise the diagnosis or make a second exposure necessary (doubling the dose). It is mandatory to limit the number of Chest & Abdominal Radiographies (single radiogram). The "Chest & Abdominal "with a unique exposure can be useful, in selected cases, to verify the position of catheters/ lines/tubes. We emphasize that focusing the beam on the abdomen involves a difficult reading of the thorax, which appears with a pseudo lordotic image (oblique beam). Collimation should include: Chest Radiography in Neonates. Superiorly: at the level of the chin, nothing above this level should be irradiated. Inferiorly: just below the level of the nipples. Laterally: to include the lateral chest walls. ## Abdominal radiography in neonates Superiorly: to include the top of the diaphragm. Inferiorly: to symphysis pubis. Laterally: to include the lateral abdominal walls. ## Chest & abdominal radiography in neonates. Superiorly: at the level of the chin, nothing above this level should be irradiated. Inferiorly: to symphysis pubis. Laterally: to include the lateral chest and abdominal walls. In children, 40% of the red marrow is inside the long bones and in the skull. It is therefore necessary to respect the above-mentioned collimations, not including the limbs or the head-neck in the radiograms. In cases where it is mandatory to reveal the folding back of the catheters, the insertion point must be included in the radiogram. ## Radiation shielding The exposure of the gonads of the new-born, especially preterm, raises concerns about the potential long-term harmful effects. Generally, the positioning of shields for the male gonads is complicated because, especially in premature infants, the gonads are found near to the pubic symphysis and is very difficult to exclude them from the field of view of radiograms. In the case of the female gonads, however, it is very difficult to shield the ovaries without covering the entire pelvis. The entrance dose accepted for neonatal abdominal radiography is generally very low and the probability of occurrence of long-term effects due to this exposure is negligible. If you use proper collimation, a correct filtration addition and proper positioning of the patient, the dose to the gonads of the new-born, in the absence of lead shielding, is in the order of about a few tens μGy for males; for females it is further reduced because the ovaries are naturally shielded by 3 to 4 cm of soft tissue. The expected benefit from the use of shielding is not offset by the potential risk of obscuring the patient's anatomical structures and repeating the examination. ## Parameters and exposure mode The exposure depends on: -The method of execution with a detector in contact with the new-born or inserted in the cradle-box holder determines important differences in the delivered dose to the disadvantage of the second; the detection system employed: DR systems today are those that allow the best ratio between image quality and dose. Furthermore, the presence of additional filters should be considered. Optimization is possible only by studying the available system, and overall, the applied voltage can range from 50 to 65 kVp and 0.5 to 3 mAs with a focus-receptor distance (DFR) set at 100 cm. If possible, the patient should be exposed during the inspiration phase when the examined area is in the chest, and expiration in case the examined area is that of the abdomen alone. ## Diagnostic reference levels The latest diagnostic reference levels (LDR) are those proposed by the European project PiDRLwhich is currently being published. This document, however, only shows, for the new-born, the indication of P KA of 15 mGy*cm 2 for a AP chest radiograph, while for other views it is suggested to refer to other literature data. The most recent ones include the values in. ## Examples of good radiological practice in neonatal radiology The clinical suspicion must always be reported in the prescription of the examination in order to document the appropriateness of the latter for that specific case. When intestinal perforation or bowel obstruction is suspected, additional X-ray with lateral projection. ## Type of incubators and impact on exposure The risk of infections is to be considered among the main fatalities in the process of treating preterm babies. This is one of the reasons that have led the manufacturers of specific NICU incubators to produce cots with a box-holder placed under the bed. In this way the cassette never comes in contact with the child and the risk of infections is reduced. As a consequence, this higher focus-detector distance forces to increase exposure parameters and leads to a higher patient dose value that must be considered when purchasing these devices. Another recent modification of commercially available NICU incubators consists of interposing a scale between the child and the cassette-holder, and this allows the medical staff to carry out a constant monitoring of the weight of the new-born, keeping the patient isolated in a protected environment. All these changes have certainly been designed to benefit the new-born patient, however, from the standpoint of radioprotection, we must remember that whatever material is interposed between the patient and the image receptor, it leads to a dose increase in patients who might weigh even less than one kilogram and are usually subjected to a remarkable number of tests, due both to the seriousness of their health condition and to the length of the period of hospitalization. To quantify to what extent these changes have influenced the dose increase, a measurement campaign was carried out in 10 Italian hospitals and the data have been elaborated by AIFM. The following is a summary of the results obtained. The method used to calculate the attenuation was as follows: Measurements taken at different energy values (50, 55, 60, 65, 70 kVp) were considered; The attenuation was obtained comparing measurements of the beam attenuated by all the material in the beam, canopy with support and mattress, and by the canopy only. In general, it can be said that depending on the model, with a typical X-ray beam inherent filtration (1.5-2 mm Al) the attenuation in the range 50-70 kVp varies between 20 and 25% on average, while in case of use of additional filters, typically 1 mm of aluminium (Al) and 0.1 mm of copper (Cu), the attenuation decreases to 16 and 20% on average. The use of additional filters is therefore always recommended. In the incubators in which the inserted weighing scale results in a further attenuating factor, this is of the order of 40-50% without additional filtration, while it is of the order of 15% with added filtration, it would therefore be advisable to avoid incubators with metal supports as they attenuate the X-ray beam more than all the others, even with added filtration. ## Patient and nicu operators radioprotection This section provides quantitative information about exposure to ionizing radiation levels in a NICU: i) other patients, close to the one involved in the radiologic examination, ii) accompanying persons and iii) the ward staff. Moreover, the protection devices efficiency (e.g. mobile bulkheads and anti-X sheet) will be evaluated in the following. During the examination, hospitalized patients cannot be moved out of the ward. For this reason, during the irradiation, the other patients in the room are exposed to the diffuse beam coming from the under-examination patient close to them. In order to investigate the diffuse radiation effect, there have been some tests performed and are described as follows: the measurement of radiation diffused from the cradle involved in the examination has been achieved at different angles and from 1 mt of distance both for AP and LL projections with a mobile radiographic device equipped with CR image detector: 60 kVp, 0.5 mAs (50 mA and 0.01 s) for AP projection; 70 kVp, 0.5 mAs (50 mA and 0.01 s) for LL projection. The obtained values for a single radiogram oscillate between 0.01 ÷ 0.05 μSv/radiogram for the AP projection and between 0.03 ÷ 0.50 μSv/radiogram for the LL projection. Supposing that 90% of the radiograms are performed in AP projection and the remaining 10% in LL projection, the values for single radiogram oscillate between 0.012 ÷ 0.095 μSv/radiogram. Assuming that a patient has n. 4 adjacent cradles and that each of the close patients performs n. 1 radiogram/ day (90% in AP and 10% in LL) for 365 consecutive days, the annual dose value due to the diffuse radiation at 1 my distance is in the order of 150 μSv/year. The dose absorbed for a patient at 1 mt distance during a solar year is therefore well below 500 μSv. It is then not deemed necessary to use mobile screens (e.g. bulkheads) if the incubators are at least at 1 mt of distance from each other. The efficacy of anti-X sheets for reducing the diffuse radiation has been investigated using the same geometry described above. A Pb equivalent anti-X sheet (0.25 mm thick) has been used to cover the cradle adjacent to the one involved in the examination. Although the use of protection devices such as anti-X screens allows a 100 times lower dose reduction compared to an already low value, its use is not recommended because the expected benefit is not balanced by the risk due to loss of visual contact with the patient and interference with vital parameters monitoring equipment (taking into account the optimization principle). During the irradiation of a patient undergoing examination, the accompanying persons and any staff member present may also be exposed to the diffuse radiation. The results of environmental dose assessments in a typical NICU ward, obtained by passive environmental dosimetry, report dose values lower than the natural radiation background. For distances greater than 1 mt from the axis of the primary beam, the dose absorbed by a hypothetical individual exposed during an entire calendar year is less than the value of 1 mSv/year, equal to the exposure limit to ionizing radiation for the population currently provided for in the Italian law in force. Since the absorbed dose decreases at the inverse of the square of the distance, it is good practice, however, if there are safety conditions for the patient, to ensure that the accompanying persons and the operators are positioned as far as possible from the primary beam. The radiologic technologists performing the examination shall wear suitable Individual Protection Device being usually exposed, during the calendar year, to other sources of ionizing radiations. The "dose" communication and the appropriate patient information An adequate communication of the benefits deriving from a radiological procedure, of the ionizing radiations (IR) dose and of the potential adverse effects, represents a key priority of the therapeutic relationship Clinician-Patient, and allows to avoid unjustified concerns and the necessary examinations refuse. The parents often interact with the paediatricians or with the neonatologists asking explanations about the radiological procedures performed on the hospitalized new-borns in NICU. Nevertheless, it is not infrequent that they put the questions to the technicians or to the nurses. It is therefore important that all the operators have a certain familiarity in radioprotection, knowing the mean of the data they transmit to the patients and what represent, avoiding an "alarmistic" communication. ## Radiation protection basic notions The ionizing radiations (IR) have been classified in class 1 by the WHO, inside the group of the substances surely carcinogenic for the humans. Nevertheless, the carcinogenic effect of the RI is shown in vivo only for doses > 100 mSv. Under this threshold (low doses) currently available scientific data do not allow to esteem the harmful effects of the IR for certain, that are stochastics (or probabilistic, not dose-related) and not distinguishable from those induced by other factors. In the low doses range, as reported in the publication 103 of the International Council of Radiation Protection (ICRP), the theory of the "linear effect without threshold" (LNT, linearno-threshold) is underlined. Following this theory there is a direct linear relationship among the entity of the dose and the cell damage probability (not gravity). For these reasons a precautionary attitude is pursued in the justification principle respect according to which every single medical-radiological procedure must be preventively justified so that to guarantee that the benefits are superior to the risks. When the benefits and the risks of a procedure are evaluated, it is not often considered the risk, not negligible, of a missed diagnosis or of a delay in the beginning of the cares with effects on the child outcome. ## How to establish an effective communication In preparing an effective physician-patient communication, it is essential to identify some key messages to transmit, personalizing every single situation (potential diagnosis, the new-born's prognosis, cumulative exposure) and preparing in advance the answers to the most frequent questions, suiting the language for the interlocutors and avoiding, if possible, scientific terms or statistics and complex numbers. In the majority of the cases parents are not interested to a numerical information about the dose but to the risk that can derive from it. Therefore it is useful to remember that the radiological procedures use the radiations ionizing as the mean to get diagnostic information on our organism and to protect our health, and that the human body is provided with physical and biological mechanisms designated to protect us from RI late effects. In particular: Identify the exposure and the dose Compare the dose of the proposed procedure to other imaging techniques and the natural background Strongly underline the benefits and the clinical necessity of the procedure Ensure that the dose is personalized on the child dimension Avoid inducing worries explaining the potential risks from IR Use tables in which quantitative (i.e.0.01%) and qualitative (negligible for RX, very low for CT) estimations are reported and compare to basal tumour incidence (40-42%) and the other risks deriving from daily activities such as to cross the road or to drive a car In the physician-patient communication it is necessary to pay attention in forwarding the information both in oral and figurative language. The same numerical data, if not correctly explained, may result unjustified alarming as in the use of "equivalent thorax examinations" (i.e. 1 TC = 200 RX; would you have 200 rx in the same time') or quantitative estimations of neoplastic risk (i.e. 0.01% after RX), that are usually "personalized" by the parents especially in emotional stress situations (that 1/10000 will surely be my child!). The figurative (and oral) language to avoid, a typical example is the fast exiting of the operators from the NICU whenever a radiography is performed, with sentences like "pay attention they are taking the rx" or "quickly get out", creating unnecessary anxieties in the parents of the hospitalized children. # Conclusions This document will allow a standardization of the approach to the exposures in NICU, although oriented to a flexible methodology. # Appendix ## Execution and quality requirements -percutaneous central (cvc) vein catheterization Verify the catheter's position (the top of the catheter must be between T3 and T5 if in superior part of the vena cava and between T8 and T10 if in inferior). In case of catheter of small dimensions (1 Fr) it could be useful the use of a low osmolality contrast media that must be injected very slow in a quantity just enough to fill only the catheter. The radiological exam must be repeated after 3-5 s to allow the blood flow to eliminate the excess of contrast media from the top of the catheter, in order to identify it. -Umbilical Vein Catheterization (UVC) Verify the UVC position (the top of the catheter must be far from the hepatic veins origin, from the portal vein and from the oval foramen; UVC must be inside the venous ductus or in VCI, 0.5-1 cm over the diaphragm, T8-T9). The primary indications for the positioning of the catheter inside the umbilical vein, are the pharmacological reanimation in the delivery room, the need for a central access during the first days in critical patients for parenteral nutrition and drugs administration, or the necessity to perform an exchange-transfusion (EXT). Secondary indications are the infusion of solutions, drugs and the need of blood tests. Possible side effects to the positioning of an umbilical (UVC) venous catheter are omphalitis, omphalocele, necrotizing enterocolitis (NEC), peritonitis or damage from the infusion extravasation. -Umbilical Artery Catheterization (UAC) Low position (L3-L5, under inferior mesenteric artery), high position (T6-T9, thoracic aorta, over the celiacmesenteric-renal arteries). ## -endotracheal intubation Calculate the distance from tracheal carina (position: middle bystander of the trachea, 1-2 cm over the carina, T4 level) and be sure that the right principal bronchus has not been intubated and that there are no lobar hypoventilation phenomena. -Nasogastric probe Make sure that the top is projected inside the stomach. ## -thoracic drain The apposition of the catheter for the thoracic drain could be necessary in case of pneumothorax or pleural Practical example of an effective communication ## Question answer Why this exam? We need some information that only this exam can give us in an accurate and rapid way. Are there any risks? The risk, if it exists, is very small and it is a possible radio-induced tumour. But we are not sure that really a risk exists to the RX and TC low doses. When they may occur? The most important risk is not to make an important diagnosis in the next minutes / times / days. The potential radio-induced damage may take some years If he/she will develop a tumour after this exposition? In Italy the basic level to develop a tumour is 40-42%. The additional risk is negligible (from 40-42% to 40.01-42.01%) How can I know that the IR dose is the appropriate one for my child? We use different protocols and techniques according to the clinical questions and of the child dimension. Then we periodically compare oud delivered doses with national and international references to be confident to work in a safety range. This exam is really necessary? Yes. I understand your worries for the potential effects of the RI but the examination is important for your child. If you think about it, every time you drive your car you don't worry about the probabilities you have to be involved in a deadly accident, because the advantage to use the car is superior. This is the same thing.	None	https://ijponline.biomedcentral.com/track/pdf/10.1186/s13052-020-00905-5	None
8b9162a616107fcb45eafca1e7d920a40184cdef	pubmed	Nutritional management in head and neck cancer: United Kingdom National Multidisciplinary Guidelines	Nutritional management in head and neck cancer: United Kingdom National Multidisciplinary Guidelines Nutritional support and intervention is an integral component of head and neck cancer management. Patients can be malnourished at presentation, and the majority of patients undergoing treatment for head and neck cancer will need nutritional support. This paper summarises aspects of nutritional considerations for this patient group and provides recommendations for the practising clinician. ## Recommendations - A specialist dietitian should be part of the multidisciplinary team for treating head and neck cancer patients throughout the continuum of care as frequent dietetic contact has been shown to have enhanced outcomes. (R) - Patients with head and neck cancer should be nutritionally screened using a validated screening tool at diagnosis and then repeated at intervals through each stage of treatment. (R) - Patients at high risk should be referred to the dietitian for early intervention. (R) - Offer treatment for malnutrition and appropriate nutrition support without delay given the adverse impact on clinical, patient reported and financial outcomes. (R) - Use a validated nutrition assessment tool (e.g. scored Patient Generated-Subjective Global Assessment or Subjective Global Assessment) to assess nutritional status. (R) - Offer pre-treatment assessment prior to any treatment as intervention aims to improve, maintain or reduce decline in nutritional status of head and neck cancer patients who have malnutrition or are at risk of malnutrition. (G) - Patients identified as well-nourished at baseline but whose treatment may impact on their future nutritional status should receive dietetic assessment and intervention at any stage of the pathway. (G) - Aim for energy intakes of at least 30 kcal/kg/day. As energy requirements may be elevated post-operatively, monitor weight and adjust intake as required. (R) - Aim for energy and protein intakes of at least 30 kcal/kg/day and 1.2 g protein/kg/day in patients receiving radiotherapy or chemoradiotherapy. Patients should have their weight and nutritional intake monitored regularly to determine whether their energy requirements are being met. (R) - Perform nutritional assessment of cancer patients frequently. (G) - Initiate nutritional intervention early when deficits are detected. (G) - Integrate measures to modulate cancer cachexia changes into the nutritional management. (G) - Start nutritional therapy if undernutrition already exists or if it is anticipated that the patient will be unable to eat for more than 7 days. Enteral nutrition should also be started if an inadequate food intake (60 per cent of estimated energy expenditure) is anticipated for more than 10 days. (R) - Use standard polymeric feed. (G) - Consider gastrostomy insertion if long-term tube feeding is necessary (greater than four weeks). (R) - Monitor nutritional parameters regularly throughout the patient's cancer journey. (G) - Pre-operative: ○ Patients with severe nutritional risk should receive nutrition support for 10-14 days prior to major surgery even if surgery has to be delayed. (R) ○ Consider carbohydrate loading in patients undergoing head and neck surgery. (R) - Post-operative: ○ Initiate tube feeding within 24 hours of surgery. (R) ○ Consider early oral feeding after primary laryngectomy. (R) # Introduction Nutrition and Dietetic services should be organised to provide a seamless service at any stage of the patient pathway. There should be access to dedicated, site-specific dietitians for high-quality service delivery and contribution as a core member of the head and neck multidisciplinary team.Early identification of highrisk patients and intervention with nutrition support should be included as part of the planning for every patient when treatment options are being considered. This should include quality of life (QoL) issues to address psychosocial, rehabilitation and survivorship needs of patients and carers. ## Recommendation - A specialist dietitian should be part of the multidisciplinary team for treating head and neck cancer patients throughout the continuum of care as frequent dietetic contact has been shown to have enhanced outcomes (R) ## Nutritional screening The purpose of nutritional screening is to identify patients who are malnourished or at risk of becoming malnourished as early as possible. 1,2 All inpatients on admission and all outpatients should be screened to identify those who require early nutritional intervention and prompt referral. Early nutritional intervention is essential to correct preexisting nutritional deficiencies with regular reviews throughout the patient's journey in order to optimise nutritional status and correct nutrition-related problems at each stage of treatment. [bib_ref] ESPEN Guidelines on Enteral Nutrition: surgery including organ transplantation, Weimann [/bib_ref] Recommendation - Offer treatment for malnutrition and appropriate nutrition support without delay given the adverse impact on clinical, patient reported and financial outcomes (R) ## Nutritional assessment Following nutritional screening a full nutritional assessment should be undertaken in a pre-treatment assessment clinic setting and at regular intervals during a patient's treatment trajectory 1,2 [fig_ref] TABLE I NUTRITIONAL: SCREENING AND ASSESSMENT TOOLS• Ability to chew and swallow • Clinical signs... [/fig_ref]. ## Recommendations - Use a validated nutrition assessment tool (e.g. scored Patient Generated-Subjective Global Assessment or Subjective Global Assessment) to assess nutritional status (R) - Offer pre-treatment assessment prior to any treatment as intervention aims to improve, maintain or reduce decline in nutritional status of head and neck cancer patients who have malnutrition or are at risk of malnutrition (G) - Patients identified as well-nourished at baseline but whose treatment may impact on their future nutritional status should receive dietetic assessment and intervention at any stage of the pathway (G) ## Cancer cachexia Cachexia syndrome results in decreased appetite, weight loss, metabolic alterations and an inflammatory state that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. Pro-inflammatory processes can lead to insulin resistance, increased loss of body fat, muscle mass and production of acute phase proteins. Cytokine-induced metabolic alterations can prevent cachectic patients from regaining body cell mass during nutritional support, and are not relieved by conventional nutritional intervention. Attempts to modulate these changes by other means should be integrated into the management of cancer patients. As a minimal goal body weight should be maintained and further loss prevented. The management approach should be multifactorial and includes assessment and ongoing monitoring with intensive nutritional support, anti-inflammatory treatment, symptom control as well as oncological treatment options to reduce the catabolic effect of the cancer.Estimating nutritional requirements Cancer itself does not have a consistent effect on resting energy expenditure, but may be influenced by oncological treatment. Resting energy expenditure can be unchanged, increased, or decreased. 2 Cancer patients are mildly hypermetabolic with an excess energy expenditure of between 138 and 289 kcal/ day. Total energy expenditure and protein requirements for non-obese ambulatory patients using their actual body weight can be estimated as follows: Energy, 30-35 kcal/kg/day and protein, 1.2 g/kg/ day.These may be less accurate for severely malnourished, morbidly obese and surgical patients. ## Recommendations - Aim for energy intakes of at least 30 kcal/kg/ day. As energy requirements may be elevated post-operatively, monitor weight and adjust intake as required (R) - Aim for energy and protein intakes of at least 30 kcal/kg/day and 1.2 g protein/kg/day in patients receiving radiotherapy or chemoradiotherapy - Patients should have their weight and nutritional intake monitored regularly to determine whether their energy requirements are being met (R) ## Refeeding syndrome Refeeding is a syndrome consisting of metabolic disturbances that occur as a result of reintroduction of nutrition to patients who are starved or severely malnourished. It can occur irrespective of the feeding route. The main feature is hypophosphataemia but can feature abnormal sodium and fluid balance; changes in glucose, protein, and fat metabolism, thiamine deficiency, hypokalaemia and hypomagnesaemia. [bib_ref] Refeeding syndrome: what it is, and how to prevent and treat it, Mehanna [/bib_ref] The nationwide incidence of refeeding syndrome in head and neck cancer is unknown. By defining refeeding syndrome as a reduction in serum phosphate to below 0.4 mmol/l, 1,7 retrospective data from a regional cancer centre found 37.5 per cent of patients to be at risk as defined by National Institute for Health and Care Excellence criteria (see Box II) with an incidence rate of 9.5 per cent. A suggested management plan for refeeding syndrome is shown in [fig_ref] FIG. 1: Management of re-feeding syndrome [/fig_ref]. Patient has one or more of the following: ## Recommendations - Body mass index less than 16 kg/m 2 - Unintentional weight loss greater than 15 per cent within last three to six months - Little or no nutritional intake for more than 10 days - Low levels of potassium, phosphate, or magnesium prior to feeding Or patient has two or more of the following: - Body mass index less than 18.5 kg/m 2 - Unintentional weight loss greater than 10 per cent within last three to six months - Little or no nutritional intake for more than 5 days - A history of alcohol abuse or drugs, including insulin, chemotherapy, antacids or diuretics ## Nutrition support The aims of nutrition support are to: - Improve the subjective QoL - Enhance anti-tumour treatment effects - Reduce the adverse effects of anti-tumour therapies, - Prevent and treat undernutrition. Nutritional support should be considered in the following scenarios: - Body mass index <18.5 kg/m 2 - Unintentional weight loss >10 per cent over three to six months - A BMI <20 kg/m 2 and unintentional weight loss over three to six months - Minimal intake >5 days - Increased nutritional requirements due to catabolism. ## Types of nutrition support Nutritional intervention should be tailored to meet the needs of the patient and be realistic for the patient to achieve. There are three main methods of nutrition support: oral, enteral and parenteral. Parenteral nutrition support is rarely used in the head and neck setting. It should however be considered if required. Oral nutrition support Nutritional interventions include relaxation of previous therapeutic diets to minimise further nutritional compromise and to positively influence QoL outcomes. [bib_ref] Impact of nutrition on outcome: a prospective randomized controlled trial in patients..., Ravasco [/bib_ref] Food fortification is first line advice; however, this may not necessarily be appropriate due to the side effects and intensity of treatment regimens. Patients may require more intensive nutritional support methods from the beginning of treatment over and above traditional food fortification methods with the ## S36 early use of oral nutrition support, e.g. nutritionally complete liquid supplements. This can be initiated at any point from diagnosis. There are a variety of oral nutritional support products available. The choice will depend on patient preference, current macro and micro nutrient intake and local policy. ## Enteral nutrition (en) support The choice of feeding route will depend upon local arrangements, however clinical considerations should include: site of tumour, treatment plan and intent, predicted duration of enteral feeding and patient choice. [bib_ref] When is the optimal time for placing a gastrostomy in patients undergoing..., Talwar [/bib_ref] [bib_ref] Gastrostomy in head and neck cancer: current literature, controversies and research, Bradley [/bib_ref] The types of tubes available are nasogastric, nasojejunal, tracheooesophageal fistulae tubes, orogastric, gastrostomy, gastro-jejunostomy and jejunostomy. Nasogastric, nasojejunal, oro gastric, tracheaoesophageal fistulae tubes are all recommended for short-term use (less than four weeks). National Institute for Health and Care Excellence guidelines on enteral feeding suggest that if enteral feeding is expected to be required for longer than four weeks then gastrostomy insertion is recommended. 2 Consideration should be made with regard to the timing and method of gastrostomy placement. Screening and assessment for suitability and method of gastrostomy insertion by endoscopic, radiological or surgical approach is essential. Assessment of comorbidities and contraindications should be undertaken in order to prevent complications of tube insertion prior to oncological treatment. Variation exists for the preferred method of insertion and is dependent on local policy. There are no nationally agreed selection criteria for gastrostomy placement in head and neck patients. Comparison between studies is difficult and made more challenging by limitations in study design as well as the inability to stratify data meaningfully into groups with adequate patient numbers by similar treatment modality, type of gastrostomy and timing of tube placement. 9,10 Evidence-based practice guidelines, based on a systematic review of literature across the entire nutrition care pathway, following a National Health and Medical Research Council's process for assessing the level of evidence and evaluating the body of literature, have been published.Although the optimal method of tube feeding remains unclear, [bib_ref] Gastrostomy in head and neck cancer: current literature, controversies and research, Bradley [/bib_ref] [bib_ref] Percutaneous endoscopic gastrostomy versus nasogastric tube feeding for patients with head and..., Wang [/bib_ref] it is widely accepted that prophylactic tube feeding compared with reactive tube feeding or oral intake alone improves nutritional outcomes with reduced weight loss, and can therefore contribute towards clinical, financial and QoL aspects. [bib_ref] Early nutritional intervention improves treatment tolerance and outcomes in head and neck..., Paccagnella [/bib_ref] However, highlevel evidence base is yet to be generated to confirm the benefits. [bib_ref] Prophylactic feeding tubes for patients with locally advanced head-and-neck cancer undergoing combined..., Orphanidou [/bib_ref] [bib_ref] Nutritional support for head and neck cancer patients receiving radiotherapy: a systematic..., Garg [/bib_ref] Appropriate decision making around prophylactic tube feeding must consider all factors that impact on nutrition including patient demographics, tumour site and staging, impact of treatment modalities on the patient's ability to meet and sustain nutritional requirements, nutritional status, dysphagia, type and placement technique of feeding tube and associated morbidity. [bib_ref] Head and neck cancer, Talwar [/bib_ref] [bib_ref] When is the optimal time for placing a gastrostomy in patients undergoing..., Talwar [/bib_ref] [bib_ref] Gastrostomy in head and neck cancer: current literature, controversies and research, Bradley [/bib_ref] While there is no universally accepted definition of gastrostomy dependency, the principle is recognised and reported. [bib_ref] Predictors of PEG dependence after IMRT+/-chemotherapy for oropharyngeal cancer, Sanguineti [/bib_ref] In clinical studies, gastrostomy tube is used as a proxy measure for poor swallowing in the absence of reviewing nutritional outcome data, intensity and frequency of dietary counselling and swallowing rehabilitation and coordination of these services before, during and after treatment. [bib_ref] When is the optimal time for placing a gastrostomy in patients undergoing..., Talwar [/bib_ref] [bib_ref] Gastrostomy in head and neck cancer: current literature, controversies and research, Bradley [/bib_ref] Enteral nutrition The type and volume of EN will depend upon the patients' symptoms and current intake and is likely to change throughout and following treatment. 2 There are no data to suggest a role for cancer-specific enteral formulae and standard polymeric feeds should be used in this population group. There are a range of nutritionally complete feeds available. Local policies and feed contract arrangements determine the type and make. ## Immune-enhanced nutrition Immunonutrition are feeds containing amino acids, nucleotides and lipids. There are no additional benefits to immunonutrition pre-operatively over standard nutrition support. Preliminary data suggest that in the perioperative period, N-3 enriched nutrition support may improve nutritional outcomes including weight, lean body mass and fat mass, reduce post-operative infections and reduce hospital stay. [bib_ref] A systematic review of the role of immunonutrition in patients undergoing surgery..., Stableforth [/bib_ref] Monitoring nutritional support Monitoring nutritional intervention is essential, as compliance with recommendations can be a problem. Monitoring should involve the multidisciplinary team, including dietitians, medical teams, speech and language therapist and clinical nurse specialists. ## Recommendations - Start nutritional therapy if undernutrition already exists or if it is anticipated that the patient will be unable to eat for more than 7 days. Enteral nutrition should also be started if an inadequate food intake (60 per cent of estimated energy expenditure) is anticipated for more than 10 days (R) - Use standard polymeric feed (G) - Consider gastrostomy insertion if long-term tube feeding is necessary (greater than four weeks) (R) - Monitor nutritional parameters regularly throughout the patient's cancer journey (G) Nutrition considerations during surgical treatment Enhanced recovery after surgery programmes are starting to be developed and implemented across Head and Neck Centres. Nutritional interventions are part of enhanced recovery and should be considered at all stages of the pathway from diagnosis to survivorship and wellbeing. Pre-operative nutrition Inadequate oral intake for more than 14 days is associated with a higher mortality. Patients with severe nutritional risk should receive nutrition support for 10-14 days prior to major surgery even if surgery has to be delayed. [bib_ref] ESPEN Guidelines on Enteral Nutrition: surgery including organ transplantation, Weimann [/bib_ref] [bib_ref] A systematic review of the role of immunonutrition in patients undergoing surgery..., Stableforth [/bib_ref] Carbohydrate loading is becoming standard practice in some centres for all patients undergoing head and neck cancer surgery. It has been shown to be safe and well tolerated in patients undergoing head and neck surgery. The type of carbohydrate-loading products used will depend on local contractual arrangements. Enteral nutrition is indicated even in patients without obvious undernutrition, if it is anticipated that patients will be unable to eat for more than 7 days peri-operatively. Box III indicates criteria for initiating pre/peri-operative nutrition support and identifies patients with severe nutritional risk. BOX III CRITERIA FOR INITIATING PRE-OPERATIVE NUTRITIONAL SUPPORT 2,5 Indications: - Weight loss >10-15 per cent in 6 months - Body mass index <18.5 kg/m 2 - Subjective Global Assessment Grade C - Serum albumin <30 g/l - Unable to maintain intake above 60 per cent of recommended intake for more than 10 days Post-operative nutrition Early post-operative tube feeding (within 24 hours) is indicated in patients in whom early oral nutrition cannot be initiated. Nutrition support, especially enteral nutrition, reduces morbidity. In some centres, as part of the enhanced recovery programme, very early nutritional intervention is being trialled. Standard polymeric enteral feeds are suggested post-operatively with currently very limited evidence to support the use of immunonutrition. Early oral feeding after primary total laryngectomy (from as early as 1 day post-operation to 7 days) is thought to reduce length of stay as there has been shown to be no difference in fistulae rates compared with delayed oral feeding of >7 days. ## Nutritional management of chyle leaks This is a rare complication with an incidence of 1-2 per cent following radical neck dissections, and less common with selective neck dissections often performed in current practice. The management may be conservative, including dietary manipulation or further surgery. A post-operative leak gives the fluid a milky appearance. A triglyceride level >110 mg/dl is diagnostic of a chyle leak. If the triglyceride level is <110 mg/dl, further analysis is required to demonstrate the presence of chylomicrons. A triglyceride level <50 mg/dl usually rules out a diagnosis of a chyle leak unless a patient is malnourished or has been fasted. The principal aims of nutritional management are to reduce the flow of chyle whilst maintaining nutritional status, ensuring adequate fluid balance and replacing electrolyte losses. The nutritional management is to use a fat free or high medium chain triglyceride (MCT) product. Medium chain triglyceride is recommended because it is directly absorbed into the portal system resulting in less chyle production. In clinical practice fat free products can be more accessible and practical than MCT feeds. If dietary manipulation is unsuccessful parenteral nutrition may be required. This should not be used as first line management except in extreme cases, e.g. very high-volume leaks (>1000 ml). There is no consensus on how to nutritionally manage chyle leaks, how long nutrition management should be pursued, or what constitutes an acceptable amount of chyle output. [bib_ref] Chyle leaks: consensus on management?, Smoke [/bib_ref] [bib_ref] Nutritional management of chyle leaks: an update, Mcray [/bib_ref] The nutritional intervention is usually dependant on clinician preference. ## Recommendations - Pre-operative: ○ Patients with severe nutritional risk should receive nutrition support for 10-14 days prior to major surgery even if surgery has to be delayed (R) ○ Consider carbohydrate loading in patients undergoing head and neck surgery (R) - Post-operative: ○ Initiate tube feeding within 24 hours of surgery (R) ○ Consider early oral feeding after primary laryngectomy (R) - Chyle leak: ○ Confirm chyle leak by analysis of drainage fluid for triglycerides and chylomicrons (R) ○ Commence nutritional intervention with fat free or MCT nutritional supplements either orally or via a feeding tube (R) ○ Consider parenteral nutrition in severe cases when drainage volume is consistently high (G) Nutritional considerations during curative radiotherapy ± chemotherapy Concomitant mucositis during radiotherapy ± chemotherapy results in weight loss, which cannot be completely prevented by nutritional counselling alone. [bib_ref] ESPEN Guidelines on Enteral Nutrition: non-surgical oncology, Arends [/bib_ref] Intensive dietary counselling and oral nutrition support to increase dietary intake and to prevent treatment associated weight loss is recommended for patients undergoing radiotherapy of the head and neck. [bib_ref] Effect of nutritional interventions on nutritional status, quality of life and mortality..., Langius [/bib_ref] This is also advised to prevent interruptions to radiation treatment. Tube feeding is recommended if the cancer interferes with swallowing or if mucositis is anticipated which may interfere with oral and/or pharyngeal swallowing. [bib_ref] Nutrition outcomes following implementation of validated swallowing and nutrition guidelines for patients..., Brown [/bib_ref] The optimal method of tube feeding remains unclear, therefore, the risks and benefits of both proactive and reactive approaches should be discussed by the dietitian with the patient to ensure individualised nutritional care.Prophylactic tube feeding compared to oral intake alone or reactive tube demonstrates reduced weight loss in the short term, may reduce unplanned hospital admissions and may improve QoL during and after treatment.The Clinical Oncological Society of Australia recommends that patients should be seen weekly during radiotherapy. However, in some centres twice weekly follow up is provided. Intensity Modulated radiotherapy is now used for the treatment of head and neck cancer. This treatment has not been found to reduce nutrition related toxicity and patients should be managed in the same way as conventional radiotherapy. Patients receiving biological agents such as cetuximab with radiotherapy should be nutritionally managed in the same way as those receiving chemoradiotherapy. 1 ## Recommendations - Weekly dietetic intervention is offered for all patients undergoing radiotherapy treatment to prevent weight loss, increase intake and reduce treatments interruptions (R) - Offer prophylactic tube feeding as part of locally agreed guidelines, where oral nutrition is inadequate (R) Nutritional considerations during palliative chemotherapy and radiotherapy The use of chemotherapy and radiotherapy may be used to relieve symptoms caused by the cancer where the goal is to improve the QoL but not treat the disease. Palliative chemotherapy and radiotherapy is increasingly used in the treatment of head and neck cancer and the dietitian has a role in supporting the nutritional needs of patients receiving these treatments. Patients may experience side effects from these treatments which affect their ability to take adequate nutrition or require dietary intervention to support their QoL. [bib_ref] When is the optimal time for placing a gastrostomy in patients undergoing..., Talwar [/bib_ref] Rehabilitation Patients are at high risk of developing late and longterm effects of treatment resulting in eating difficulties requiring dietary modification, supplementation and alternative feeding. Patients should be seen fortnightly for at least six weeks post-treatment and patients should be reviewed by the dietitian for up to six months or for as long as they require management of chronic toxicities, weight loss or tube feeding.Guidance for clinical management and a strategic framework for structured head and neck 'local support' services as part of the multidisciplinary team are limited, but should be interpreted at a local level to deliver high-quality patient-centred nutritional care. [bib_ref] Head and neck cancer, Talwar [/bib_ref] Recommendation - Offer nutritional intervention (dietary counselling and/or supplements) for up to three months after treatment (R) ## Survivorship The number of patients living with cancer or its longterm side effects is increasing. Many of our cancer survivor patients have unmet needs. It is recommended that patients are offered education and support events (Health and Wellbeing Clinics) after completion of treatment and rehabilitation.Dietitians can play a key role in these events by offering tailored healthy eating advice that takes into consideration the longterm side effects that head and neck cancer patients may experience. Macmillan cancer support is currently developing a healthy eating toolkit that can be adapted for use with head and neck cancer patients. ## Recommendation - Patients who have completed their rehabilitation and are disease free should be offered healthy eating advice as part of a health and wellbeing clinic (G) ## Quality of life Head and neck-specific validated tools exist to evaluate QoL. These tools may include factors relating to eating and drinking, but there is no nutrition-specific module to assess the relationship between QoL, nutritional status, malnutrition and nutrition support in this patient group. [bib_ref] Head and neck cancer, Talwar [/bib_ref] Reduction in QoL can be directly related to weight loss and malnutrition with an improvement seen when dietary counselling and aggressive nutritional support is maintained during treatment. The impact of having a feeding tube on patients' QoL requires further evaluation. ## Recommendation - Quality of life parameters, including nutrition and swallowing, should be measured at diagnosis and at regular intervals posttreatment (G) ## Key points - Nutrition has an important role in the management of head and neck cancer and its associated treatment modalities - Specialist site specific dietitians should be part of the multidisciplinary team for treating head and neck cancer patients as frequent dietetic contact has been shown to enhance outcomes - Comprehensive nutritional assessment is necessary to ensure early recognition of patients who have or are at risk of developing malnutrition to allow timely and appropriate intervention - Nutritional interventions are varied and have an important role throughout the course of the disease, from diagnosis through to terminal care - Effective nutritional interventions should ultimately aim to improve QoL and enhance the beneficial effects of treatment. [fig] FIG. 1: Management of re-feeding syndrome (reproduced with permission from Mehanna et al. 7 ). B TALWAR, R DONNELLY, R SKELLY et al. [/fig] [table] TABLE I NUTRITIONAL: SCREENING AND ASSESSMENT TOOLS• Ability to chew and swallow • Clinical signs of weight loss e.g. ill-fitting dentures/clothing • Medical history which may affect nutritional intake e.g. coeliac disease, diabetes• 25-35 kcal/kg/day dependant on activity level. Can increase further if major complications.• 30-35 ml/kg/day increases in infection and excessive fluid losses Vitamins and minerals: • As per recommended daily amounts unless considered deficient Proposed treatment • Disease status, tumour site • Nutritional implications of previous and current treatment plan Anthropometry • Height • Weight • Weight history • Percentage weight change • Body mass index; <18.5 kg/m 2 suggests undernutrition • Triceps skinfold thickness indicates fat stores • Mid arm muscle circumference indicates lean tissue mass • Hand grip strength assesses muscle function Biochemistry • Urea and electrolytesindicate fluid status although can be disrupted by disease state and treatment • Albuminnot good indicator of nutritional status due to its long half-life (17-20 days) and it is affected by stress and sepsis • Pre-albuminshorter half-life 2-3 days but also affected by infection and stress • C-reactive proteinindication of acute phase response • Transferrinaffected by inflammation and infection • Total lymphocyte countaffected by infection • Refeeding syndrome risk Social information • Alcohol intake • Smoking • Substance misuse • Social support • Dentition • Access to food and cooking skills • Social and financial circumstances • Time taken to eat and drink • Patient perception of nutritional status [/table]	None	https://www.cambridge.org/core/services/aop-cambridge-core/content/view/A3A569F7731936A37C8FA6772E681AF7/S0022215116000402a.pdf/div-class-title-nutritional-management-in-head-and-neck-cancer-united-kingdom-national-multidisciplinary-guidelines-div.pdf	Abstract Nutritional support and intervention is an integral component of head and neck cancer management. Patients can be malnourished at presentation, and the majority of patients undergoing treatment for head and neck cancer will need nutritional support. This paper summarises aspects of nutritional considerations for this patient group and provides recommendations for the practising clinician. Recommendations • A specialist dietitian should be part of the multidisciplinary team for treating head and neck cancer patients throughout the continuum of care as frequent dietetic contact has been shown to have enhanced outcomes. (R) • Patients with head and neck cancer should be nutritionally screened using a validated screening tool at diagnosis and then repeated at intervals through each stage of treatment. (R) • Patients at high risk should be referred to the dietitian for early intervention. (R) • Offer treatment for malnutrition and appropriate nutrition support without delay given the adverse impact on clinical, patient reported and financial outcomes. (R) • Use a validated nutrition assessment tool (e.g. scored Patient Generated–Subjective Global Assessment or Subjective Global Assessment) to assess nutritional status. (R) • Offer pre-treatment assessment prior to any treatment as intervention aims to improve, maintain or reduce decline in nutritional status of head and neck cancer patients who have malnutrition or are at risk of malnutrition. (G) • Patients identified as well-nourished at baseline but whose treatment may impact on their future nutritional status should receive dietetic assessment and intervention at any stage of the pathway. (G) • Aim for energy intakes of at least 30 kcal/kg/day. As energy requirements may be elevated post-operatively, monitor weight and adjust intake as required. (R) • Aim for energy and protein intakes of at least 30 kcal/kg/day and 1.2 g protein/kg/day in patients receiving radiotherapy or chemoradiotherapy. Patients should have their weight and nutritional intake monitored regularly to determine whether their energy requirements are being met. (R) • Perform nutritional assessment of cancer patients frequently. (G) • Initiate nutritional intervention early when deficits are detected. (G) • Integrate measures to modulate cancer cachexia changes into the nutritional management. (G) • Start nutritional therapy if undernutrition already exists or if it is anticipated that the patient will be unable to eat for more than 7 days. Enteral nutrition should also be started if an inadequate food intake (60 per cent of estimated energy expenditure) is anticipated for more than 10 days. (R) • Use standard polymeric feed. (G) • Consider gastrostomy insertion if long-term tube feeding is necessary (greater than four weeks). (R) • Monitor nutritional parameters regularly throughout the patient's cancer journey. (G) • Pre-operative: ○ Patients with severe nutritional risk should receive nutrition support for 10–14 days prior to major surgery even if surgery has to be delayed. (R) ○ Consider carbohydrate loading in patients undergoing head and neck surgery. (R) • Post-operative: ○ Initiate tube feeding within 24 hours of surgery. (R) ○ Consider early oral feeding after primary laryngectomy. (R) • Chyle Leak: ○ Confirm chyle leak by analysis of drainage fluid for triglycerides and chylomicrons. (R) ○ Commence nutritional intervention with fat free or medium chain triglyceride nutritional supplements either orally or via a feeding tube. (R) ○ Consider parenteral nutrition in severe cases when drainage volume is consistently high. (G) • Weekly dietetic intervention is offered for all patients undergoing radiotherapy treatment to prevent weight loss, increase intake and reduce treatments interruptions. (R) • Offer prophylactic tube feeding as part of locally agreed guidelines, where oral nutrition is inadequate. (R) • Offer nutritional intervention (dietary counselling and/or supplements) for up to three months after treatment. (R) • Patients who have completed their rehabilitation and are disease free should be offered healthy eating advice as part of a health and wellbeing clinic. (G) • Quality of life parameters including nutritional and swallowing, should be measured at diagnosis and at regular intervals post-treatment. (G)

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